External Control Research Articles

Caging Bioactive Triarylimidazoles: An Approach to Create Visible Light-Activatable Drugs.

Imidazoles are crucial structural components in a variety of small-molecule inhibitors designed to target different kinases in anticancer treatment. However, the effectiveness of such inhibitors is often hampered by nonspecific effects and the development of resistance. Photopharmacology provides a compelling solution by enabling external control over drug activity with spatiotemporal precision. Herein, we introduce a novel strategy for caging bioactive triarylimidazole-based drug molecules. This approach involves introducing a dialkylamino group as a photoremovable group on the carbon atom of the imidazole ring, which intrinsically modulates the core structure from planar imidazole to tetrahedral 2H-imidazole, enabling the caged compound to be selectively uncaged upon visible light exposure. We applied this innovative caging technique to SB431542, a triarylimidazole-based small-molecule inhibitor that targets the pivotal TGF-β signaling pathway, the dysregulation of which is linked to several human diseases, including cancer. Our results demonstrated the selective inhibition of human breast cancer cell migration in vitro upon light activation, highlighting the potential of our approach to transform triarylimidazole-based drug molecules into visible light-activatable drugs, thereby facilitating spatiotemporal regulation of their pharmacological activity.

Interactions Enable Thouless Pumping in a Nonsliding Lattice

A topological “Thouless” pump represents the quantized motion of particles in response to a slow, cyclic modulation of external control parameters. The Thouless pump, like the quantum Hall effect, is of fundamental interest in physics, because it links physically measurable quantities, such as particle currents, to geometric properties of the experimental system, which can be robust against perturbations and, thus, technologically useful. So far, experiments probing the interplay between topology and interparticle interactions have remained relatively scarce. Here, we observe a Thouless-type charge pump in which the particle current and its directionality inherently rely on the presence of strong interactions. Experimentally, we utilize a two-component Fermi gas in a dynamical superlattice which does not exhibit a sliding motion and remains trivial in the single-particle regime. However, when tuning interparticle interactions from zero to positive values, the system undergoes a transition from being stationary to drifting in one direction, consistent with quantized pumping in the first cycle. Remarkably, the topology of the interacting pump trajectory cannot be adiabatically connected to a noninteracting limit, highlighted by the fact that only one atom is transferred per cycle. Our experiments suggest that Thouless charge pumps are promising platforms to gain insights into interaction-driven topological transitions and topological quantum matter. Published by the American Physical Society 2024

Effects of Oral ALZ-801/Valiltramiprosate on Plasma Biomarkers, Brain Hippocampal Volume, and Cognition: Results of 2-Year Single-Arm, Open-Label, Phase 2 Trial in APOE4 Carriers with Early Alzheimer's Disease.

ALZ-801/valiltramiprosate is a small-molecule oral inhibitor of beta amyloid (Aβ) aggregation and oligomer formation being studied in a phase 2 trial in APOE4 carriers with early Alzheimer's disease (AD) to evaluate treatment effects on fluid and imaging biomarkers and cognitive assessments. The single-arm, open-label phase 2 trial was designed to evaluate the effects of the ALZ-801 265 mg tablet taken twice daily (after 2weeks once daily) on plasma fluid AD biomarkers, hippocampal volume (HV), and cognition over 104 weeks in APOE4 carriers. The study enrolled subjects aged 50-80 years, with early AD [Mini-Mental State Examination (MMSE) ≥ 22, Clinical Dementia Rating-Global (CDR-G) 0.5 or 1], apolipoprotein E4 (APOE4) genotypes including APOE4/4 and APOE3/4 genotypes, and positive cerebrospinal fluid (CSF) AD biomarkers or prior amyloid scans. The primary outcome was plasma p-tau181, HV evaluated by magnetic resonance imaging (MRI) was the key secondary outcome, and plasma Aβ42 and Aβ40 were the secondary biomarker outcomes. The cognitive outcomes were the Rey Auditory Verbal Learning Test and the Digit Symbol Substitution Test. Safety and tolerability evaluations included treatment-emergent adverse events and amyloid-related imaging abnormalities (ARIA). The study was designed and powered to detect 15% reduction from baseline in plasma p-tau181 at the 104-week endpoint. A sample size of 80 subjects provided adequate power to detect this difference at a significance level of 0.05 using a two-sided paired t-test. The enrolled population of 84 subjects (31 homozygotes and 53 heterozygotes) was 52% females, mean age 69 years, MMSE 25.7 [70% mild cognitive impairment (MCI), 30% mild AD] with 55% on cholinesterase inhibitors. Plasma p-tau181 reduction from baseline was significant (31%, p = 0.045) at 104 weeks and all prior visits; HV atrophy was significantly reduced (p = 0.0014) compared with matched external controls from an observational Early AD study. Memory scores showed minimal decline from baseline over 104 weeks and correlated significantly with decreased HV atrophy (Spearman's 0.44, p = 0.002). Common adverse events were COVID infection and mild nausea, and no drug-related serious adverse events were reported. Of 14 early terminations, 6 were due to nonserious treatment-emergent adverse events and 1 death due to COVID. There was no vasogenic brain edema observed on MRI over 104 weeks. The effect of ALZ-801 on reducing plasma p-tau181 over 2 years demonstrates target engagement and supports its anti-Aβ oligomer action that leads to a robust decrease in amyloid-induced brain neurodegeneration. The significant correlation between reduced HV atrophy and cognitive stability over 2 years suggests a disease-modifying effect of ALZ-801 treatment in patients with early AD. Together with the favorable safety profile with no events of vasogenic brain edema, these results support further evaluation of ALZ-801 in a broader population of APOE4 carriers, who represent two-thirds of patients with AD. https://clinicaltrials.gov/study/NCT04693520 .

