Search Results (75)

Idiopathic Parkinson’s disease (iPD) represents the most prevalent form of Parkinson’s disease; however, the molecular mechanisms underlying its development remain only partially understood. N6-methyladenosine (m6A), the most abundant internal RNA modification in eukaryotic mRNA, has emerged as a key regulator of gene expression and has been implicated in neurodegenerative disorders. In this study, we performed integrated differential expression, weighted gene co-expression network analysis (WGCNA), and differential co-expression (DECO) analyses using peripheral blood RNA-seq data from Latin American controls and early iPD patients to investigate m6A-associated transcriptional alterations. WGCNA and differential expression analyses identified 1207 hub genes and 237 differentially expressed genes, respectively. The integration of these datasets with curated m6A-related genes yielded 12 overlapping candidate genes associated with early iPD. Subsequent DECO analysis revealed three significant m6A regulator–target differential co-expression links involving the m6A factors VIRMA, YTHDF3, and HNRNPA2B1. Experimental validation in an independent exploratory cohort confirmed altered expression of these regulators and increased m6A enrichment of NRCAM and PKHD1 transcripts. To our knowledge, this study represents the first integrative transcriptomic evaluation of m6A-associated regulatory patterns in early iPD within a Latin American population. Collectively, our findings suggest that selective m6A-associated transcriptional network alterations may contribute to the systemic molecular signatures observed in early iPD, warranting further validation in larger and mechanistically oriented studies. Full article

Background: Traditional reliance on intraradicular posts for the restoration of root-filled teeth is decreasing due to advances in adhesive dentistry. Immediate pre-endodontic dentin sealing (IPDS) aims to protect dentin during endodontic procedures and improve adhesive outcomes. For teeth with minimal remaining structure and absent ferrule, internal adhesive ferrule approaches using fiber-reinforced composites or fiber mesh offer an alternative to posts. Methods: Four endodontically treated teeth with severely reduced coronal structure were restored using the IPDS protocol, reinforcement with an internal adhesive ferrule ring and fiber composites, and postless adhesive build-ups. Clinical and radiographic assessments were performed up to 2.5 years post-treatment. Results: All teeth remained asymptomatic, with stable periodontal and periapical conditions. Restorations maintained structural integrity and favorable adhesive performance. Conclusions: Within the limitations of this small case series, the IPDS approach combined with fiber-reinforced postless restorations showed favorable short-term clinical outcomes. Given the small sample size, case heterogeneity, and lack of a control group, these observations should be considered preliminary, and well-designed, long-term controlled studies are required to confirm the durability and broader applicability of this technique. Full article

Streptococcus pneumoniae (S. pneumoniae) is a leading cause of pneumonia, meningitis, and sepsis worldwide, posing a major threat to young children and older adults. In China, it is a key pathogen responsible for life-threatening invasive pneumococcal disease (IPD)—including pneumonia, bacteremia, and meningitis—and contributes substantially to hospitalizations and deaths each year. The high disease burden, together with rising antibiotic resistance, underscores the urgent need for more effective strategies for prevention and control. Currently, the most established pneumococcal vaccines include polysaccharide vaccines (e.g., PPV23) and polysaccharide conjugate vaccines (e.g., PCV13), both of which provide effective protection against pneumococcal infections. However, challenges remain, such as the T-cell-independent nature of polysaccharide antigens and inadequate coverage against prevalent strains, which hinder to improve their overall effectiveness. In this review, we trace the progression from pneumococcal pathogenesis to vaccine development. We first outline the mechanisms of colonization, invasion, and key virulence factors, and then critically summarize historical and current vaccine strategies. A systematic literature search was conducted in PubMed and Web of Science (2010–present) using relevant keyword and MeSH combinations. A total of 10,273 articles were identified from PubMed; after removal of duplicates and non-full-text records, 260 research articles were included in the final analysis. Based on this body of evidence, we evaluate emerging approaches toward broadly protective, serotype-independent vaccines and discuss how advances in antigen design, delivery systems, and adjuvants may further optimize next-generation pneumococcal vaccines. Full article

