Maximum Effect Research Articles

Access to primary care and mortality in excess for patients with cancer in France: Results from 21 French Cancer Registries.

The impact of geographical accessibility on cancer survival has been investigated in few studies, with most research focusing on access to reference care centers, using overall mortality and limited to specific cancer sites. This study aims to examine the association of access to primary care with mortality in excess of patients with the 10 most frequent cancers in France, while controlling for socioeconomic deprivation. This study included a total of 151,984 cases diagnosed with the 10 most common cancer sites in 21 French cancer registries between 2013 and 2015. Access to primary care was estimated using two indexes: the Accessibilité Potentielle Localisée index (access to general practitioners) and the Scale index (access to a range of primary care clinicians). Mortality in excess was modelized using an additive framework based on expected mortality based on lifetables and observed mortality. Patients living in areas with less access to primary care had a greater mortality in excess for some very common cancer sites like breast (women), lung (men), liver (men and women), and colorectal cancer (men), representing 46% of patients diagnosed in our sample. The maximum effect was found for breast cancer; the excess hazard ratio was estimated to be 1.69 (95% CI, 1.20-2.38) 1 year after diagnosis and 2.26 (95% CI, 1.07-4.80) 5 years after diagnosis. This study revealed that this differential access to primary care was associated with mortality in excess for patients with cancer and should become a priority for health policymakers to reduce these inequalities in health care accessibility.

Research on the dangerous scenarios of propylene oxide leakage from tank in a chemical plant in an industrial park of Tongling City, China

ABSTRACT Propylene oxide (PO) is toxic, flammable and explosive. Accidents from the release of PO from large-scale storage tanks can have disastrous consequences associated with meteorological conditions. Therefore, this study explores the dangerous scenarios of PO leakage from a 1000 m3 spherical tank in a chemical plant located in an industrial park during various seasons using the Aerial Location of Hazardous Atmospheres software. Our results show that the maximum hazard distance of poisoning, flash fire and vapour cloud explosion caused by leakage and diffusion from the PO storage tank occur in the summer season and the affected distances were 2900, 372, and 374 m, respectively. In regard the thermal radiation resulting from a pool fire scenario, the longest threat distance was 110 m in the summer. For the boiling liquid expanding vapour explosion (BLEVE), the maximum thermal effect was 2100 m in winter. The BLEVE scenario has the largest impact area and its toxic vapour cloud is the primary accident. Adequate safety management and technical measures should be put in place for the prevention and emergency response of accidental PO release in the factory.

Corporate strategic aggression and environmental investment decisions: Evidence from A-share listed firms

Corporate strategy greatly influences corporate investment activities. This study seeks to better understand the relationship between the level of corporate strategic aggression and environmental investment decisions based on 2011–2020 data. We find that increasing the intensity of strategic aggression effectively increases environmental investment. Moreover, this effect is incentivized by good corporate environmental, social, and governance performance, innovation ability, and management tone manipulation. Although financing constraints may hinder the positive effects of corporate aggression on environmental investment, independent directors and corporate risk promote maximum positive effects. These findings enable companies to identify strategically motivating factors for improving environmental protection.

Evaluation of Bioequivalence and Pharmacokinetic Profiles for Topical Desonide Cream Using Chinese Skins

