Maximum Effect Research Articles

Population pharmacokinetic and pharmacodynamic model of evogliptin: Severe uremia increases the bioavailability ofevogliptin.

Uremia, a condition characterized by the retention of uremic toxins due to impaired renal function, may affect drug metabolism mediated by CYP3A4 enzymes. Evogliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor diabetic drug that is primarily metabolized by CYP3A4. This study aimed to construct a population pharmacokinetic (PK) and pharmacodynamic (PD) model for evogliptin in patients with varying degrees of renal disease, including end-stage renal disease on hemodialysis. A total of 688 evogliptin concentration and 598 DPP-4 activity data were available from 46 subjects. PK and PD data analyses were performed using a nonlinear mixed-effects model. The PK of evogliptin was optimally described by a two-compartment model with first-order absorption. The significant covariates in the final model included blood amylase and triglyceride on F1 (relative bioavailability). The simulation findings, together with previously reported PK data, provided evidence of a significant inhibition of the first-pass effect of evogliptin in patients with renal impairment. A direct link sigmoidal Emax model was developed to describe the relationship between evogliptin concentration and DPP-4 inhibition. The PD model predicted significant inhibition of DPP-4 at maximum effect (Emax: 88.9%) and a low EC50 value (1.08 μg/L), indicating the high potency and efficacy of evogliptin. The developed PK/PD model accurately predicted exposure and the resulting DPP-4 activity of evogliptin in renal impairment. The findings of this study suggest that renal impairment and associated biochemical changes may impact the bioavailability of CYP3A4-metabolized drugs.

Optimization of Photocatalytic Degradation of Rhodamine B and Indigo Carmine Dyes Using Eco‐Friendly Kaolinite‐Silver Oxide Quantum Dots Nanocomposite Under Sunlight Irradiation

ABSTRACTIn this work, we present a simple method for the pyrofabrication of a new kaolinite‐ silver oxide quantum dots nanocomposite (Kao‐Ag2O/QDs) that is used for the degradation of rhodamine B (RhB) and indigo carmine (IC) dyes. A homogenous combination of kaolinite and silver nitrate was sintered up to 350 °C to create the extremely effective photocatalyst (Kao‐Ag2O/QDs). Various analytical techniques were employed to characterize the Kao‐Ag2O/QDs photocatalyst such as XRD, FTIR, XPS, SEM–EDX, TEM, DTA/TGA, ZP, BET, and UV–Vis DRS. The degradation of RhB and IC dyes through the photocatalyst was carried out in aqueous solutions utilizing several pH dye solutions and sustainable solar energy in atmosphere conditions. The nanocomposite that was prepared had shown an enhanced specific surface area of 53.3005 m2/g, a pore size of 8.1197 nm, and a total pore volume of 0.216 cm3/g. It also displayed an optical band gap energy of 2.9 eV. The study creates that employing the ideal dose of 2000 and 1500 mg/L of the Kao‐Ag2O/QDs photocatalyst at neutral conditions (pH = 7) resulted a maximum degradation effectiveness of RhB and IC of 91.06 and 93.46% after 90 min, respectively. RhB and IC dyes degradation followed Langmuir first‐order kinetics with a rate constant of 0.0217 and 0.0216 min−1 at pH = 7, respectively. The photocatalytic degradation activity for RhB dye is based on hydroxyl radicals (˙OH) and superoxide radicals (˙O2−), while the mechanism of IC removal is based on superoxide radicals (˙O2−), as revealed by scavenger‐based radical trapping studies. A triple reusability study found that the Kao‐Ag2O photocatalyst is highly stable with degradation efficiencies of RhB and IC dyes from the initial 91.09 to 90.04, 88.54, and 86.27% and from the initial 93.46 to 92.8, 91.4 and 89.32%, respectively. The optimal situations for the parameters were identified by the Box–Behnken design (BBD), which was well matched with photocatalytic degradation tests.

Medication adherence and antithrombotic therapy outcomes: insights from a post-hoc analysis of the AFIRE trial

