Search Results (1,671)

Background and Objectives: Oral alitretinoin (9-cis-retinoic acid), a dual retinoic acid receptor/retinoid X receptor agonist, is approved for severe chronic hand eczema (CHE) refractory to potent topical corticosteroids but is also prescribed off-label in routine practice. Long-term real-world data on both uses are limited. We evaluated 10-year prescribing patterns, effectiveness, tolerability, and lipid changes at one Korean academic center. Materials and Methods: Patients prescribed oral alitretinoin between January 2016 and December 2025 were identified from the hospital prescribing database; those with an evaluable course of ≥1 month formed the effective-treatment cohort and underwent chart review. Treatment success was defined as final chart-derived Investigator Global Assessment (IGA) 0/1. Success by initial dose was compared using Fisher exact test; paired lipid changes using paired t-test and Wilcoxon signed-rank test. Results: Of 161 patients, 38 (23.6%) received a single prescription; 99 formed the effective-treatment cohort (50 women, 49 men; mean age 50.7 ± 16.0 years). CHE was the leading indication (70/99, 70.7%), followed by palmoplantar pustulosis (PPP, n = 14), mycosis fungoides (MF, n = 6), parapsoriasis, porokeratosis, palmoplantar keratoderma, and Darier disease. Overall success was 66.7% (66/99) over a mean treatment duration of 12.4 months, highest in CHE (77.1%) and more variable off-label (PPP 42.9%; MF 33.3%). Initiation at 30 mg was associated with higher success than 10 mg (71.1% vs. 43.8%; p = 0.044), but this association did not persist after restriction to patients maintained on their initial dose (62.2% vs. 50.0%; p = 0.498) or after Firth penalized logistic regression adjusting for age, sex, and indication (adjusted odds ratio 1.84; 95% CI 0.56–5.90; p = 0.309). Adverse events occurred in 21 patients (21.2%), most commonly dyslipidemia (n = 12) and headache (n = 7); mean triglyceride rose 42.1 mg/dL and total cholesterol 14.0 mg/dL (both p < 0.001), and new elevation above conventional thresholds occurred in 25.8% (triglyceride) and 27.5% (total cholesterol) of patients with normal baseline values. Thirty patients (30.3%) discontinued, most often for insufficient effectiveness. Conclusions: Alitretinoin showed favorable effectiveness in CHE and variable, exploratory responses off-label. The apparent advantage of 30 mg initiation was not independent of indication and dose adjustment. Lipid elevation was common, supporting routine surveillance. Off-label findings, particularly in PPP and MF, should be interpreted cautiously given small subgroups and non-standardized retrospective assessment. Full article

To address the challenges of GNSS signal blockages and severe multipath effects in complex urban environments, this paper proposes a tightly coupled precise point positioning (PPP)/inertial navigation system (INS) integration method based on an adaptive robust Kalman filter (ARKF) for smartphones. The proposed method integrates a robust estimation module based on the IGG-III weight function and an adaptive factor derived from vehicle dynamic intensity and geometric precision indicators, to mitigate observation outliers and dynamic model errors. To evaluate the positioning performance of this algorithm, two typical vehicle experiments based on the GNSS and inertial measurement unit (IMU) chipsets of the Xiaomi Mi 8, as well as an external H30 IMU, were conducted. Experimental results show that in the urban expressway environment, the horizontal root mean square (RMS) error of the loosely coupled PPP/INS solution was reduced by 74.17% compared with the conventional PPP solution, while the maximum horizontal positioning error of the tightly coupled PPP/INS solution was reduced by 44.82% compared with the loosely coupled PPP/INS solution. In the complex urban road and tunnel environments, the proposed ARKF-based tightly coupled PPP/INS method achieved a 36.79% reduction in horizontal RMS error compared with the tightly coupled PPP/INS solution based on the standard extended Kalman filter (EKF) and demonstrated more robust positioning performance in the tunnel. Full article