Introduction: Skin-blanching assay has been established as a surrogate method for assessing bioequivalence of topical corticosteroids. This study aimed to apply the skin-blanching assay to evaluate the bioequivalence of a test desonide cream (T) compared with the reference Desonide® (R) using Chinese skins. Additionally, the pharmacokinetics and safety profiles were also assessed. Methods: By detecting the degree of skin blanching under different dose durations in a pilot dose-duration-response study, the area under the observed effect-time curve (AUEC) and half of the maximum effect (ED50) was calculated. Based on this, the skin color of different time points after a dose duration of ED50, D1 (0.5 × ED50), and D2 (2 × ED50) were detected as a pharmacodynamic indicator to compare between test and reference creams. Single-center, single-dose, randomized, open-label, two-cycle crossover pharmacokinetic studies were designed to make sure the exposure of tested formulationswas not higher than that of the reference formulations. Subjects experiencing adverse events (AEs) were monitored and utilized for safety analysis. Results: These studies involved 12 subjects for the dose-duration-response study, 100 subjects for the bioequivalence study, and 12 subjects for the pharmacokinetic study. The results showed that the population ED50 was 0.88 ± 0.45 h; the mean ratio of area under effective curve from 0 to 24 h (AUEC0–24h) of test and reference preparations was 0.95, with a 90% confidence interval as 88.09–101.72%, indicating the bioequivalence of the test formulation and Desonide®. The maximum plasma concentration (Cmax) and area under the concentration time curve from time 0 to the last time point (AUC0–t) of T and R were 20.8 ± 11.5 pg/mL versus 19.7 ± 10.1 pg/mL, respectively, and 451.04 ± 363.65 pgh/mL versus 541.47 ± 581.41 pgh/mL, respectively. The systemic exposure of a single dose of the test cream was not higher than that of the reference preparation. All of the volunteers experienced grade 1 AEs, suggesting that single administration of the test desonide cream is well tolerated in the Chinese healthy population. Conclusions: This study demonstrated the applicability of skin-blanching assay in Chinese skins and established the bioequivalence of test and reference desonide creams.

A side-by-side comparison of fine-tuning options for treatment of medically refractory epilepsy: Antiseizure medications, vagus nerve stimulation and ketogenic diet therapies

There are many treatment options available for patients with medically refractory epilepsy including antiseizure medications, surgery, devices and ketogenic diet therapy. Ketogenic diet therapy has been shown to be a safe and effective treatment option in adult and pediatric patients. In order to obtain maximal clinical effectiveness and tolerability of any treatment option, adjustments are often necessary. This article outlines the “fine-tuning” options available for antiseizure medications, vagus nerve stimulation and ketogenic diet therapies and demonstrates that ketogenic diet therapies offer a wider array of personalizing and fine-tuning options.

Effect of chitosan conjugates with oxycinnamic acids and <i>Bacillus subtilis</i> bacteria on the activity of protective proteins and resistance of potato plants to <i>Phytophthora infestans</i>

The effect of chitosan conjugates with caffeic (ChCA) and ferulic (ChFA) acids in combination with Bacillus subtilis bacteria on the transcriptional activity of PR protein genes and proteome changes in potato plants during infection with Phytophthora infestans (Mont.) de Bary was studied. Plants grown from mini tubers of the Luck variety were sprayed with solutions of ChCA and ChFA, suspension of B. subtilis bacteria strains 26D and 11 VM, composites of ChCA of ChFA together with bacteria. 3 days after treatment, some of the plants were infected with P. infestans. A decrease in the degree of development of the pathogen of late blight on potato leaves in all treatment options was revealed. The maximum protective effect was manifested when plants were treated with bacteria B. subtilis strain 26D in combination with conjugates of chitosan and oxycinnamic acids. The mechanisms of increasing the resistance of potato plants to P. infestans were associated with the activation of transcriptional activity of genes encoding the main protective protein (PR‑1), chitinase (PR‑3), thaumatin-like protein (PR‑5), protease inhibitor (PR‑6), peroxidase (PR‑9), ribonuclease (PR‑10). The revealed activation of the expression of marker genes of systemic acquired resistance and induced systemic resistance under the influence of joint treatment of plants with B. subtilis and chitin conjugates with oxycinnamic acids indicate the synergistic development of protective reactions in potato plants in this variant. By the method of two-dimensional electrophoresis of S. tuberosum leaf proteins followed by MALDI-TOF analysis, 12 proteins were identified, the presence of which in the leaves differed depending on the variant of the experiment. In all treatment variants, suppression of serine-threonine protein phosphatase activity was observed, reflecting the development of the hypersensitivity reaction. Different variants of the experiment formed weakly expressed clusters, which indicates multiple mechanisms of regulation of the synthesis of protective proteins involved in the reaction to treatment with bacteria, chitosan conjugates and infection with P. infestans.

Integrating molecular dynamics simulation with small- and wide-angle X-ray scattering to unravel the flexibility, antigen-blocking, and protease-restoring functions in a hindrance-based pro-antibody.