The Relationship between Resilience, locus of Control, and General Health with the Academic Performance among Students of Yazd University of Medical Sciences

Introduction: Improving students' academic performance is related to various factors. Identifying and modifying these factors can improve academic performance. The study investigated the relationship between resilience, locus of control, and general health with students' academic performance. Method: The study is a cross-sectional descriptive-analytical study consisting of 415 students. Resilience, source of control, and public health were investigated by using standard questionnaires, and the correlation of these scores with the academic performance of the students was evaluated. Results: A comparison of the average scores of resilience, locus of control, and general health with the student's academic status showed that those who had a GPA higher than 16.92 had a higher score of resilience, locus of control, and general health, but it was not reported significant. In comparing the internal and external control dimensions of the source of control, it was shown that people with an external source have a significantly higher grade point average. Also, there is a relationship between the variables of resilience, source of control, and general health with academic performance, and between the variables of source of control and resilience with academic performance. Significant was reported. Conclusion: It is recommended to organize practical education areas and workshops to enhance resilience, general health, and life skills based on the findings of the academic progress study.

IMMU-11. CLINICAL EXPERIENCE WITH THE CONCEPT OF MULTIPHASE COMBINED TREATMENT FOR ADULTS WITH GBM

Abstract BACKGROUND We published survival data of 50 adults with GBM treated with individualized multimodal immunotherapy (IMI) as part of a multiphase combined treatment (Van Gool et al, https://doi:org/10.1016/bs.mcb.2023.06.001). Analysis was repeated with new observation data. METHODS Patient definition for retrospective analysis: start IMI between 27/05/2015 and 31/10/2023, >18y, newly diagnosed, IDH1 wild-type, MGMT promoter-methylation status documented, survival known, no second malignancy. RESULTS Forty (14 female, 26 male) GBM patients were MGMT-promoter-unmethylated (unmeth), while 31 (15 female, 16 male) were MGMT-promoter-methylated (meth). Comparing the molecular subgroups, both respective median age; 48 years (range 18-65) and 54 years (range 26-72), and respective Karnofsky performance index; 70 (range 50-100) and 80 (range 60-100), were equal. Patient distribution (< complete resection, complete resection, not documented) was equal: 17/15/8 (unmeth) versus 17/11/3 (meth). Both groups were treated similarly: in median 37 (range 0-147) sessions of modulated electrohyperthermia, in median 37 (range 5-147) bolus injections of Newcastle Disease Virus, in median 2 (range 0-6) IO-Vac® vaccines with a median total number of 30.7x10e6 DCs (range 0-158x10e6). The median overall survival (mOS) for the total group was 27 months. The 2-year overall survival (OS) was 57.9 % and the 3-year OS 37.1 %. The mOS for unmeth patients was 22.1 month, with a 2-year OS of 42.7%. The mOS for meth patients was 37.7 months, with a 2-year OS of 75.5%. Sampling five control arms of contemporary RCTs as external control arm (Liau et al, JAMA Oncol 2023) showed for unmeth and meth patients a mOS of 14.6 resp. 21.3 months with a 2-year OS of 21% resp. 42%, which reflects the current prognosis for these patients. CONCLUSIONS Our analysis confirms that the integration of IMI during and after standard of care improves the OS. Similar multiphase combined treatment strategy, including IMI, should be considered to treat childhood GBM.