Purpose: Proton beam therapy (PBT) offers superior dosimetric sparing of organs at risk compared to photon radiotherapy for non-small cell lung cancer (NSCLC); however, comparative clinical evidence regarding survival benefits remains conflicting. This systematic review and meta-analysis aimed to evaluate the clinical outcomes and toxicity profiles of PBT versus photon radiotherapy, with a specific focus on time-dependent survival patterns. Methods: We searched PubMed, EMBASE, and Cochrane CENTRAL databases for comparative studies published up to 10 October 2025. Primary outcomes were overall survival (OS), progression-free survival (PFS), and local progression-free survival (LPFS). Individual patient data (IPD) were reconstructed from Kaplan–Meier curves when hazard ratios (HRs) were not reported. Odds ratios (ORs) were calculated for survival at fixed time points (1, 3, and 5 years) and for toxicity endpoints. Results: Seven studies comprising 244,604 patients were included, encompassing retrospective cohorts, multi-institutional datasets, and one randomized trial. In the overall pooled analysis, PBT showed no statistically significant superiority over photon radiotherapy for OS (HR = 0.91, 95% CI: 0.69–1.19, p = 0.483), PFS (HR = 1.09, 95% CI: 0.81–1.47, p = 0.572), or LPFS (HR = 0.89, 95% CI: 0.47–1.69, p = 0.732). Sensitivity and subgroup analyses restricted to Stage I and Stage I–II NSCLC similarly failed to demonstrate significant differences in survival outcomes. However, exploratory time point analysis utilizing ORs revealed a distinct temporal pattern: PBT was associated with improved odds of all-cause mortality at 1 year (OR = 0.60, 95% CI: 0.49–0.73, p < 0.001). This survival advantage dissipated over time, with no significant differences observed at 3 years or 5 years. Regarding safety, PBT did not significantly reduce the odds of grade ≥ 2 radiation pneumonitis (OR = 0.98, 95% CI: 0.41–2.33, p = 0.967) or grade ≥ 3 events (OR = 1.40, p = 0.540) compared to photons. Conclusions: While long-term oncologic control appears comparable between proton and photon radiotherapy, exploratory analyses suggest that PBT is associated with improved odds of 1-year overall survival. This potential early benefit, observed in retrospective cohorts, likely reflects the mitigation of acute treatment-related mortality. These findings are hypothesis-generating and support the use of PBT for patients at high risk of toxicity and advocate for a model-based approach to patient selection. Full article

Streptococcus pneumoniae contributes significantly to morbidity, mortality, and healthcare costs worldwide due to severe Invasive Pneumococcal Disease (IPD), particularly among young children and vulnerable populations. This review critically examines the current state of pneumococcal disease epidemiology, the evolution of vaccine strategies, and persistent challenges to achieve global control of the disease. The implementation of Pneumococcal Conjugate Vaccines (PCVs) has yielded substantial public health gains, establishing herd protection and sharply reducing vaccine-type IPD incidence. However, this success has been fundamentally challenged by serotype replacement, where non-vaccine serotypes have subsequently emerged to cause a significant proportion of the residual disease burden. This epidemiological shift has necessitated the development and deployment of higher-valency PCVs (PCV15, PCV20, and PCV21) to expand serotype coverage. Furthermore, optimal protection requires personalized strategies for high-risk cohorts where vaccine effectiveness can be compromised. In this context, the review details how pneumococcal vaccination—and particularly PPSV23—serves as an indispensable diagnostic tool to evaluate a broad spectrum of Inborn Errors of Immunity (IEI) and in particular humoral defects. Diagnostic challenges are strained by non-standardized assays and the limited panel of unique serotypes available for testing in the PCV era. The scientific priority is now the development of universal protein-based vaccines, to provide protection against all serotypes and non-encapsulated strains by targeting conserved virulence factors. This integrated approach, combining expanded PCV coverage with novel vaccine technology, is essential to mitigate the ongoing public health burden of pneumococcal disease. Full article

The increasing integration of renewable energy sources (RES) and rising energy demand have created challenges in maintaining stability in interconnected power systems, particularly in terms of frequency, voltage, and tie-line power. While traditional load frequency control (LFC) and automatic voltage regulation (AVR) strategies have been widely studied, they often fail to address the complexities introduced by RES and nonlinear system dynamics such as boiler dynamics, governor deadband, and generation rate constraints. This study introduces the Arithmetic Optimization Algorithm (AOA)-optimized PI(1+DD) controller, chosen for its ability to effectively optimize control parameters in highly nonlinear and dynamic environments. AOA, a novel metaheuristic technique, was selected due to its robustness, efficiency in exploring large search spaces, and ability to converge to optimal solutions even in the presence of complex system dynamics. The proposed controller outperforms classical methods such as PI, PID, I–P, I–PD, and PI–PD in terms of key performance metrics, achieving a settling time of 7.5 s (compared to 10.5 s for PI), overshoot of 2.8% (compared to 5.2% for PI), rise time of 0.7 s (compared to 1.2 s for PI), and steady-state error of 0.05% (compared to 0.3% for PI). Additionally, sensitivity analysis confirms the robustness of the AOA-optimized controller under ±25% variations in turbine and speed control parameters, as well as in the presence of nonlinearities, demonstrating its potential as a reliable solution for improving grid performance in complex, nonlinear multi-area interconnected power systems. Full article