Spatial hindrance-based pro-antibodies (pro-Abs) are engineered antibodies to reduce monoclonal antibodies' (mAbs) on-target toxicity using universal designed blocking segments that mask mAb antigen-binding sites through spatial hindrance. By linking through protease substrates and linkers, these blocking segments can be removed site-specifically. Although many types of blocking segments have been developed, such as coiled-coil and hinge-based Ab locks, the molecular structure of the pro-Ab, particularly the region showing how the blocking fragment blocks the mAb, has not been elucidated by X-ray crystallography or cryo-EM. To achieve maximal effect, a pro-Ab must have high antigen-blocking and protease-restoring efficiencies, but the unclear structure limits its further optimization. Here, we utilized molecular dynamics (MD) simulations to study the dynamic structures of a hinge-based Ab lock pro-Ab, pro-Nivolumab, and validated the simulated structures with small- and wide-angle X-ray scattering (SWAXS). The MD results were closely consistent with SWAXS data (χ2 best-fit = 1.845, χ2 allMD = 3.080). The further analysis shows a pronounced flexibility of the Ab lock (root-mean-square deviation = 10.90 Å), yet it still masks the important antigen-binding residues by 57.3%-88.4%, explaining its 250-folded antigen-blocking efficiency. The introduced protease accessible surface area method affirmed better protease efficiency for light chain (33.03 Å2) over heavy chain (5.06 Å2), which aligns with the experiments. Overall, we developed MD-SWAXS validation method to study the dynamics of flexible blocking segments and introduced methodologies to estimate their antigen-blocking and protease-restoring efficiencies, which would potentially be advancing the clinical applications of any spatial hindrance-based pro-Ab.

Cytotoxic and Anti-HSV-1 Effects of Caulerpin Derivatives.

Marine organisms represent a potential source of secondary metabolites with various therapeutic properties. However, the pharmaceutical industry still needs to explore the algological resource. The species Caulerpa lamouroux Forssk presents confirmed biological activities associated with its major compound caulerpin, such as antinociceptive, spasmolytic, antiviral, antimicrobial, insecticidal, and cytotoxic. Considering that caulerpin is still limited, such as low solubility or chemical instability, it was subjected to a structural modifications test to establish which molecular regions could accept structural modification and to elucidate the cytotoxic bioactive structure in Vero cells (African green monkey kidney cells, Cercopithecus aethiops; ATCC, Manassas, VA, USA) and antiviral to Herpes simplex virus type 1. Substitution reactions in the N-indolic position with mono- and di-substituted alkyl, benzyl, allyl, propargyl, and ethyl acetate groups were performed, in addition to conversion to their acidic derivatives. The obtained analogs were submitted to cytotoxicity and antiviral activity screening against Herpes simplex virus type 1 by the tetrazolium microculture method. From the semi-synthesis, 14 analogs were obtained, and 12 are new. The cytotoxicity assay showed that caulerpin acid and N-ethyl-substituted acid presented cytotoxic concentrations referring to 50% of the maximum effect of 1035.0 µM and 1004.0 µM, respectively, values significantly higher than caulerpin. The antiviral screening of the analogs revealed that the N-substituted acids with methyl and ethyl groups inhibited Herpes simplex virus type 1-induced cytotoxicity by levels similar to the positive control acyclovir.

Enhancing power grid resilience to winter storms via generator winterization with equity considerations

We develop two-stage stochastic programming models for generator winterization that enhance power grid resilience while incorporating social equity. The first stage in our models captures the investment decisions for generator winterization, and the second stage captures the operation of a degraded power grid, with the objective of minimizing load shed and social inequity. To incorporate equity into our models, we propose a concept called adverse effect probability that captures the disproportionate effects of power outages on communities with varying vulnerability levels. Grid operations are modeled using DC power flow, and equity is captured through mean or maximum adverse effects experienced by communities. We apply our models to a synthetic Texas power grid, using winter storm scenarios created from the generator outage data from the 2021 Texas winter storm. Our extensive numerical experiments show that more equitable outcomes, in the sense of reducing adverse effects experienced by vulnerable communities during power outages, are achievable with no impact on total load shed through investing in winterization of generators in different locations and capacities.