Abstract Background The AFIRE (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease) trial established noninferiority in efficacy and superiority in safety endpoints of rivaroxaban monotherapy over rivaroxaban plus antiplatelet therapy (combination therapy) in patients with atrial fibrillation (AF) and stable coronary artery disease (CAD). However, the impact of medication adherence to rivaroxaban on AFIRE study outcomes remains unclear. Purpose This post-hoc analysis aimed to explore the influence of medication adherence on AFIRE trial results. Methods Among 2,120 patients, participants were classified into adherent and non-adherent groups based on self-reported measures, which were further verified through on-site visits to the facilities. Adherent patients were defined as those who reported consistently taking their medication as prescribed. The primary efficacy endpoint comprised stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or all-cause death, including cerebral events. Analysis also examined differences in the primary efficacy endpoint between adherent and non-adherent patients. Results Of the 2,120 patients, 2,012 (94.9%) were adherent to rivaroxaban, while 108 (5.1%) were non-adherent. Among adherent patients, rivaroxaban monotherapy showed significantly better efficacy outcomes compared to combination therapy (hazard ratio [HR] 0.73; 95% confidence interval [CI] 0.54–0.98; p=0.04, Figure 1A). However, primary efficacy outcomes did not significantly differ among non-adherent patients (HR 0.64, 95% CI 0.23–1.81, p=0.40, Figure 1B). Adherent patients exhibited improved outcomes relative to non-adherent patients, though this difference was not statistically significant (HR 1.68; 95% CI 0.99–2.85; p=0.05, Figure 2A). In clinically high-risk patients with a history of angina pectoris, those who demonstrated adherence to medication (n=1281) exhibited significantly better efficacy outcomes compared to non-adherent patients (n=68) (HR 1.97; 95% CI 1.09–3.56; p=0.03, Figure 2B). Conclusions Rivaroxaban monotherapy versus combination therapy showed favorable efficacy outcomes in patients with good adherence, consistent with the overall AFIRE trial. However, these benefits were not observed in non-adherent patients. Adherence to rivaroxaban is crucial for achieving its maximum therapeutic effect as monotherapy.Figure1Figure2

A prospective analysis of the efficacy and safety of ethacizine during premature atrial contractions and premature ventricular contractions

Abstract Background Ethacizine, a class Ic antiarrhythmic agent, is prescribed for managing severe or refractory supraventricular and ventricular arrhythmias, including premature atrial (PACs) and ventricular contractions (PVCs). Despite its use, there is a lack of substantial research exploring the therapeutic effects of ethacizine at present. Purpose The study evaluated the efficacy and safety of ethacizine in addressing PACs and PVCs, in cases where other antiarrhythmic medications proved ineffective. Methods We performed a prospective analysis of ethacizine treatment (50 mg. b.i.d.) for early (30-45 days) and late periods (150-210 days), in male (n=58; 59.2%) and female (n=40; 40.8%) patients aged ≥ 18 years (18-72 y.o; mean age 45 years), with 46 cases of PACs and 52 cases of PVCs, who had previously been treated with another antiarrhythmic medication (bisoprolol, metoprolol, sotalol, verapamil, amiodarone, or propafenone) and had not achieved the target rate of extrasystoles (≤1000/24h). Results The findings reveal a substantial decrease in the mean parameters of PACs during both, the early period (initial 6877 ± 2432, following 761 ± 341); (88,9%); t([45]) = [13,336], p = [< .001) and the late period (initial 6877 ± 2432, following 574 ± 294); (91,7%); t([45]) = [15,124], p = [< .001). The quantitative reduction in PACs reached a maximum of 93.8% in the early period (19406 PACs □ 1211 PACs) and 94.3% in the late period (19406 PACs □ 1105 PACs). The mean parameters of PVCs in the early period experienced a significant reduction (initial 3205 ± 1145, following 550 ± 194); (82,8%); t([51]) = [8,284], p = [< .001). Similarly, the mean PVC values in the late period exhibited a noteworthy decrease (initial 3205 ± 1145, following 490 ± 181); (84,8%); t([51]) = [8,553], p = [< .001). For PVCs, the maximum effect observed in the early period was 94.8% (18929 PVCs □ 989 PVCs), and in the late period, it reached 95% (18929 PVCs □ 950 PVCs). The target rate in the late period (≤1000/24h.) for PACs reached 89%, and for PVCs - 86% (Figure 1). Adverse effects were noted in a mere four subjects (4%). These events manifested as 2nd-degree AV block (Mobitz 1), sustained ventricular tachycardia, asymptomatic nonsustained polytopic ventricular tachycardia, and asymptomatic transient ST-segment elevation observed through 24-hour ECG holter monitoring. Conclusion A prospective study on ethacizine treatment (50 mg. b.i.d.) confirmed its effectiveness and safety in reducing PACs and PVCs. It demonstrated a sustained reduction in extrasystole occurrences for an extended period, achieving the target rate with minimal side effects. Ethacizine merits consideration for addressing extrasystolic arrhythmia, particularly in cases where other antiarrhythmic medications prove ineffective.Results of the study