Public–private partnerships (PPPs) are implemented through individual contracts, but their performance is often judged with indicators observed at broader sectoral or national levels. This study develops a measurement alignment framework comprising intervention–measurement alignment, statistical visibility, attribution distance, outcome completeness, and comparison credibility and applies it to Croatian PPPs. The analysis combines the national PPP register with Eurostat data for 2000–2024. It uses a six-sector difference-in-differences benchmark, applies small-cluster inference and a 9999-draw Webb wild-cluster bootstrap, adds hours worked and national-accounts gross fixed capital formation, and evaluates timing, pandemic, contamination, spillover, intensity, and leave-one-out sensitivity. In the six-sector benchmark sample, the current-price GVA coefficient is 0.149 and statistically uncertain, whereas the real GVA coefficient is 0.256 and remains supported by the wild-cluster bootstrap (p = 0.009). In the 16-sector comparison sample, current-price and real GVA estimates remain positive but are estimated with wider uncertainty. Employment, hours worked, real productivity, and real investment show no robust broad effects, while event-study diagnostics reveal poorer pre-treatment comparability in the 16-sector comparison sample. The evidence supports a cautious positive output association, not a general causal growth claim, and demonstrates that PPP accountability requires indicators aligned with project mechanisms, geography, timing, and accounting visibility. The framework explicitly recognizes environmental performance as a required outcome domain, but the available sector-level data do not permit a direct estimate of PPP environmental impacts. Full article

Proteases are widely studied hydrolases as “green technologies” for degrading structures within complex matrices, although combining different classes poses challenges for catalytic stability. To the best of our knowledge, this is the first study to specifically evaluate the biochemical control of Cryptosporidium spp. oocysts using plant- and microbial-derived proteases. This study evaluated the compatibility and sanitizing potential of the microbial serine protease subtilisin Carlsberg (HPF-1SCA) and the plant cysteine protease papain (1PPP), both individually and in a 15% (w/v) combination, hypothesizing a synergistic effect due to their distinct catalytic specificities, as a potential biochemical approach to reduce contamination by these zoonotic protozoa of global importance, which are highly resilient to conventional disinfectants. The experimental design comprised five distinct treatment groups: a negative control (distilled water), a positive chemical control (0.04% v/v NaClO), treatment with isolated papain (15% w/v), treatment with isolated microbial HPF formulation (15% w/v), and a combined treatment using both enzymes simultaneously (15% w/v each). Concurrently, an in silico molecular docking investigation was conducted to elucidate the predicted binding scores, structural compatibility, and preferential binding mechanisms of these enzymes toward the Cryptosporidium Oocyst Wall Protein (COWP). In vitro compatibility assays revealed an immediate antagonistic effect due to mutual proteolysis, reducing overall proteolytic activity by 45% after 72 h. Despite this antagonism, the enzyme mixture (G5) and the isolated microbial protease (G4) achieved a 93% reduction in oocysts, equivalent to the conventional 0.04% NaClO treatment (G2), while papain (G3) achieved 65%. All these results represented statistically significant efficacy (p < 0.01) compared to the negative control (G1). In silico molecular docking studies provided a structural predictive basis for the experimental data, suggesting that subtilisin Carlsberg (HPF-1SCA) exhibits more favorable predicted binding scores and structurally compatible interfaces, compared to papain, particularly toward the major oocyst structural proteins COWP8 (estimated ΔG = −15.2 kcal·mol⁻¹) and COWP6 (estimated ΔG = −13.3 kcal·mol⁻¹). This provides robust evidence for initial target recognition and molecular anchoring, although these static models do not definitively confirm catalytically productive cleavage conformations. In summary, this in vitro proof-of-concept demonstrates that microbial proteases show promise for the biochemical destabilization of oocysts without generating toxic chlorinated byproducts. While these baseline findings align with the One Health concept, future field-scale validations assessing enzyme stability under variable environmental conditions and in vivo infectivity assays are required before practical application in sanitation protocols. Full article