Sustainable conversion of polystyrene waste into polymeric surfactants to be evaluated as pour point deperssants for waxy crude oil

Disposing of polystyrene trash is an environmental concern, and converting it into value-added products is appealing . This research study focuses on implementing a sustainable method to convert polystyrene waste into polymeric nonionic surfactants. The polymeric nonionic surfactant additives were prepared by grafting polystyrene waste (WPS) with a methacrylic monomer (MMA), followed by an esterification reaction with polyethylene glycol of different molecular weights (400 and 1000). The chemical composition of the synthesized compounds was justified by spectroscopic analysis. Interfacial tension (IFT) was investigated to gain insights into the behavior of the polymeric nonionic surfactants produced at the interface. The modified waste polymers were evaluated as pour depressants and paraffin inhibitors. Additionally, the rheological properties of the modified waste polymers were examined. The findings revealed that, the IFT between oil and water decreased from 21 to 7 mN/m for WSPA400 and even further to 4 mN/m for WSPA1000. At a concentration of 500 ppm, WPSA1000 exhibited the maximum depression effect than WPSA400, reducing the pour point temperature from 27 °C to 12 °C and 3 °C, respectively. Also, At 500 ppm, the amount of wax deposition declined from 8.5 g to 1.90 g and 0.95 g after treating the crude oil with WPSA 400 and WPSA 1000. The rheological measurements further revealed that the WPSA1000 additive outperformed the WPSA400 additive in terms of enhancing the fluidity of oil. In order to acquire a more comprehensive understanding of the mechanisms involved in pour point depression, the utilization of polarizing optical microscopy was used to explore the effect of WPSA1000 as a pour point depressant.

Substrate Moisture and Temperature Effects on Limestone Reaction Rate in a Peat-Based Substrate

ABSTRACT Lime reaction rate in a container substrate is influenced by temperature and moisture, which are factors that vary between batches of substrate during manufacturing, storage, and crop production. The effects of temperature and moisture on the duration required to achieve a stable substrate-pH are useful information for substrate companies and growers, as well as a key component when modeling lime reaction over time. The pH of a 70 peat : 30 perlite (by volume) substrate was quantified over time under a range of different storage temperature (1.9 to 33.3°C) and substrate volumetric water content (VWC, 0.168 to 0.568 L of H2O/L of substrate). The lime source was a horticultural dolomitic carbonate limestone screened to the fraction that passed through a 100 US mesh but was retained on a 200 US mesh (0.075–0.15 mm) incorporated at 2.67 g·L−1 of substrate. Experiments provided two data sets for calibration and validation. Lime reaction rate increased with increasing substrate temperature and substrate moisture level. The duration required to reach a target substrate-pH value of 6.0 was used to indicate 90% of maximum pH effect from lime. Duration varied from 4 days with the combined high temperature (20.6 and 33.3 °C) and high VWC (0.468 and 0.568 L H2O/L of substrate) to 53 days with low temperature (1.9 °C) and low VWC (0.168 L H2O/L of substrate) for the calibration data set. At an example low VWC of 0.168 L of H2O/L of substrate, the duration required to reach substrate-pH 6.0 at 1.9, 7.8, 10, 20.6, and 33.3°C was 53, 38, 34, 23, and 17 days, respectively. Similarly, if the temperature was held constant at 33.3°C, reducing VWC from 0.568 L H2O/L to 0.128 L H2O/L would decrease lime reaction rate from 100% to 21%, requiring five times the duration to reach an equilibrium pH. Results can be used to compare the relative effects of moisture and temperature on lime reaction rate for substrate manufacturers and growers.

Liriodendrin stimulates proliferation and milk protein synthesis of mammary epithelial cells via the PI3K-DDX18 signaling.