This paper presents a non-intrusive method for estimating the distance between a camera and a human subject using a monocular vision system and statistically derived interpupillary distance (IPD) values. The proposed approach eliminates the need for individual calibration by utilizing average IPD values based on biological sex, enabling accurate, scalable distance estimation for diverse users. The algorithm, implemented in Python 3.12.11 using the MediaPipe Face Mesh framework, extracts pupil coordinates from facial images and calculates IPD in pixels. A sixth-degree polynomial calibration function, derived from controlled experiments using a uniaxial displacement system, maps pixel-based IPD to real-world distances across three intervals (20–80 cm, 80–160 cm, and 160–240 cm). Additionally, a geometric correction is applied to compensate for in-plane facial rotation. Experimental validation with 26 participants (15 males, 11 females) demonstrates the method’s robustness and accuracy, as confirmed by relative error analysis against ground truth measurements obtained with a Bosch GLM120C laser distance meter. Males exhibited lower relative errors across the intervals (3.87%, 4.75%, and 5.53%), while females recorded higher mean relative errors (6.0%, 6.7%, and 7.27%). The results confirm the feasibility of the proposed method for real-time applications in human–computer interaction, augmented reality, and camera-based proximity sensing. Full article

Background/Objectives: The optimal surgical management of perforated gastric cancer (PGC) in emergency settings remains controversial. Urgent upfront one-stage gastrectomy (1SG) and two-stage gastrectomy (2SG) with damage-control surgery followed by elective gastrectomy have been proposed. The aim of the present systematic review is to compare short- and long-term outcomes between 1SG and 2SG in the treatment of PGC. Methods: A systematic review and individual patient data (IPD) meta-analysis of studies reporting data of patients undergoing 1SG vs. 2SG for PGC was conducted. The time-dependent effects of surgical interventions were assessed using a likelihood ratio test. Hazard function plots were generated via marginal prediction. Results: Ten retrospective series (579 patients) were included. Overall, 482 patients (83%) underwent 1SG, while 97 patients (17%) were treated with 2SG. A trend toward better short-term oncological outcomes and safety profiles for 2SG compared to 1SG was observed. Long-term outcomes were comparable between 1SG and 2SG, and the IPD meta-analysis showed no statistically significant difference between the two approaches in terms of OS or hazard for mortality at all time points. A trend towards a higher hazard for mortality was observed for 1SG in the first 20 months postoperatively. Conclusions: Our analysis suggests that 1SG and 2SG yield comparable short-term outcomes, although 2SG may be associated with a lower medium-term mortality risk. Further research is needed to identify key factors to improve clinical judgments and decision-making in PGC. Full article

Parkinson’s disease (PD) associated with GBA1 mutations—recently termed Sidransky syndrome—differs from idiopathic PD (iPD) by earlier onset, more rapid progression, and higher rates of non-motor symptoms. Our objective was to assess whether GBA1 mutations contribute to olfactory dysfunction in PD and in asymptomatic carriers of the mutation. We compared olfactory and motor functions in 119 participants: Sidransky syndrome (n = 18), iPD (n = 30), GBA1 variant carriers without PD (n = 21), Gaucher disease patients (n = 20), and healthy controls (n = 30). All were evaluated with the Brief Smell Identification Test (BSIT^®) and the motor part of the Movement Disorders Society Unified PD Rating Scale (MDS-mUPDRS). Mean age was 59.2 ± 11.7 years. Mean disease duration was 2.5 ± 2.2 years in Sidransky syndrome and 5.4 ± 4.9 years in iPD. We found that both PD groups had significantly lower BSIT^® scores than non-PD groups (p < 0.001), particularly for leather, smoke, natural gas, pineapple, clove, rose, and lemon. Sidransky syndrome patients scored lower than iPD patients (p = 0.04). No significant olfactory deficits were observed in GBA1 carriers or Gaucher patients without PD. We conclude that hyposmia is more pronounced in Sidransky syndrome than in iPD. However, normal olfaction in non-parkinsonian GBA1 carriers suggests that GBA1 variants alone do not account for olfactory loss in PD. Hyposmia likely reflects broader PD pathology rather than a direct effect of the GBA1 mutation. Full article