COMPARATIVE STUDY OF BIOACTIVE COMPOUNDS IN MILK THISTLE SEED VARIETIES IN SULAIMANI, IRAQ

This study was conducted using two different varieties of milk thistle, var. marianum, and var. albiflorum. The plant samples were collected from the Sulaimani region to determine silymarin content, bioactive constituents, and antioxidant activity. HPLC analysis showed that var. marianum contains a high amount of silymarin (365.680±3.815 mg/g). Silybin B, Silychristin A, and Silybin A were the major flavonolignans in these varieties—the var. marianum contains silybins B, silychristin A, and silybin A (174.880±6.495, 86.720±2.113, and 54.960±2.483 mg/g) respectively. The hexane extract analysis of milk thistle seeds of the marianum and albiflorum varieties identified 26 (95.229±1.318) and 19 (94.547±6.541) phytochemical compounds, respectively. Both varieties contain a higher amount of oleic acid, which was found to be 14.800±0.481 and 31.940±0.726 in both varieties, respectively. This study evaluates the scavenging effect of milk thistle plants using a DPPH assay. The result indicated that the var. marianum had a maximum scavenging effect of 72.944% compared to the var. albiflorum, (61.846%). The stronger IC50 was obtained by var. marianum with 17.027±0.064 µg/mL.

Development of the calf grimace scale for pain and stress assessment in castrated Angus beef calves

Grimace scales have been used to assess pain in various animal species. This study aimed to develop the calf grimace scale (CGS), evaluate its responsiveness and the effect of external factors (change of environment and dam separation, and restraint) on CGS. Sixty-nine Angus calves, 6–8 weeks old, were randomly allocated into castrated (n = 34) and sham castrated (n = 35) groups. Images were extracted from videos pre- (M1-M4), during- (M5), and post-castration/sham castration (M6, M7). Six facial action units (FAUs) were identified: ear position, orbital tightening, tension above the eye, nostril dilation, straining of chewing muscle, and mouth opening. Final CGS median scores increased after castration (P < 0.001) for both non-restrained (M7 versus M2) and restrained (M6 versus M3) calves, indicating scale responsiveness. Final CGS median scores increased (P < 0.001) when calves were subjected to external factors before castration (M1 [baseline] versus M2 and M3). However, there was no difference (P > 0.05) in CGS median scores before and after sham castration, regardless of restraint (M3 versus M6, and M2 versus M7), indicating that the external factors may have reached a maximum effect. The CGS is composed of six FAUs, responsive to acute pain and can identify stress unrelated to pain.

Development of Technology for the Synthesis of Nanocrystalline Cerium Oxide Under Production Conditions with the Best Regenerative Activity and Biocompatibility for Further Creation of Wound-Healing Agents

Background/Objectives: The issue of effective wound healing remains highly relevant. The objective of the study is to develop an optimal method for the synthesis of nanosized cerium oxide powder obtained via the thermal decomposition of cerium carbonate precipitated from aqueous nitrate solution for the technical creation of new drugs in production conditions; the select modification of synthesis under different conditions based on the evaluation of the physicochemical characteristics of the obtained material and its biological activity, and an evaluation of the broad-spectrum effect on cells involved in the regeneration of skin structure as well as antimicrobial properties. Methods: Several modes of the industrial synthesis of cerium dioxide nanoparticles (NPs) were carried out. The synthesis stages and the chemical and physical parameters of the obtained NPs were described using transmission electron microscopy (TEM), X-ray diffraction, Raman spectroscopy, and mass spectrometry. The cell cultures of human fibroblasts and keratinocytes were cultured with different concentrations of different nanoceria variations, and the cytotoxicity and the metabolic and proliferative activity were investigated. An MTT test and cell counting were performed. The antimicrobial activity of CeO2 variations at a concentration of 0.1–0.0001 M against Pseudomonas aeruginosa was studied. Results: The purity of the synthesized nanoceria powders in all the batches was &gt;99.99%. According to TEM data, the size of the NPs varied from 1 nm to 70 nm under different conditions and methodologies. The most optimal technology for the synthesis of the nanoceria with the maximum biological effect was selected. A method for obtaining the most bioactive NPs of optimal size (up to 10 nm) was proposed. The repeatability of the results of the proposed method of nanoceria synthesis in terms of particle size was confirmed. It was proven that the more structural defects on the surface of the CeO2 crystal lattice, the higher the efficiency of the NPs due to oxygen vacancies. The strain provided the best redox activity and antioxidant properties of the nanoceria, which was demonstrated by better regenerative potential on various cell lines. The beneficial effect of synthesized nanoceria on the proliferative and metabolic activity of the cell lines involved in skin regeneration (human fibroblasts, human keratinocytes) was demonstrated. The antimicrobial effect of synthesized nanoceria on the culture of the most-resistant-to-modern-antibiotics microorganism Pseudomonas aeruginosa was confirmed. The optimal concentrations of the nanoceria to achieve the maximum biological effect were determined (10−3 M). Conclusions: It was possible to develop a method for the industrial synthesis of nanoceria, which can be used to produce drugs and medical devices containing CeO2 NPs.