Liriodendrin is a lignan compound that is involved in a wide variety of physiological functions, however it is unknown whether liriodendrin plays an important role in milk production in the mammary glands. In this study, we explored the role and molecular mechanism of Liriodendrin in milk synthesis of mammary epithelial cells (MECs). Bovine MECs were treated with liriodendrin (0, 0.45, 0.9, 1.35, 1.8, and 2.25mM) for 24 h. Liriodendrin dose-dependently increased cell number, cell cycle transition, and milk protein synthesis, as well as Cyclin D1 and mTOR phosphorylation, with the maximal effects observed at a dose of 1.35mM. Liriodendrin increased the expression of DDX18, which mediated liriodendrin stimulation of Cyclin D1 and mTOR mRNA expression. PI3K inhibition and DDX18 knockdown experiments further confirmed that liriodendrin regulates the mRNA expression of Cyclin D1 and mTOR via the PI3K-DDX18 signaling. Mouse feeding experiment showed that liriodendrin dose-dependently promotes β-casein and DDX18 expression in mouse mammary gland. In this study, DDX18 was found to be a novel positive regulator that plays a role in cell proliferation and synthesis of milk protein. These findings reveal that liriodendrin stimulates proliferation and milk protein synthesis of MECs via the PI3K-DDX18 signaling.

The Immunological and Epidemiological Effectiveness of Pediatric Single-Dose Vaccination against Hepatitis A 9 to 11 Years after Its Implementation in the Tyva Republic, the Russian Federation.

Since 2012, universal single-dose HAV vaccination in children aged 3 years and older has been implemented in the Tyva Republic, a region of the Russian Federation. The aim of this prospective non-interventional observational single-center study was to determine the immunological and epidemiological effectiveness of single-dose vaccination against hepatitis A 9 to 11 years after its implementation. The anti-HAV IgG antibodies were determined in two independent cohorts of children who were vaccinated with a single dose of monovalent pediatric inactivated vaccine (HAVRIX® 720 EU) in Tyva in 2012 and recruited 9 years (Year 9 Cohort) and 11 years (Year 11 Cohort) after immunization. The seroprotection rates defined as anti-HAV antibody concentrations ≥10 mIU/mL reached 99.4% (95% CI: 98.2-99.9% [501/504]) in the Year 9 Cohort, but decreased significantly to 75.4% (95% CI: 73.0-77.6% [1006/1335]) in the Year 11 Cohort (p < 0.0001). The anti-HAV geometric mean concentrations decreased from 1446.3 mIU/mL (95% CI: 1347.1-1545.4 mIU/mL) in the Year 9 Cohort to 282.6 mIU/mL (95% CI: 203.8-360.8, p < 0.0001) in the Year 11 Cohort. The HAV vaccination program resulted in zero rates of hepatitis A incidence in the Tyva Republic since 2016. However, the limited monitoring of HAV RNA in sewage and environmental samples demonstrated the ongoing circulation of both the regional epidemic strain of HAV genotype IA and another genotype IA strain imported recently from other parts of the Russian Federation, probably due to subclinical infections in non-vaccinated children under 3 years of age. Taken together, these data indicate the effectiveness of the single-dose HAV vaccination strategy but suggest the need to expand the vaccination program to include children aged 12 months and older to achieve maximum effectiveness.