Trust in Transit: External Migration Control and Migrants’ Perceptions of Humanitarian Borderwork in the Sahel

The Sahel region has become a focal point for externalisation policies seeking to prevent the onward travel of migrants bound for North Africa and Europe. In this context, humanitarian actors are increasingly called upon to implement migration control policies or to address migrants’ vulnerabilities during journeys characterised by ‘extended temporariness’. This paper builds upon the concepts of the humanitarian border and institutional trust to develop a typology of organisations and to explore how migrants in transit perceive these forms of humanitarian borderwork. By employing the concept of trust as an analytical prism to examine social navigation, risk-assessments and the felt externalisation of migration control, we argue that transit migrants’ mistrust in humanitarian organisations is a ripple effect of the externalisation process. This leads to cumulative ripples, such as protection gaps for individuals travelling from West to North Africa. The article compares two key locations for West African transit migration in Niger and Mali, exhibiting similar characteristics but differing in the extent and visibility of external migration-related programming. Through qualitative content analysis of interviews conducted with 90 transit migrants between 2020 and 2021, we identify the perceived involvement of organisations in migration control and the phase in the migration trajectory as key factors influencing (mis)trust in organisations. We further trace the effects of (mis)trust on migrant strategies, including exit, risk-acceptance, and self-protection. The results highlight the far-reaching impacts of different externalisation environments on migrant safety and strategies, as well as on the ability of humanitarian organisations to provide protection in vulnerable migration situations.

The Impact of Performance Reporting on Investment Behavior: Evidence from Disclosure Reform in the U.K.

ABSTRACT I examine the real effects of a disclosure mandate that, with the aim of enhancing performance reporting, requires a subset of London Stock Exchange (LSE) firms to describe operational and strategic aspects of value creation, such as business operations and strategies, in their annual reports. Using an instrumented difference-in-differences design, I find that compliance with this initiative, evidenced by more disclosures of performance measures and commentaries relating to business operations and strategies, promotes intangible investments. My analysis of external and internal control systems suggests that enhanced performance reporting promotes investments because it attracts long-term investors and reduces CEO pay sensitivity to earnings performance. JEL Classifications: D22; D82; O30; M41.

An optoionic hydrogel with UV-regulated ion conductivity for reprogrammable iontronics: Logic processing and image sensing.

The development of smart hydrogels capable of actively controlling ion conductivity is of paramount importance for iontronics. Most current work in this field focuses on enhancing the hydrogels' ion conductivity. Few successes have been seen in achieving spatial regulation of ion flow through external control. Among various controls, light gives the best spatial and temporal resolution for practical iontronic applications. However, developing hydrogels that can generate drastic ion concentration change upon photoirradiation for tunable conductivity is challenging. Very few molecules can enable photoion generation, and most of them are hydrophobic and low quantum yield. Here, we present an optoionic hydrogel that uses triphenylmethane leuconitrile (TPMLN) for ultraviolet-regulated ion conductivity. Through postpolymerization TPMLN synthesizing, we can incorporate high concentration of the hydrophobic TPMLN in hydrogels without compromising the hydrogel's mechanical integrity. Upon light irradiation, the hydrogel's local conductivity can change an unprecedented 10-fold. We also demonstrated soft optoionic devices that are capable of logic processing and photo imaging.

Developing Internal and External Proportional Integral Derivative Water Surface Controller in HEC-RAS

Developing Internal and External Proportional Integral Derivative Water Surface Controller in HEC-RAS

Efficacy of a non-pharmaceutical multimodal intervention program in a group setting for patients with mild cognitive impairment: A single-arm interventional study with pre-post and external control analyses