Effects of meteorological factors on tuberculosis and potential modifiers in Zhejiang Province, China

Although some studies have explored the role of meteorological factors in the development of tuberculosis (TB), the majority have been confined to single regions, leading to inconsistent findings. Consequently, we conducted a multi-city study not only to determine whether meteorological factors significantly influence the risk of developing TB but also to assess the magnitude of these effects and explore potential modifying factors. Data on daily reported TB cases and meteorological factors were collected from January 1, 2013, to December 31, 2022, across 11 cities in Zhejiang Province. A distributed lag non-linear model using a quasi-Poisson distribution was employed. Multivariate meta-regression was used to obtain overall pooled estimates and assess heterogeneity. From 2013 to 2022, 267,932 TB cases were reported in Zhejiang Province. Notably, a nonlinear relationship was observed between temperature and TB, with the relative risk (RR) peaking at 1.0 °C (RR = 1.882, 95% CI 1.173–3.020). The effect of low temperature was immediate and significant for a 13-day lag period, with the maximum effect at lag0 (RR = 1.014, 95% CI 1.008–1.021). The exposure-response curve between relative humidity (RH) and TB exhibited an M-shape, with the RR peaking at 47.7% (RR = 1.642, 95% CI 1.044–2.582). The lag effect of low RH was significant at lag 25–59, with the highest RR observed at lag 32 (RR = 1.011, 95% CI 1.001–1.022). Gross domestic product (GDP) per person, population density, and latitude demonstrated significant modification effects. Our study showed that low temperature and RH were associated with an increased risk of TB. Additionally, GDP per person, population density, and latitude may play important roles in explaining the association between RH and TB. These findings provide scientific evidence for the development of geographically specific public health policies.

Evaluating the Potential of Marine Algae as Sustainable Ingredients in Poultry Feed

Algae are a complex source of crucial nutrients, including proteins, minerals, vitamins, and carbohydrates. The use of marine algae, specifically Sargassum species, Gracilaria species, and Spirulina species, as feed ingredients in poultry feed was examined in the current research. This study’s aims were to carry out lipid profiling, proximate analysis, and heavy metal toxicity testing, as well as to evaluate the presence of hazardous hydrocarbons in the algae and investigate the effect of the fatty acid profile of Sargassum species on broilers. The proximate analysis was conducted on the algae types containing considerable quantities of fats and proteins and a sizable quantity of omega-3 fatty acids. This research assessed the productive effectiveness of broilers with 2.5%, 6%, and 10% algal additions in their diet. Fatty acid profiling of Sargassum species was performed at 1% and 2% levels in the bursa, fat pads, heart, liver, spleen, thymus, thighs, and breast. The findings showed no significant differences in the development performance or feed utilization efficiency of broilers with 2.5%, 6%, and 10% algae supplementation in their diet. The results of fatty acid profiling showed changes in the heart, liver, and spleen at 1% and 2% supplementations levels. However, this research concludes that if algae partially replaces the imported feed proteins used in animal feed, then these can achieve maximum beneficial effects on poultry health and performance. Algae are sustainable, easy to produce, and cost-effective sources of nutrients and contain numerous bioactive compounds, which will contribute to sustainability and food safety.

MARKETING IN THE SPHERE OF PUBLIC ADMINISTRATION

The article reveals the relevance of using marketing tools in the field of public administration. The concept of «marketing» is analyzed, the approaches of modern scientists to this concept are considered. Today, there are about 2,000 definitions of the concept of «marketing», in which the main tasks, processes and concepts of marketing are reflected in various combinations. A significant impact on the variety of definitions of marketing was made by the variety of points of view on the goals, objectives and content of marketing and marketing activities. Quite often, definitions of marketing are based on concepts of an economic nature (for example, profit maximization, increasing income, market, competitiveness, etc.), on management concepts (planning, regulation, organization, etc.). Emphasis is placed on a large number of derivative concepts of marketing, including «state marketing», «territorial marketing», «regional marketing», etc. It is indicated that marketing in the field of public administration is, first of all, an approach in public administration that puts the satisfaction of consumers and producers of public services in a prominent place, which acts as a specific form of marketing implementation. More specifically, this is the marketing activity of management bodies and/or their representatives who act as producers, consumers or intermediaries (suppliers) in the processes of exchange of goods, services, ideas and other values. The tools of state marketing were proposed, and the results of the use of the tools were analyzed. An analysis of the main types of marketing in the field of public administration was carried out: macro-marketing; direct state marketing; state internet marketing; de-marketing This classification is generally correct, as it takes into account the subject composition and various goals of marketing in the field of public administration. It has been proven that marketing in the field of public administration is based on real mechanisms of market functioning, and is also focused on achieving the maximum social effect from increasing the degree of satisfaction of the needs of the country's population. It is proven that the state uses marketing tools in its policy. However, so far it has a single character, and the use of such tools should be systematic. The application of marketing in the field of public administration and the activities of public bodies can be a means of achieving and increasing the competitiveness of both the national economy and the entire national state.