Iron Effects in Advanced Alkaline Electrolyzer

Global warming, characterized by an alarming rise in the Earth’s temperature, is one of the serious impacts of industrialization. Transition towards a sustainable future requires the diversification of our energy sources by replacing fossil fuels with renewable energy such as green H2, to lower global CO2 emissions. Alkaline water electrolysis is one of the widely used affordable water splitting techniques that produces hydrogen gas. Since Fe contamination in this system is an unavoidable factor, it is important to understand the optimum Fe concentration for maximum performance. In this work, we are investigating the change in the total cell performance by spiking Fe2+ (0 to 140 ppm) solution at industrial standard conditions (6 M KOH, 80° C).In this work, we are investigating the change in the total cell performance by spiking Fe2+ (0 to 140 ppm) solution at industrial standard conditions (6 M KOH, 80° C). The KOH was purified prior to the experiment making sure the Fe limits are below the ICP-MS detection limit. To fully understand how Fe activates/deactivates the electrode performance, we chose NixCoy(O)OH coated on Ni mesh anode, commercial AWE cathode and Zirfon-220 as separator and performed testing in both 3-electrode set up and zero-gap electrolyzer set up. Our initial results show that, Fe effect on the total cell performance follows a bell curve where the maximum contribution comes from the activation of the anode. It must be noted that by spiking 40 -50 ppm Fe in the electrolyte the total cell potential is reduced by over 1V which is a huge gain. As we spike over 60 ppm the performance starts to go down. This can be explained by the deposition of FeOx on the anode which is a bad OER catalyst in comparison with NixCoy(O)OH. Our anode has a high active surface area from the nano sheet composition along with high conductivity from CoOx. At 20 ppm Fe in the electrolyte, the anode over potential reduced by 49 mV at 10 mA and by ~110mV at 250mA at 80 °C. Unlike bare Ni electrode as cathode, commercial cathodes are very resistant to Fe fouling only leading to a few millivolts of change. It is important to understand that Fe has maximum effect at low temperature, where the total cell potential was reduced by 200mV by adding 40 ppm Fe solution. As we increase the temperature to 80 °C, reaction kinetics gets improved and the optimum Fe concentration for maximum performance decreases.The activation in the anode performance at high Fe concentration has been verified by studying the surface morphology SEM imaging and by taking the EDX analysis. It has been seen that the anode gives maximum performance when we have sites of NixCoyFeO(OH) deposited on the anode catalyst. As our next step, we will be evaluating the changes in the surface morphology of the cathode along with the amount of Fe being deposited at each spiking. This will provide more information on how we should engineer the cell components to achieve the maximum output. Figure 1

Torque and Eddy Current Behavior of a Magnet Rotating Axial Disk Type Magnetic Coupler: Analysis and Experimental Verification

This research explored the impact of air gap on torque and eddy current behavior of a magnet-north-pole rotating axial disk-type magnetic coupler using the magnetic equivalent circuit method. A magnetic equivalent circuit (MEC) model was developed to analyze the torque and induced eddy current behavior for the magnetic N-pole rotation angle 0° to 30° axial disk type magnetic coupler (MC). Torque equations were derived by combining Kirchhoff's law and the integral method, whereas induced eddy current equations were derived using Ampere's law. Flux leakage reluctance equations were obtained using an integral method. Furthermore, the study conducted 2D finite element simulations, and the results were validated against experimental data to ensure the accuracy and reliability of the proposed MEC model. Finally, the research findings suggested that an air gap length of 4 mm was an optimum length to obtain maximum torque and minimum magnetic saturation effects for a proposed MEC model of N-pole rotating axial disk type MC.

Heat transfer characteristics of printed circuit heat exchangers under mechanical vibrations

PurposeThe purpose of this paper is to investigate the impact of mechanical vibration on the heat transfer and pressure drop characteristics of semicircular channel printed circuit heat exchangers (PCHEs), while also establishing correlations between vibration parameters and thermal performance.Design/methodology/approachBy combining experimental and numerical simulation methods, the heat transfer coefficient and pressure drop characteristics of supercritical carbon dioxide (S-CO2) in a semicircular channel with a diameter of 2 mm under vibration conditions were studied. Reinforce the research by conducting computational fluid dynamics studies using ANSYS Fluent 22.0, the experimental results were compared with the numerical simulation results to verify the accuracy of the numerical method.FindingsThe use of vibration has the potential to attenuate the degradation of wall heat transfer caused by buoyancy-induced PCHEs on the upward-facing surface. The heat transfer enhancement (HTE) was maximized by an increase of 18.2%, while the pressure drop enhancement (PDE) was elevated by over 25-fold. The capacity to enhance the heat exchange between S-CO2 and channel walls through increasing vibration intensity is limited, indicating maximum effectiveness in improving thermal performance.Originality/valueConducting heat transfer experiments on PCHEs with mechanical vibration enhancement and verifying the accuracy of the vibration numerical model. The relation based on the dimensionless factor is derived. To provide theoretical support for using vibration to enhance the heat transfer capability of PCHEs.

Isobutyryl-carfentanyl has strong acute toxicity and analgesic effects with high addiction potential.