AimThis study aimed to evaluate the efficacy of a non-pharmaceutical multimodal intervention program consisting of physical exercise, cognitive stimulation, and health education in a group setting to slow the progression of mild cognitive impairment (MCI). MethodsA single-arm interventional study was conducted on 27 patients with MCI. To evaluate the efficacy of the intervention program, a pre-post analysis was performed using EuroQol-5 Dimension (EQ-5D), Mini-Mental State Examination (MMSE), Cognitive Function Instrument (CFI), 5 Cog test, depression, and physical performance before and after the 8-month intervention. Additionally, propensity score and the semi-Bayes analyses were performed to compare the intervention program with standard medical care, using the external control patients’ data for MMSE scores. ResultsTwenty-four patients completed the intervention program. During the study period, although EQ-5D and MMSE scores remained unchanged (mean change 0.02 [95 % confidence interval (CI): −0.004, 0.04], 0.5 [-0.2, 1.3]), CFI and the subcategories of 5Cog (attention and reasoning) improved (mean change −1.23 [-2.24, −0.21], 4.3 [0.9, 7.7], 3.0 [0.4, 5.6]). In the additional analysis comparing changes in MMSE scores, patients who underwent the intervention program had less decline than the external control patients (mean change −1.7 [-2.1, −1.3]) with an observed mean difference of 2.25 [1.46, 3.03], and propensity score-adjusted difference of 2.26 [1.46, 3.05]. The semi-Bayesian approach also suggested that the intervention slowed the progression of MCI. ConclusionA non-pharmaceutical multimodal intervention program could contribute to slowing cognitive decline in patients with MCI.

Mycobacterium immunogenum acquisition from hospital tap water: a genomic and epidemiologic analysis.

We identified 23 cases of Mycobacterium immunogenum respiratory acquisition linked to a colonized plumbing system at a new hospital addition. We conducted a genomic and epidemiologic investigation to assess for clonal acquisition of M. immunogenum from hospital water sources and improve understanding of genetic distances between M. immunogenum isolates. We performed whole-genome sequencing on 28 M. immunogenum isolates obtained from August 2013 to July 2021 from patients and water sources on four intensive care and intermediate units at an academic hospital. Study hospital isolates were recovered from 23 patients who experienced de novo respiratory isolation of M. immunogenum and from biofilms obtained from five tap water outlets. We also analyzed 10 M. immunogenum genomes from previously sequenced clinical (n = 7) and environmental (n = 3) external control isolates. The 38-isolate cohort clustered into three clades with pairwise single-nucleotide polymorphism (SNP) distances ranging from 0 to 106,697 SNPs. We identified two clusters of study hospital isolates in Clade 1 and one cluster in Clade 2 for which clinical and environmental isolates differed by fewer than 10 SNPs and had less than 0.5% accessory genome variation. A less restrictive combined threshold of 40 SNPs and 5% accessory genes reliably captured additional isolates that met clinical criteria for hospital acquisition, but 12 (4%) of 310 epidemiologically unrelated isolate pairs also met this threshold. Core and accessory genome analyses confirmed respiratory acquisition of multiple clones of M. immunogenum from hospital water sources to patients. When combined with epidemiologic investigation, genomic thresholds accurately distinguished hospital acquisition.

Development of Consensus-Based Best Practice Guidelines for the Peri- and Post-operative Care of Pediatric Patients with Spinal Deformity and Programmable Implanted Devices

Study Design. Modified Delphi consensus study. Objective. To develop consensus-based best practices for the care of pediatric patients who have implanted programmable devices (IPDs) and require spinal deformity surgery. Summary of Background Data. Implanted programmable devices (IPDs) are often present in patients with neuromuscular or syndromic scoliosis who require spine surgery. Guidelines for monitoring and interrogating these devices during the peri-operative period are not available. Methods. A panel was assembled consisting of 25 experts (i.e., spinal deformity surgeons, neurosurgeons, neuro-electrophysiologists, cardiologists, and otolaryngologists). Initial postulates were based on literature review and results from a prior survey. Postulates addressed the following IPDs: vagal nerve stimulators (VNS), programmable ventriculo-peritoneal shunts (VPS), intrathecal baclofen pumps (ITBP), cardiac pacemakers and implantable cardioverter-defibrillators (ICD), deep brain stimulators (DBS), and cochlear implants. Cardiologist and otolaryngologists participants responded only to postulates on cardiac pacemakers or cochlear implants, respectively. Consensus was defined as ≥80% agreement, items that did not reach consensus were revised and included in subsequent rounds. A total of three survey rounds and one virtual meeting were conducted. Results. Consensus was reached on 39 total postulates across six IPD types. Postulates addressed general spine surgery considerations, use of intraoperative monitoring and cautery, use of magnetically-controlled growing rods (MCGRs), and use of an external remote controller to lengthen MCGRs. Across IPD types, consensus for the final postulates ranged from 94.4-100%. Overall, experts agreed that MCGRs can be surgically inserted and lengthened in patients with a variety of IPDs and provided guidance for the use of intraoperative monitoring and cautery, which varied between IPD types. Conclusion. Spinal deformity correction surgery often benefits from the use of intraoperative monitoring, monopolar and bipolar cautery, and MCGRs. Final postulates from this study can inform the peri- and post-operative practices of spinal deformity surgeons who treat patients with both scoliosis and IPDs. Level of Evidence. V- Expert opinion