Exposure-Response Analysis of Tofacitinib in Active Psoriatic Arthritis: Results from Two Phase 3 Studies.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). These post hoc exposure-response (E-R) analyses of pooled data from two Phase 3 studies (NCT01877668 and NCT01882439) characterized the relationships between tofacitinib exposure and efficacy (American College of Rheumatology [ACR] criteria), and changes in hemoglobin (Hgb) in patients with PsA. Efficacy data for the proportion of patients receiving tofacitinib 5 or 10 mg twice daily, or placebo, achieving ACR ≥20%, ≥50%, or ≥70% response criteria (ACR20, ACR50, and ACR70, respectively) at Month 3, were modeled jointly using a four-category ordered categorical exposure-response model (ACR20 non-responder, ACR20 responder but not ACR50 responder, ACR50 responder but not ACR70 responder, and ACR70 responder). A maximum drug effect (Emax) model (using average concentrations of tofacitinib at steady state [Cavg]) adequately described the exposure-ACR response rate relationship. Model-predicted response rates for tofacitinib 5 and 10 mg twice daily were 51% and 58%, respectively, for ACR20; 29% and 36% for ACR50; and 15% and 20% for ACR70. The E-R relationship between tofacitinib exposure and changes in Hgb was assessed using an indirect response model, which generally predicted Hgb concentration-time profiles across treatments well. The proportions of patients experiencing a decrease in Hgb of >2 g/dL were similar with tofacitinib 5 mg twice daily or placebo. These results were generally consistent with previous analyses in rheumatoid arthritis and psoriasis, and support the use of tofacitinib 5 mg twice daily for active PsA.

Improved Malaria Therapy with Cationic Nanocapsules Demonstrated in Plasmodium berghei-Infected Rodents Using Whole Blood Surrogate Population PK/PD Modeling

Objectives: Investigating how nanoparticle systems interact in whole blood (WB) is critical to evaluating the effectiveness of malaria therapy. Methods: We decided to establish a pharmacokinetic/pharmacodynamic (PK/PD) model of the quinine population in WB using Plasmodium berghei-infected mice, with a subsequent model comparison for nanocapsules coated with polysorbate (NCP80) or prepared with Eudragit® RS (NCEUD). The WB quinine population pharmacokinetic model in rats was developed using plasma and partition coefficients for rat erythrocytes. Mouse WB quinine population PK/PD modeling was developed using allometrically scaled literature-free mouse quinine pharmacokinetic data and covariate values to obtain a WB population pharmacokinetic model for quinine and nanocapsules in mice. This allowed for PK/PD modeling of the quinine population with the WB concentration and parasitemia data in mice. All models were built in NONMEN. Results: The WB quinine concentration profiles in rats were characterized using a two-compartment model. Nanoencapsulation reduced clearance and central compartment volume and increased peripherical compartimental volume. A maximum effect model described the PK/PD of the quinine WB population in mice, demonstrating that NCEUD enhances the antimalarial effect. Conclusions: Quinine WB is a good surrogate for describing the response to exposure in malaria. NCEUD outperformed NCP80 and free quinine, suggesting that cationic surfaces improve the potential for treating malaria.

MIRD Pamphlet No. 31: MIRDcell V4-Artificial Intelligence Tools to Formulate Optimized Radiopharmaceutical Cocktails for Therapy.