Isobutyryl-carfentanyl is the most recently discovered fentanyl analogue with a chemical structure that is similar to that of carfentanyl. Its analogue, carfentanyl, is regarded as one of the most lethal drugs in the world, with a potency of 10,000 times that of morphine. Therefore, isobutyryl-carfentanyl may possess a comparably high potency and its harmful effects cannot be ignored. This study was designed to assess the analgesic effect of isobutyryl-carfentanyl and the potential risks associated with its misuse. In this study, we assessed the acute toxicity of isobutyryl-carfentanyl by up-and-down-procedure, the analgesic efficacy by hot-plate test, the abuse potential by conditioned place preference (CPP), drug self-administration, and drug discrimination tests, and compared it with fentanyl and carfentanyl. The estimated median lethal dose (LD50) of isobutyryl-carfentanyl administered were 175mg/kg (intragastric administration, IG), 15.84mg/kg (intraperitoneal injection, IP), 15.84mg/kg (subcutaneous injection, SC), and 1.6mg/kg (intravenous injection, IV), respectively. The 50% maximal analgesic effect (ED50) of isobutyryl-carfentanyl was determined to be 0.00319mg/kg, with an analgesic potency 14 times that of fentanyl and 0.82 times that of carfentanyl. Isobutyryl-carfentanyl exhibited a significant positional preference at a minimum dose of 0.1mg/kg, while fentanyl exhibited a significant positional preference at a minimum dose of 0.3mg/kg. In the heroin (0.05mg/kg/infusion) self-administration substitution experiment, isobutyryl-carfentanyl showed significant self-administration behaviour at doses of 0.0005-0.001mg/kg/infusion, with the maximum number of infusions observed at a dose of 0.001mg/kg. In the heroin (1mg/kg) drug discrimination experiment, fentanyl (0.005-0.02mg/kg), carfentanyl (0.0005-0.002mg/kg), and isobutyryl-carfentanyl (0.001-0.005mg/kg) were tested in the dose-effect curves. The results showed that all three drugs exhibit dose-dependent increase in the number of drug-associated nose pokes responses and reduction in the rate of nose pokes. The subjective effect potency of isobutyryl-carfentanyl was found to be 4.4 times that of fentanyl and 0.5 times that of carfentanyl. In summary, isobutyryl-carfentanyl has high acute toxicity and analgesic effect, with strong psychological dependence approximately 5 times that of fentanyl and 0.5 times that of carfentanyl, and has extremely high abuse potency.

Landscape genetics of spruce grouse at the trailing edge of the boreal forest

Populations on the periphery of a species range generally occupy marginal or less continuous habitat and can have greater extinction risk than populations in the range‐center. For climate‐sensitive populations on the trailing edge of a species' distribution (i.e. low latitude or low elevation), the effects of climate change are expected to compound these threats, increasing the vulnerability of these populations. The spruce grouse Canachites canadensis is a boreal forest specialist that is expected to experience range contraction at the trailing edge of its range due to climate change. In this study, we investigated the genetic structure, genetic diversity, and connectivity of spruce grouse in Minnesota, along the southeastern range limit in the United States. Clustering algorithms and genetic diversity indices suggested a single continuous population occurred throughout northern Minnesota. We detected no signatures of recent inbreeding or population bottlenecks. We used maximum likelihood population effects modeling and identified coniferous forest land cover and lower average spring temperatures as predictors of gene flow. We used two approaches based on circuit theory to map the potential for gene flow and identified regions of consistently high gene flow in the northwest and northeast of the study area. Omniscape, which incorporated additional parameters representing the likely origins of dispersers and the maximum dispersal distance, suggested a more continuous gene flow landscape than did Circuitscape. Our work highlights the current genetic integrity of one of the largest populations of the eastern subspecies of spruce grouse C. c. canadensis in the United States, identifies key landscape attributes for functional connectivity, and demonstrates complementary approaches of Circuitscape and Omniscape for gene flow mapping.

Comparison of Different Doses of Oral and Ocular Propranolol for Retinopathy of Prematurity: A Network Meta-Analysis.