State of the Art and Science of Immunocytochemistry.

Immunocytochemistry (ICC) is a widely available and extensively used ancillary method in diagnostic cytopathology with great variability in all test phases and a low level of adequate quality management. The non-standardized ICC landscape is now challenged with the introduction of the new European (EU) In Vitro Diagnostic Medical Devices Regulation (IVDR). According to this regulation, ICC on cytological slides falls under the category of Laboratory-Developed Tests (LDT), which requires rigorous standardization, validation, and thorough quality management. Complete standardization of pre-analytical and analytical steps in ICC is impossible due to the complexity of the method and the constantly evolving antibodies, detection systems, and platforms. However, similar to the approach in immunohistochemistry, improving and standardizing "best practices" in quality management will result in high-quality, correct, accurate, and reliable ICC results. In this review, the current challenges of ICC in diagnostic cytopathology will be discussed, along with practical insights into ICC standardization and validation. Control slides prepared in the same manner as the patient samples, optimized ICC protocols, and participation in external quality control for ICC are the pillars of good quality management and essential to ensure safe and reliable patient diagnostics.

Establishing Quality Assurance for HIV-1 Rapid Test for Recent Infection in Thailand through the Utilization of Dried Tube Specimens.

The present study focuses on establishing the quality assurance of laboratories for recent infections (RTRI) in Thailand. We developed a cold-chain independent method, using fully characterized plasma obtained from the Thai Red Cross Society, and prepared as dried tube specimens (DTS). Twenty microliters of HIV-seronegative, recent, and long-term infected samples were aliquoted into individual tubes and dried at room temperature, 20-30 degrees Celsius, in a biosafety cabinet overnight to ensure optimal preservation. The DTS external quality control and external quality assessment were tested for homogeneity and stability following the ISO/Guide 35 guidelines. The DTS panels were distributed to 48 sites (FY 2022) and 27 sites (FY 2023) across 14 and 9 provinces, respectively, in Thailand. The results from participating laboratories were collected and evaluated for performance. The results were scored, and acceptable performance criteria were defined as the proportion of panels correctly tested, which was set at 100%. The satisfactory performance ranged from 96% to 100% and was not significantly different among the 13 health regions. The developed and implemented DTS panels can be used to monitor the quality of RTRI testing in Thailand.

Lazertinib versus Platinum-Based Chemotherapy with Epidermal Growth Factor Receptor (EGFR)-Positive Non-Small-Cell Lung Cancer after Failing EGFR-Tyrosine Kinase Inhibitor: A Real-World External Comparator Study.

Lazertinib is a third-generation tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR-TKI) that selectively inhibit common EGFR mutation and T790M mutation in non-small-cell lung cancer (NSCLC) patients. No previous studies have compared lazertinib to platinum-based chemotherapy. We have compared lazertinib with platinum-based chemotherapy in EGFR-mutated NSCLC patients after previous EGFR-TKI therapy. We retrospectively compared 200 patients from LASER201, LASER301, and LASER-PMS studies to 334 patients who were treated with platinum-based chemotherapy after previous EGFR-TKI from the Samsung Medical Center. After propensity score matching (PSM), we selected 156 patients from each group. The primary outcome was progression-free survival (PFS), with overall survival (OS), objective response rate (ORR), and time to treatment discontinuation (TTD) as secondary outcomes. The median follow-up of PFS was 15.61 months in the lazertinib group and 21.67 months in the external control group. The PFS was significantly longer in patients who were treated with lazertinib than those treated with platinum-based chemotherapy (10.97 months vs. 5.10 months; adjusted hazard ratio (HR) 0.40; 95% confidence interval (CI), 0.29-0.55; p < 0.01) after PSM. Lazertinib showed superior OS (32.23 months vs. 18.73 months; adjusted HR 0.45; 95% CI, 0.29-0.69; p < 0.001), ORR (64.1% vs. 47.4%), and TTD (11.66 months vs. 6.73 months; adjusted HR 0.54; 95% CI, 0.39-0.75; p < 0.001) compared to platinum-based chemotherapy. Based on this retrospective, external control study, lazertinib has demonstrated significantly better efficacy compared with platinum-based chemotherapy. The external controls provide important context to evaluate efficacy in single-arm studies.