Radiopharmaceutical cocktails have been developed over the years to treat cancer. Cocktails of agents are attractive because 1 radiopharmaceutical is unlikely to have the desired therapeutic effect because of nonuniform uptake by the targeted cells. Therefore, multiple radiopharmaceuticals targeting different receptors on a cell is warranted. However, past implementations invivo have not met with convincing results because of the absence of optimization strategies. Here we present artificial intelligence (AI) tools housed in a new version of our software platform, MIRDcell V4, that optimize a cocktail of radiopharmaceuticals by minimizing the total disintegrations needed to achieve a given surviving fraction (SF) of tumor cells. Methods: AI tools are developed within MIRDcell V4 using an optimizer based on the sequential least-squares programming algorithm. The algorithm determines the molar activities for each drug in the cocktail that minimize the total disintegrations required to achieve a specified SF. Tools are provided for populations of cells that do not cross-irradiate (e.g., circulating or disseminated tumor cells) and for multicellular clusters (e.g., micrometastases). The tools were tested using model data, flow cytometry data for suspensions of single cells labeled with fluorochrome-labeled antibodies, and 3-dimensional spatiotemporal kinetics in spheroids for fluorochrome-loaded liposomes. Results: Experimental binding distributions of 4 211At-antibodies were considered for treating suspensions of MDA-MB-231 human breast cancer cells. A 2-drug combination reduced the number of 211At decays required by a factor of 1.6 relative to the best single antibody. In another study, 2 radiopharmaceuticals radiolabeled with 195mPt were each distributed lognormally in a hypothetical multicellular cluster. Here, the 2-drug combination required 1.7-fold fewer decays than did either drug alone. Finally, 2 225Ac-labeled drugs that provide different radial distributions within a spheroid require about one half of the disintegrations required by the best single agent. Conclusion: The MIRDcell AI tools determine optimized drug combinations and corresponding molar activities needed to achieve a given SF. This approach could be used to analyze a sample of cells obtained from cell culture, animal, or patient to predict the best combination of drugs for maximum therapeutic effect with the least total disintegrations.

Synergistic inhibition effect and mechanism of an inhibitor for entire process inhibition of coal spontaneous combustion

Traditional coal spontaneous combustion (CSC) inhibitors, while effective, have limitations such as frequent application or short-term efficacy. To this end, we developed a slow-release and water-soluble synergistic inhibitor (SWSI) to achieve long-term CSC inhibition. The SWSI was formulated by integrating synergistic antioxidants (SA) composed of ascorbic acid (AsA) and Fe-superoxide dismutase (Fe-SOD) dissolved in a super absorbent polymer (SAP) encapsulated within hydrogel microcapsules. The effectiveness of SWSI was evaluated through simultaneous thermal analysis and in-situ free radical tests. The formulation optimization demonstrated that AsA and Fe-SOD had the maximum synergistic inhibition effect at a 1:1 molar ratio. The optimal SA: SAP ratio of 3:1 achieved the lowest oxygen consumption rate and highest inhibition rate. The encapsulation formulation, consisting of 3% SA, 6% PAM, 1% CaCl2, and 0.5% citric acid, generated the highest swelling ratio. Simultaneous thermal analysis and in-situ free radical tests indicated that SWSI greatly increased feature temperatures and the apparent activation energy, lowered reaction heat, and substantially reduced free radical concentration in the full oxidation process. The newly developed SWSI offers a significant advancement in long-term CSC prevention by integrating physical and chemical inhibition, which provides sustained and effective inhibition throughout the entire oxidation process.

Effect of peptide hydrophilicity on membrane curvature and permeation.

Using a well-developed reaction coordinate in umbrella sampling, we studied the single peptide permeation through a model cancerous cell membrane, varying the hydrophilicity and the charge of the peptides. Two peptides, melittin and pHD108, were studied. The permeation mechanism differs from a barrel-stave-like mechanism to toroidal pore and vesicle formation based on the number and the placement of the hydrophilic amino acids in the peptide. Membrane curvature changes dynamically as the permeation process occurs. In the case of vesicles, the peptide traverses along a smooth, homogenous pathway, whereas a rugged, steep pathway was found when lipid molecules did not line up along the wall of the membrane (barrel-stave-like mechanism). A mechanism similar to a toroidal pore consists of multiple minima. Higher free energy was found for the permeating terminal containing charged amino acid residues. Vesicle formation was found for pHD108 peptide N-terminal with a maximum membrane thinning effect of 54.4% with free energy cost of 8.20 ± 0.10kcal mol-1 and pore radius of 2.33 ± 0.07nm. Insights gained from this study can help to build synthetic peptides for drug delivery.

Effect of 10-valent pneumococcal conjugate vaccine on trends of pneumococcal meningitis in children under five years, Uganda, 2003-2022.