Background/Objectives: Healthcare workforce shortages and the challenges facing healthcare professionals are among the most pressing issues confronting contemporary health systems. This study examines the social representations of public, private, and public–private partnership (PPP) healthcare organisational models and professional practice elicited from public-sector physicians and nurses in Portugal. Methods: A cross-sectional survey was conducted between October 2022 and May 2023 using a non-probability sample of 308 physicians and nurses classified as public-sector professionals. Participants completed a free-association task concerning the public, private, and PPP healthcare models and their professional practice. The evoked terms were examined using prototypical analysis within the structural approach to Social Representations Theory. The representation of the public healthcare sector included elements such as accessibility, universality, equity, slowness, disorganisation, and resource limitations. The private healthcare sector was characterised by elements including cost, profit, speed, organisation, inaccessibility, and service quality. Results: The representation of PPPs included better management, efficiency, profit, interests, and quality, alongside a relatively frequent “No opinion” response. Professional practice was characterised by elements including caring, dedication, empathy, resilience, exhaustion, perceived undervaluation, and remuneration. Conclusions: These findings describe the social representations elicited from the present sample of public-sector physicians and nurses and should not be interpreted as evidence of objective differences between healthcare organisational models or as direct measures of motivation, resilience, burnout, sector preference, or working conditions. The findings are exploratory and hypothesis-generating and may inform future comparative research involving professionals working across different healthcare settings, as well as studies using dedicated measures of professional and occupational outcomes. Full article

Streptococcus cristatus (S. cristatus) belongs to the viridans group of streptococci and is a commensal of the human upper respiratory tract. With the non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase, GapN, and the oxidative part of the pentose phosphate pathway (oxPPP), S. cristatus can use two different metabolic pathways to provide reduced nicotinamide adenine dinucleotide phosphate (NADPH), an essential cofactor of anabolic reactions such as fatty acid and amino acid biosynthesis. Regarding their NADP-reducing capacity, streptococci can be categorized into three groups: those that have only GapN, those that use only the oxPPP, and those that use both pathways. Here, we report on the experimental and computational characterization of the catalytic properties of the three NADP-reducing enzymes: GapN, glucose-6-phosphate dehydrogenase (G6PDH), and 6-phosphogluconate dehydrogenase (6PGDH) of S. cristatus. Kinetic analyses showed moderate substrate and cofactor affinities, with GapN displaying the tightest substrate binding, followed by 6PGDH and G6PDH, in agreement with structural and computational predictions. All three enzymes preferentially utilized NADP⁺, with only G6PDH exhibiting limited NAD⁺ promiscuity. Growth-phase-dependent activity patterns suggest dynamic adjustment of NADPH-generating pathways, with reduced GapN contribution and sustained oxPPP activity in the stationary phase. Regulatory screening indicated limited allosteric control, though feedback inhibition by NADPH and the ATP sensitivity of G6PDH point to conserved redox regulatory mechanisms. Comparative analysis across streptococci supports the concept that the coexistence of GapN and the oxidative pentose phosphate pathway in S. cristatus may provide metabolic flexibility by offering alternative routes for NADPH generation. Full article

Robust evaluation methods are essential for assessing the sustainability of public–private partnerships (PPPs) and advancing the Sustainable Development Goals (SDGs). This study examines the United Nations Economic Commission for Europe (UNECE) People-first PPP and Infrastructure Evaluation and Rating System (PIERS) through three green PPP initiatives in Slovenia, focusing on energy efficiency, renewable energy and sustainable mobility. Using structured scoring across five dimensions—access and equity, economic effectiveness, environmental sustainability, replicability and stakeholder engagement—the analysis considers project-level performance, national SDG alignment and methodological applicability. The results indicate strong overall sustainability performance, but identify stakeholder engagement as a significant weakness, largely due to institutional constraints. Comparison with Slovenia’s national SDG progress in 2023–2025 shows broad alignment between project outcomes and wider sustainability achievements. The methodological review also identifies scope for improving the applicability and adaptability of PIERS indicators. Although primarily designed as a self-assessment tool, PIERS provides a systematic framework for integrating SDG principles into PPP management, especially in relation to SDGs 7, 9, 11 and 13. The study contributes empirical evidence and methodological insights for more sustainable public investment governance. Full article