DEVELOPMENT OF AN INFORMATION AND LOGIC MODEL FOR PREVENTING EMERGENCIES DUE TO IMPACT ON PROTECTIVE ELEMENTS OF SMALL SHELTER FACILITIES BY SHOCK AND IMPULSE LOAD

The article examines problems of preventing emergencies due to damage to small shelter facilities caused by the impact of unmanned aerial vehicles (UAVs), which, in turn, leads to shock-impulse loading of their upper hemisphere and the following destruction. The development of a civilian protection system against terrorist attacks on civilian infrastructure in the form of an extensive network of small shelter facilities increases the level of individual and collective protection of the population, especially in cities that fall within the area of enemy missile and artillery strikes. Therefore, when designing and building settlements, it is necessary to provide for the possibility of protecting the civilian population from both shrapnel-type damage, which already has a practical implementation in existing projects, and from possible high-precision destruction of the upper hemisphere of small shelter facilities by a UAV warhead of high explosive or thermobaric type. Relevant design solutions should focus on preventing terrorist emergencies due to shock-impulse loading of the upper hemisphere of small shelters, which is formed by considering the information-logic model for preventing local-level emergencies due to shock-impulse loading of small shelter facilities. The information-logic model assumes the existence of two security management loops for a small shelter: external and internal. It is worth noting that the external loop is an integral part of the overall urban (regional) air defence system and includes the block of measures to directly affect the threat (striking UAV) in the form of firearms and electronic warfare. The result of the successful development of management decisions by the external control loop is eliminating the threat of an enemy attack UAV. On the other hand, the experience and individual elements of the UAV are the basis for the formation of initial conditions of the mathematical model for preventing terrorist emergencies due to the shock and impulse load of small shelter facilities. The initial conditions represent the result of the development of two consecutive blocks: a block for collecting UAV characteristics and a block for analysing the shock-impulse load that occurs or is predicted based on the characteristics of the attacking UAV. The basis of the internal control loop is the mitigation design unit, which determines further information exchange within this loop. In particular, it triggers the block for improving the effectiveness of protection, which receives statistical and predictive information on emergencies that have occurred (nature of damage and consequences). It allows for continuous updating of information on the characteristics of construction materials used in the construction of shelter facilities and the effectiveness of design solutions, forming characteristics of a small shelter. The result of the corresponding block is the formation of boundary conditions of the mathematical model for preventing terrorist emergencies due to the shock and impulse loading of small shelters. The basis of the block for forming the coupling equation of the mathematical model for preventing terrorist emergencies due to shock-impulse loading of small shelter facilities is the theoretical and practical achievements of the theory of reliability and its derivative theory of plasticity. An appropriate solution to the problem of preventing terrorist emergencies due to shock and impulse loading of small shelter facilities allows further implementation of management decisions to improve the efficiency of protection. Thus, the study solved an urgent scientific problem, namely, the formation of an information-logical model for the prevention of local-level emergencies due to shock-impulse loading of small shelter facilities, the implementation of which allows to form management decisions to improve the security of small shelters and is the basis for further development of an appropriate mathematical model and methodology. Keywords: information-logic model, shock-impulse load, small shelter facility, emergency.

The effect of external fixator on bone metabolism in patients with open fracture of extremities.

This experiment aimed to explore the influence mechanism of external fixator on open fracture. A total of 128 patients with open tibiofibular fractures were included in this study. The patients were randomly divided into external fixator group (n=64) and control group (n=64) according to the order of admission. Double-blind controlled observation was used. The levels of osteocalcin (BGP), β-CTX, P1 NP, BALP, including haptoglobin (Hp), ceruloplasmin (CER), serum adrenocorticotropic hormone (ACTH), cortisol (COR), C-reactive protein (CRP), white blood cell (WBC) and interleukin-6 (IL-6) were recorded in different groups. The postoperative VAS score and quality of life were recorded. Log-rank was used to analyze the difference in postoperative adverse reaction rates among different groups. External fixation stent treatment increased BGP, PINP, and BALP expression and decreased β-CTX, Hp, CER, ACTH, COR, CRP, WBC, and IL-6 levels. Patients in the external fixation stent group had significantly lower VAS score quality of life scores and incidence of adverse events than the control group. External fixation stents protect open fracture patients by promoting bone metabolism.