Pneumococcal meningitis, a vaccine-preventable disease caused by Streptococcus pneumoniae (Spn) is the leading bacterial meningitis in under five children. In April 2014, Uganda introduced routine immunization with 10-valent Pneumococcal Conjugate Vaccine (PCV10) for infants. The target coverage for herd immunity is ≥ 90% with three doses (PCV10-dose 3). We assessed the effect of PCV10 introduction and coverage on the trends of pneumococcal meningitis in under five children. We analyzed laboratory-confirmed pediatric bacterial meningitis (PBM) data at two high-volume WHO-accredited sentinel surveillance hospitals in Kampala City and Gulu District, from 2003 to 2022. We used confirmed cases to estimate the minimum incidence of pneumococcal meningitis in the host districts and calculated annual incidence of pneumococcal meningitis per one million populations, and the proportion of confirmed PBM attributable to Spn. We divided the study period into 2003-2013 (pre-PCV10) and 2014-2022 (post-PCV10), and conducted interrupted time series analysis using autoregressive integrated moving average models for the effect of PCV10 on trends of pneumococcal meningitis and PBM attributable to Spn. We analyzed reported PCV10 data in DHIS2 from 2014 to 2022 for annual PCV10-dose 3 coverage. Among the 534 confirmed PBM cases, 331(62%) were pneumococcal meningitis; 227(69%) from Gulu District and 104(31%) from Kampala City. The majority (95%) of the isolates were not serotyped. The majority (57%) were male and unimmunized (98%); median age = 14(IQR = 6-27) months with most (55%) aged ≥ 12 months. The case-fatality rate was 9%. During Pre-PCV10 period, the overall incidence of pneumococcal meningitis in the host districts increased; slope change = 1.0 (95%CI = 0.99999, 1.00001) but declined in post-PCV10 period (2014-2022) by 92% from 86 cases /1,000,000 in 2014 to 7/1,000,000 in 2022, slope change= -1.00006 (95%CI=-1.00033, -0.99979). Whereas there was an immediate decline in the proportion of confirmed PBM attributable to Spn in the host districts, level change=-1.84611(95%CI=-1.98365,-1.70856), an upward trend was recorded from 2016 to 2022, slope change = 1.0 (95%CI = 0.99997, 1.00003). During 2015-2022, PCV10-dose 3 coverage was largely > 90% for Gulu District and 52-72% for Kampala City. The PCV10 routine immunization program reduced the incidence of pneumococcal meningitis in Kampala City and Gulu District. There was no effect on the confirmed PBM proportionately attributable to Spn. Kampala City persistently recorded PCV10-dose3 coverage < 90%. We recommend enhancing serotyping and periodic nasopharyngeal carriage surveys to ascertain the maximum vaccine effectiveness and monitor Spn serotypes, and strengthening routine immunization in Kampala City.

The Use of Good Governance Principles in Educational Institution Administration by Administrators of Vocational Educational Institutions in Chonburi Province

Background and Aims: Administrators are considered to be the people who play the most important role in promoting and developing a culture of democracy and good governance in educational institutions. The management ability of the administrators affects various operations in the educational institution in order to achieve maximum efficiency and effectiveness. This research aims to study and compare the use of good governance principles. Including guidelines for managing educational institutions under vocational education in Chonburi Province. Considering the gender, position, and work experience of executives in each area. Methodology: The research sample consisted of 269 administrators and teachers in educational institutions under vocational education in Chonburi Province. The research instrument was a questionnaire with a 5-level rating scale with a confidence value of 0.97 and the concordance value (IOC) ranged from 0.8 to 1.00. There was a question about the use of good governance principles in the management of educational institutions among the said administrators. For data analysis, basic statistics were used, including frequency, percentage, mean, and standard deviation. Including testing with t-test and F-test to get accurate and reliable results. Results: (1) The results of the study found that opinions regarding the use of good governance principles in the administration of educational institutions by administrators under the vocational education department in Chonburi Province Overall it is at a high level. (2) When classifying the use of good governance principles by gender It was found that overall there was no difference. But when considering each aspect It was found that the moral aspect transparency. And the responsibility aspect is significantly different at the 0.05 level, while there is no difference in other aspects. (3) For classification by status It was found that school administrators and teachers used good governance principles in the overall management of educational institutions. But when considering each aspect It was found that the principles of participation responsibility and value for money are significantly different at the 0.05 level, while other aspects are not different. (4) Classification according to work experience It was found that the overall use of good governance principles was not different. But when considering transparency, it was found that there was a statistically significant difference at the 0.05 level. While the rule of law, morality, value for money responsibility and there was no difference in participation. Conclusion: The administration of an educational institution according to the principles of good governance consists of two groups of important people: 1) administrators, who are responsible for setting a clear vision, strategy, and policy for educational institution administration. 2) Teachers, whose role is to perform their duties in teaching and promoting the learning of pupils and students. Using a variety of teaching methods to develop students' full potential.