Multiple sclerosis (MS) is an immune-mediated central nervous system disease with mapped genetic risk loci but unresolved cross-layer regulatory mechanisms. We harmonised 30 primary public MS datasets spanning bulk transcriptomics (552 samples, 367 MS/185 healthy control [HC]), DNA methylation arrays (475 samples, 244 MS/231 HC) with sorted-cell whole-genome bisulfite sequencing (WGBS) assessment, single-cell RNA sequencing (RNA-seq; 517,533 cells from 81 donors), and cerebrospinal fluid (CSF) and brain white-matter proteomes, and UK Biobank Pharma Proteomics Project (UK Biobank-PPP) plasma proteomic statistics (407 MS/39,979 HC) for external validation. We prioritised MS-associated genes showing inverse-concordant, cohort-level methylation–expression associations and orthogonal support across layers. After harmonised reprocessing and per-stratum differential testing, a bulk-RNA × methylation inverse-concordance filter followed by an independent proteomic and/or donor-level single-cell anchor identified two Tier-1 candidates (IKZF1’s anchor is a candidate-panel-adjusted donor-level pseudobulk association, not transcriptome-wide significance): ITGB2 and IKZF1. ITGB2 showed the strongest cross-layer support: RNA down-regulation, promoter hypermethylation and reduced plasma abundance in UK Biobank MS cases, a pattern consistent with altered leukocyte-integrin adhesion. Pathway and network analyses linked the candidates predominantly to leukocyte and lymphocyte activation and differentiation, leukocyte-integrin adhesion, and interferon and cytokine-signalling immune modules. These findings nominate MS-relevant regulatory candidates and provide a reusable multi-omics framework for hypothesis generation and validation. Full article

Peripheral neuropathy degrades gait mechanics, elevating peak plantar pressures (PPP) and tissue ulceration risks. This exploratory pilot study evaluates custom orthotics using thermo-mechanically synthesized re-entrant auxetic foam insoles with targeted dome-shaped inserts. Bilateral dynamic gait analysis was conducted across a heterogeneous cohort (N = 9) utilizing a P-Walk 600 pressure plate and a MARVUE 2D motion capture system inside standardized footwear. To address small-sample limits, a non-parametric bootstrap resampling analysis (B = 1000) was executed. Native auxetic foam demonstrated high internal consistency ((σ*) = 12.063 kPa, Consistency Rank = 1), showing a strong numerical propensity to restrict load distribution variability compared to factory-installed over-the-counter (OTC) memory foam controls. While initial cell-adaptation cycles were observed, custom insoles reduced PPP by up to 62.2% in systemic polyneuropathies, shifting signatures beneath the exploratory clinical safety target (<200 kPa) in 55% of simulated cases. Conversely, customization triggered an adverse volumetric crowding effect in focal mononeuropathies, suggesting un-customized native auxetic foam as the preferred structural configuration for this specific cohort to avoid premature cell densification. Re-entrant cellular structures accommodate heterogeneous pathomechanics, offering an exploratory pathway for patient-specific orthotic optimization. Full article

Certification schemes are increasingly positioned as institutional mechanisms that may support sustainable food markets, yet the joint longitudinal relationship between certified production penetration, certified supply-chain infrastructure and organic market uptake remains insufficiently integrated in European-scale empirical analyses. This study examined how certified organic production, supply-chain infrastructure, and market uptake co-evolved across Europe. A country–year panel of 995 observations from 41 European countries (2000–2024) was assembled from FiBL statistics and analysed using descriptive trend analysis, Spearman correlations, linear mixed-effects models with country random intercepts, and k-means clustering. Certified organic systems expanded substantially: mean organic farmland share rose from 2.80% to 9.73%, retail sales share from 1.42% to 4.49%, and per capita consumption from €25.82 to €87.60. Organic area share remained positively associated with organic retail sales share after adjustment for PPP-adjusted GDP per capita (β = 1.247, p < 0.001), with a similar pattern for the secondary per capita consumption outcome (β = 36.426, p < 0.001). Certified supply-chain actors were strongly intercorrelated (producers–processors ρ = 0.824). Organic farmland share was the most consistent correlate of market uptake, including after adjustment for GDP per capita, whereas absolute operator counts and supply-chain infrastructure indicators were more difficult to interpret independently because of collinearity. A four-cluster typology showed that countries with the largest certified production bases were not those with the most mature markets. These findings are consistent with the interpretation that certification penetration may support market development by providing credible institutional signals, but trust creation, information asymmetry reduction, and legitimacy were not directly measured. The results, therefore, indicate an association between certification-system development and market uptake, while also showing that production expansion and market maturity are distinct dimensions of the sustainability transition. Full article