Inherited platelet disorders (IPDs) are rare bleeding disorders characterized by impaired platelet function and/or reduced blood platelet count. Their diagnosis typically relies on complex laboratory methods, including flow cytometry, aggregometry, and molecular genetic analysis. In recent years, immunofluorescence microscopy has been established as an alternative diagnostic method for IPDs. Background/Objectives: This study aims to validate a quantitative approach enhancing reproducibility through automated image analysis for diagnosing IPDs using immunofluorescence microscopy, with Bernard–Soulier Syndrome (BSS) and Glanzmann thrombasthenia (GT) as model IPDs. Methods: Native blood smears from patients with suspected BSS or GT were stained using a standardized immunofluorescence protocol targeting platelet surface glycoproteins, granules, and cytoskeletal components. The slides were analyzed using an automated fluorescence microscope, and a rule-based subpopulation analysis was implemented to quantify fluorescence signals. The results were compared to those of a healthy control group, as well as data from flow cytometry and molecular genetic testing. Results: The automated analysis successfully differentiated BSS and GT patients from healthy controls based on distinct fluorescence signal patterns. In BSS samples, CD42b (GPIbα) expression was absent or severely reduced, while GT samples showed a deficiency of CD41/CD61 (GPIIb/IIIa). The platelet size distribution confirmed macrothrombocytopenia in BSS patients. Flow cytometry and molecular genetic testing corroborated these findings, supporting the diagnostic reliability of the automated immunofluorescence microscopy approach. Conclusions: This proof-of-principle study demonstrates that automated quantitative immunofluorescence microscopy is a viable alternative for diagnosing IPDs, offering a standardized, objective, and efficient method, particularly in settings where flow cytometry is not feasible. Full article

The interspinous process device (IPD) has emerged as a viable alternative for managing lumbar degenerative pathologies. Nevertheless, limited research exists regarding mechanical failure modes including device failure and spinous process fracture. This study developed a novel IPD (IPD-NEW) and systematically evaluated its biomechanical characteristics through finite element (FE) analysis and in vitro cadaveric biomechanical testing. Six human L1–L5 lumbar specimens were subjected to mechanical testing under four experimental conditions: (1) Intact spine (control); (2) L3–L4 implanted with IPD-NEW; (3) L3–L4 implanted with Wallis device; (4) L3–L4 implanted with Coflex device. Segmental range of motion (ROM) was quantified across all test conditions. A validated L1–L5 finite element model was subsequently employed to assess biomechanical responses under both static and vertical vibration loading regimes. Comparative analysis revealed that IPD-NEW demonstrated comparable segmental ROM to the Wallis device while exhibiting lower rigidity than the Coflex implant. The novel design effectively preserved physiological spinal mobility while enhancing load distribution capacity. IPD-NEW demonstrated notable reductions in facet joint forces, device stress concentrations, and spinous process loading compared to conventional implants, particularly under vibrational loading conditions. These findings suggest that IPD-NEW may mitigate risks associated with facetogenic pain, device failure, and spinous process fracture through optimized load redistribution. Full article

Background: V116 is a 21-valent pneumococcal conjugate vaccine (PCV) designed for adults. It contains the most prevalent serotypes associated with invasive pneumococcal disease (IPD) in adults in regions with established pediatric vaccination programs. This Phase 3 study compared the safety, tolerability, and immunogenicity of V116 with 23-valent pneumococcal polysaccharide vaccine (PPSV23) in adults ≥50 years of age. Methods: In this randomized, active comparator-controlled, parallel-group, multisite, double-blind study, participants were randomized 1:1 to receive a single dose of V116 or PPSV23 (NCT05569954). Primary immunogenicity outcomes assessed the opsonophagocytic activity (OPA) responses for (i) non-inferiority for 12 serotypes common to V116 and PPSV23 based on V116/PPSV23 geometric mean titers (GMTs) at Day 30, and (ii) superiority for nine serotypes unique to V116 using V116/PPSV23 GMTs and the proportions of participants with a ≥4-fold rise in OPA responses from baseline to 30 days post-vaccination. The primary safety outcome was evaluated as the proportion of participants with solicited injection-site and systemic adverse events through Day 5 post-vaccination, and vaccine-related serious adverse events up to 6 months post-vaccination. Findings: V116 was non-inferior to PPSV23 for all 12 common serotypes, superior to PPSV23 for all nine unique serotypes based on V116/PPSV23 GMTs, and superior to PPSV23 for eight of the nine serotypes unique to V116, based on the proportion of participants with a ≥4-fold rise in OPA responses (except for serotype 15C). The safety profile of V116 was comparable to that of PPSV23. Interpretation: In regions with established vaccination programs, V116 could broaden the serotype coverage for residual pneumococcal disease in adults. Full article