Age and orbital forcing in the upper Silurian Cellon section (Carnic Alps, Austria) uncovered using the WaverideR R package

The type-Silurian Cellon section in the Carnic Alps in Austria underpins much of the current Silurian conodont zonations, forming the basis for the Silurian timescale. However, the Silurian record of the Cellon section lacks radiometric and astrochronological age constraints, making it difficult to gain insights into the processes pacing Silurian (anoxic) events. To attain age constraints and investigate the pacing Silurian (anoxic) events by astronomical cycles, a cyclostratigraphic study was conducted on high-resolution pXRF (CaO, Al2O3, and Fe2O3) and induration records spanning the Ludlow and Pridoli parts of the Cellon section. Astronomical cycles ranging from precession to the 405-kyr eccentricity cycle were first recognised visually in the field and in proxy records. The visual detection of astronomical cycles served as an input for the WaverideR R package, enabling the tracking of the 405-kyr eccentricity period in each proxy’s continous wavelet transform scalograms. These tracked period curves were combined with external age controls through multiple Monte Carlo simulations, generating an (absolute) age model. This age model is used to assign ages and durations and their respective uncertainties to a hiatus in the Ludfordian, conodont zones, lithological units, geochronological units and events, yielding new ages for Silurian stage boundaries (e.g., Gorstian-Ludfordian boundary at 425.92 ± 0.65 Ma, the Ludfordian-Pridoli boundary at 423.03 ± 0.53 Ma, the Silurian-Devonian boundary at 418.86 ± 1.02 Ma), and new durations for the Ludfordian at 2.89 ± 0.35 Myr and Pridoli at 4.24 ± 0.46 Myr. Furthermore, the imprint of astronomical cycles in the Cellon section itself indicates that the Linde, Klev and Silurian-Devonian boundary events all occur after a 2.4-Myr eccentricity node, indicating pacing by astronomical forcing, similar to other Devonian and Cretaceous anoxic events. The Lau event, however, does not appear to coincide with a 2.4-Myr eccentricity node.

A principal-agent analysis of inter-agency cooperation in EU border management

ABSTRACT In the wake of the 2015 Migration Crisis, the European Union has embarked on an extensive process to reinforce external border controls and make horizontal cooperation between EU agencies critical. This article leverages the principal-agent model to elucidate the impact of inter-agency cooperation on agency autonomy and, by extension, the management of the EU’s external borders. The findings reveal that inter-agency cooperation leads to a situation in which the participating agencies enjoy more room for manoeuvre than originally granted by the EU legislature. This research sheds light on the proactive efforts of the concerned agencies in working alongside their counterparts to bolster their institutional standing and policy turf, thereby fuelling the institutionalisation of joint implementation in EU border management.

Thermosensory Spiking Activity of Proteinoid Microspheres Cross-Linked by Actin Filaments.

Actin, found in all eukaryotic cells as globular (G) or filamentous (F) actin, undergoes polymerization, with G-actin units changing shape to become F-actin. Thermal proteins, or proteinoids, are created by heating amino acids (160-200 °C), forming polymeric chains. These proteinoids can swell in an aqueous solution at around 50 °C, producing hollow microspheres filled with a solution, exhibiting voltage spikes. Our research explores the signaling properties of proteinoids, actin filaments, and hybrid networks combining actin and proteinoids. Proteinoids replicate brain excitation dynamics despite lacking specific membranes or ion channels. We investigate enhancing conductivity and spiking by using pure actin, yielding improved coordination in networks compared with individual filaments or proteinoids. Temperature changes (20 short-peptide supramolecular C to 80 °C) regulate conduction states, demonstrating external control over emergent excitability in protobrain systems. Adding actin to proteinoids reduces spike timing variability, providing a more uniform feature distribution. These findings support theoretical models proposing cytoskeletal matrices for functional specification in synthetic protocell brains, promoting stable interaction complexity. The study concludes that life-like signal encoding can emerge spontaneously within biological polymer scaffolds, incorporating abiotic chemistry.