Limpopo Province is one of South Africa’s major potato-producing regions, yet the field-level composition and community structure of plant-parasitic nematodes (PPNs) remain insufficiently documented. This study surveyed 30 potato fields in four districts to determine the occurrence, abundance and district-level patterns of PPN genera and to identify whether any detected genera had recognised plant-virus vector relevance. Composite root-zone soil samples were collected during autumn 2019. Nematodes were extracted from 250 cm³ soil subsamples, and PPNs were identified to genus level. Data included PPN, total nematodes, plant-parasitic percentage (PPP), fungal-feeder, bacterial-feeder, Wasilewska Index and Nematode Channel Ratio values. Ten plant-parasitic genera were detected in 25 of 30 fields (83.3%). Meloidogyne had the greatest mean density and prominence value, while Meloidogyne and Helicotylenchus were the most frequent genera. Waterberg had the highest median PPP and the lowest median WI, indicating dominance of PPN in the sampled fields. A virus-vector assessment showed that Nanidorus was the only detected genus that belongs to a nematode family with recognised tobravirus-vector potential. The findings provide an improved baseline for nematode surveillance in Limpopo potato fields and indicate that future monitoring should combine genus- and species-level nematode diagnostics with virus testing where Nanidorus or other trichodorids are detected. Full article

Accurate and reliable positioning is a fundamental requirement for marine applications, particularly in hydrographic surveying, where real-time data acquisition is essential. Despite recent advances in Global Navigation Satellite System (GNSS) technologies, the comparative performance of different real-time correction strategies under marine conditions remains insufficiently addressed. This study presents a comparative performance analysis of three real-time GNSS positioning solutions—Precise Point Positioning–Real-Time Kinematic (PPP-RTK), Network RTK (NRTK), and Single-Baseline RTK (SBL-RTK) with Post-Processed Kinematic (PPK) coordinates adopted as the reference. Performance was assessed using statistical accuracy metrics in accordance with the International Hydrographic Organization (IHO) S-44 standards. At the 95% confidence level, the Total Horizontal Uncertainty (THU) values were 5.6 cm for PPP-RTK and 4.5 cm for NRTK, while the Total Vertical Uncertainty (TVU) values were 3.6 cm and 6.8 cm, respectively. Both NRTK and PPP-RTK solutions met IHO S-44 standards. Under the test conditions considered in this study, the SBL-RTK solution exhibited lower performance than the other solutions, mainly due to the higher proportion of float and stand-alone solution epochs. The findings indicate that the NRTK solution is suitable for near-shore hydrographic surveys where cellular connectivity is available. PPP-RTK represents a reliable alternative for marine applications through satellite-based correction services. This study contributes to the evaluation and selection of appropriate GNSS-based positioning strategies for hydrographic surveying. Full article