Background: Dental implantology has undergone significant advancements with the integration of digital workflows, transforming the processes of planning, designing, surgical delivery, and prosthetic rehabilitation. Among these innovations, intraoral optical scanning (IOS) has emerged as a preferred method over traditional analogue impressions. This preference is due to its cost-effectiveness, efficiency, and streamlined patient-friendly use while producing clinically acceptable results in terms of trueness and precision, particularly for short-span implant prostheses. Methods: However, the clinical utility of intraoral scanning is significantly affected by the lack of reference points and difficulties in moisture and bleeding control at the time of immediate implant placement surgery in the fully edentulous arch. Current evidence supports the general consensus that the traditional analog impression technique still provides superior trueness and precision compared to IOS, specifically in full-arch implant cases. Results: The continuous quest for precision in dental implantology has led to the introduction of photogrammetry, which is now considered the most accurate technique for the digital scanning of dental implants. Photogrammetry has demonstrated superior results compared to those obtained using the analog technique. Conclusions: The aim of this case report is to provide an overview of analog techniques, digital intraoral optical scanning, and photogrammetry, setting the stage for the introduction of a novel technique involving a dedicated optical scan-transfer device (IPD^®) that can be scanned with ease using IOS, either intra- or extra-orally, due to its unique design features and digital properties. Full article

Against the background of the development of control systems, Data Driven Control (DDC) methods are becoming more and more popular, given the system’s independence from physical models and the possibility of quickly tuning the controller. The usefulness of such tuning algorithms increases with the complexity of the plants. Nonlinear models are the main class of processes for which such laws are amenable. According to the literature, a class of DDC methods exist that perform online estimation of plant behavior with an unknown structure, which is generically called Model Free. This title is assumed by two types of algorithms, which contain it in the name. One is the gradient-based algorithm, Model Free Adaptive Control, defined by Hou, which uses the concept of dynamic linearization through pseudo partial derivatives (PPD) and pseudo gradient (PG). The other is a non-gradient based algorithm, Model Free Control, defined by Fliess and Join, which uses the concept of the ultralocal model and intelligent PID controllers (iPID). For the gradient-based methods, in the compact form of dynamic linearization (CFDL), i.e., partial form dynamic linearization (PFDL), two algorithms are proposed to determine the initial value of the time-varying parameters PPD and PG from the dynamic performance perspective as they offer the best responses. The CFDL and PFDL variants of the MFAC control law, which have parameters that result from the application of the proposed algorithms, are compared with iP and iPD controllers on nonlinear control systems. Full article

Background: Streptococcus pneumoniae (S. pneumoniae) remains a leading cause of morbidity and mortality, particularly among vulnerable populations. This study investigates the epidemiology of pneumococcal serotypes associated with invasive pneumococcal disease (IPD) in the Comunidad Valenciana (CV) region, Spain, analysing 1587 isolates collected from 2014 to 2023. Methods: Serotyping and antimicrobial susceptibility testing were performed, and whole-genome sequencing was conducted on 104 isolates to explore their clonal relationships. Results: The most prevalent serotype was serotype 8 (17.5%), followed by serotype 3 (14.7%), with a notable increase in serotype 8 cases from 2019 onwards and a decline in serotype 19A being observed. Age distribution played a role, as serotype 8 was more frequent in individuals over ten years old. The overall recovery rate was 72%, while serotypes 3 and 15A exhibited the highest mortality rates. The vaccination coverage was highest among children under five, underscoring the need for continued surveillance to evaluate vaccine effectiveness. The antimicrobial resistance was most pronounced for erythromycin (20%) and clindamycin (16%), with serotypes 19A and 6C displaying the highest resistance levels. Whole-genome sequencing identified sequence type (ST) 53 and ST180 as the predominant STs for serotypes 8 and 3, respectively, mirroring global trends. Conclusions: These findings emphasize the necessity of continuous monitoring to inform vaccination policies and antimicrobial strategies, to ensure effective disease control and improved patient outcomes. Full article