The efficacy and safety of propranolol for retinopathy of prematurity (ROP) remain under debate. This network meta-analysis (NMA) focuses on whether a ranking may be established for different dose levels of propranolol as treatment of ROP in terms of stage progression as the primary outcome, with appearance of plus disease and need for anti-vascular endothelial growth factors (anti-VEGFs) or laser therapy as secondary endpoints. Fourteen studies (10 randomised controlled trials, three single-arm trials and one retrospective observational study) of 474 patients treated with oral or ocular propranolol were retrieved from databases up to April 2024. Meta-insight and model-based NMA were undertaken to evaluate the propranolol dose-response relationship. Studies were evaluated for model fit, risk of bias and Confidence of evidence In Network Meta-Analysis (CINeMA). Effect sizes were determined as odds ratio (OR) with 95% credible interval (CrI). Bayesian analysis showed a trend towards improved effects for propranolol given at late stages (stages 2-3; S23) of ROP progression compared with its administration at earlier stages (stages 0-1; S01). OR values for oral propranolol 1.5 and 2mg/kg/day given at S23 were 0.13 (95% CrI 0.04-0.37) and 0.16 (95% CrI 0.04-0.61), respectively, while given at S01 were 0.28 (95% CrI 0.02-2.96) and 0.78 (95% CrI 0.14-4.43), respectively. Similarly, OR of eye propranolol 0.2% at S23 was 0.37 (95% CrI 0.09-1.00) versus an S01 OR of 0.64 (95% CrI 0.21-2.04). Surface under the cumulative ranking curve (SUCRA) analyses confirmed best probability values for oral propranolol 1.5-2mg/kg followed by eye propranolol 0.2%, all at S23. Model-based NMA showed nonlinearity in the dose-response for oral propranolol with a trend to greater maximal effect for its administration at late versus early stages. For secondary endpoints, lower risk values were found with oral propranolol 1.5mg/kg/day at S23 for progression to plus disease (OR 0.14; 95% CrI 0.02-0.84) and need for anti-VEGFs (OR 0.23; 95% CrI 0.05-0.93) and laser (OR 0.16; 95% CrI 0.02-1.10) therapies also followed by eye propranolol 0.2%, and a similar profile was obtained with SUCRA analysis. Lower doses (0.5-1.0mg/kg/day) of oral propranolol retained efficacy. Threat of adverse events was estimated as risk difference versus control with no difference for eye propranolol 0.2% and oral propranolol 0.5mg/kg/day, modest increases of risk for oral propranolol 1.0 and 1.5mg/kg/day and the highest risk difference for oral propranolol 2.0mg/kg/day (0.06; 95% CI -0.01 to 0.13). A diminished risk of disease progression and need for additional treatment was obtained with propranolol in ROP, but safety is a potential concern. Propranolol eye micro-drops (0.2%) can be as efficacious as oral propranolol. Nonetheless, the evidence is limited due to the paucity and quality of the available studies.

Efflux transporter inhibitory (EXTRIN) micelles for enhanced ocular drug delivery

Efflux transporters such as P-glycoprotein (P-gp) and Multidrug resistance proteins-2 (MRP-2) are often highly expressed on cornea and conjunctiva, significantly restricting the absorption of topically administered drugs into the eye. We hypothesized that nanocarrier with P-gp and MRP-2 inhibitory activity may enhance drug permeation across the cornea. Due to ease in development and scale-up, a lipidic nanocarrier was proposed and therefore lipids and surfactants were screened for P-gp and MRP-2 modulation using erythromycin (Ery), a known substrate for both P-gp and MRP-2 as model drug and freshly excised goat cornea as membrane. Out of the studied lipids/surfactants, Peceol and Pluronic F127 showed maximum inhibitory effects against P-gp and MRP-2 and were used to develop efflux transporter inhibitory micelles (EXTRIN-micelles). Dynamic laser scattering showed that EXTRIN-micelles were 348 ± 14.5 nm with PDI <0.09. Preclinical studies in rabbits demonstrated significantly higher (p < 0.05) corneal retention of EXTRIN-micelles compared to solution. Further, EXTRIN-micelles delivered significantly higher (p < 0.001) Ery concentrations to aqueous humor compared to solution. In conclusion, EXTRIN-micelles are potential carriers for enhanced ocular delivery of drugs.