Jamming introduces unintentional disruptions in the system to exploit the legitimate communicating equipment. Clustered jamming considers jammers that are present in multiple groups to disrupt the intended communication. Vehicle-to-everything (V2X) transmissions are critical for smart transportation. This research considers full-duplex environment, featuring unmanned aerial vehicles (UAVs) and cellular-base-station-aided V2X (C-V2X) systems exploiting clustered jamming using 3-dimensional (3-D) beam-forming millimeter-wave antennas. UAVs are modeled as a 3-D Poisson point process (PPP), and macro-based tower-mounted base-stations (MBSs) are modeled as a 2-D PPP. Roads are modeled as a Poisson line process. The vehicular nodes (V-Ns) are modeled on each road as a 1-D PPP. The deviations of the UAV’s millimeter-wave band antenna beam follow a Normal distribution. In this paper, for a full-duplex setting, the probabilities of coverage and equipment-association, along with the efficiency of the spectrum associated with various UAV and tower-based connections, are explored in the presence of clustered jamming. The probability of coverage and association of multiple links is derived with respect to the jamming clusters, V-Ns, MBSs, UAVs, jammers’ power, and antenna beams. The results demonstrated that jamming degrades system’s efficiency. This efficiency is further degraded whenever higher 3-D beam-width deviations of the millimeter waveband antenna and jammers are present. Therefore, robust counter-scenarios should be designed for the cases where jamming signals and varying beams disrupt the network. Full article

IBs are mineralized spicules originating from osteoblasts differentiated from tenocytes that can reduce the commercial value of fish and pose potential health risks to consumers if accidentally ingested. Runx2b exhibited higher expression in osteoblasts associated with IBs. Knockout of the runx2b gene significantly reduced osteoblast numbers and completely inhibited IB formation, confirming its essential role in osteogenic differentiation. However, how non-coding RNAs regulate this process during IB formation remains poorly understood. In this study, whole-transcriptome sequencing was performed to identify ncRNAs and mRNAs in dorsal and tail muscle tissues from six-month-old M. amblycephala with IBs (WT group, n = 3) and without IBs (Mut group, n = 3). A total of 1762 and 1992 differentially expressed (DE) transcripts were identified in dorsal and tail muscle, respectively. Specifically, in dorsal muscle, 408 DE-circular RNAs (circRNAs), 425 DE-long non-coding RNAs (lncRNAs), 171 DE-microRNAs (miRNAs), and 758 DE-messenger RNAs (mRNAs) were detected; in tail muscle, 337 DE-circRNAs, 414 DE-lncRNAs, 222 DE-miRNAs, and 1019 DE-mRNAs were identified. Gene Set Enrichment Analysis (GSEA) revealed that, in the Mut group, key osteogenic signaling pathways, specifically Wnt, MAPK, and TGF-β, were significantly enriched among downregulated genes. Several key IB formation-responsive ceRNAs were identified based on correlation analysis, and the expression and function of the critical regulatory axis, lnc007185570.1–pal-miR-3120-3p–ppp3cb, were experimentally validated. Functional assays subsequently demonstrated that this axis modulates osteoblast differentiation via the Wnt signaling pathway. These findings offer new insights into the molecular mechanisms governing osteoblast differentiation during IB formation from the perspective of ceRNA regulatory networks. Full article

Prompted by a fetus with a homozygous PPP1R13L pathogenic variant and persistent open eyelids on sonography, suggesting fusion failure, this study marks the first prenatal human description linking PPP1R13L to eyelid closure, mirroring waved with open eyelids 2(woe2) and waved 3 (wa3) mouse models. Eyelid morphogenesis involves complex epidermal–dermal interactions. We reviewed the literature to understand embryonic/fetal development and identify molecular pathways crucial for proper eyelid morphology. Known signaling pathways in eyelid closure and reopening include NF-κB, p53, Wnt, TGF-β, BMP4, MAPK, SMAD, ECM–receptor interaction, and integrin signaling. Open-eye phenotypes are associated with pathogenic variants affecting the Wnt/β-catenin pathway, p63, and the TGFβ family. Notably, SMAD molecules are common to all these pathways. Eyelid closure seems regulated by SMAD protein activation in the supraorbital epithelium and underlying mesenchyme, promoting cell proliferation and adhesion. Physiological SMAD1 downregulation is crucial for eyelid reopening. Given SMAD signaling’s importance in development, its disruption likely impacts eyelid closure or reopening. Full article