Experimental study evaluating the performance of thermal conductivity prediction models for air–water saturated weathered sandstone heritage

As a critical parameter, thermal conductivity directly determines the heat transfer and temperature variation within rocks, which can lead to mechanical damage and chemical corrosion. Consequently, understanding the thermal conductivity of stone heritage is vital for assessing their deterioration mechanisms and developing effective conservation strategies. This study obtained sandstone samples from the Yungang Grottoes and subjected them to freeze–thaw cycle experiments to generate weathered sandstone samples. Subsequently, the thermal conductivity of these samples was measured under both dry and water-saturated state using the transient plane source method. To analyze the relationship between air–water saturation, porosity, and thermal conductivity, a saturation influence coefficient was introduced. Thereafter, the effectiveness and applicability of 13 commonly used thermal conductivity mixing law prediction models were evaluated based on experimental data. The results suggested that the influence of water saturation on the thermal conductivity of rocks varies with porosity, and water saturation significantly enhances the thermal conductivity of weathered sandstone. Among the 13 common models, the Geometric mean model was found to be more accurate than other models, with superior performance in both dry (MAE, RMSE, MAPE are 0.148, 0.214, 5.59% respectively) and water-saturated (MAE, RMSE, MAPE are 0.244, 0.170, 8.4% respectively) state. The Albert model demonstrates a good fit in the dry state, whereas the Walsh model (with maximum effect), Ribaud model, and Huang model also exhibit good fitting efficacy in the water-saturated state. This study provides a solid foundation for better predicting the thermal conductivity of weathered stone heritage and developing effective preventive conservation strategies.

Exposure-Efficacy Analysis and Dopamine D2 Receptor Occupancy in Adults with Schizophrenia after Treatment with the Monthly Intramuscular Injectable Risperidone ISM.

Dopamine D2 receptor occupancy (D2RO) significantly influences the clinical effectiveness and safety of many antipsychotic drugs. Maintaining a D2RO range of 65%-80% provides the best antipsychotic effects while minimizing adverse reactions. Data from a Phase III trial were used to establish an exposure-response relationship for monthly intramuscular Risperidone ISM (75 and 100 mg) or placebo administered to adults with schizophrenia. Pharmacodynamic analysis was based on an Emax model for Positive and Negative Syndrome Scale (PANSS) developed in NONMEM. Plasma concentrations of the active moiety were derived using a previously developed population pharmacokinetic model, which was used for D2RO simulations in conjunction with a published Emax model. The optimal D2RO range (65%-80%) was reached for the median within hours following the first injection of both Risperidone ISM doses. At steady state, median D2RO for both doses remained above 65% throughout the 28-day dosing period and demonstrated lower variability than oral risperidone. PANSS response did not differ significantly between dose groups, most likely because active moiety concentrations had already reached the plateau of the concentration-response relationship. The pharmacokinetic/pharmacodynamic analysis showed a profound placebo effect (-11.7%), and an additional maximal drug effect (-6.6%) resulting in a total PANSS improvement over time of -18.3%. Pharmacokinetic/pharmacodynamic modeling quantified a PANSS improvement over time after Risperidone ISM administration. The response was not significantly different in either dose group, likely because D2RO was already above the proposed efficacy threshold (65%) within 1 h after the first Risperidone ISM injection and remained above this level following repeated administrations.

What can optimized cost distances based on genetic distances offer? A simulation study on the use and misuse of ResistanceGA.

Modelling population connectivity is central to biodiversity conservation and often relies on resistance surfaces reflecting multi-generational gene flow. ResistanceGA (RGA) is a common optimization framework for parameterizing these surfaces by maximizing the fit between genetic distances and cost distances using maximum likelihood population effect models. As the reliability of this framework has rarely been studied, we investigated the conditions maximizing its accuracy for both prediction and interpretation of landscape features' permeability. We ran demo-genetic simulations in contrasted landscapes for species with distinct dispersal capacities and specialization levels, using corresponding reference cost scenarios. We then optimized resistance surfaces from the simulated genetic distances using RGA. First, we evaluated whether RGA identified the drivers of the genetic patterns, that is, distinguished Isolation-by-Resistance (IBR) patterns from either Isolation-by-Distance or patterns unrelated to ecological distances. We then assessed RGA predictive performance using a cross-validation method, and its ability to recover the reference cost scenarios shaping genetic structure in simulations. IBR patterns were well detected and genetic distances were predicted with great accuracy. This performance depended on the strength of the genetic structuring, sampling design and landscape structure. Matching the scale of the genetic pattern by focusing on population pairs connected through gene flow and limiting overfitting through cross-validation further enhanced inference reliability. Yet, the optimized cost values often departed from the reference values, making their interpretation and extrapolation potentially dubious. While demonstrating the value of RGA for predictive modelling, we call for caution and provide additional guidance for its optimal use.