Twofold Difference Research Articles

Analysis of different strains of the turquoise killifish identify transcriptomic signatures associated with heritable lifespan differences.

The African turquoise killifish Nothobranchius furzeri represents an emerging short-lived model for aging research. Captive strains of this species are characterized by large differences in lifespan. To identify the gene expression correlates of this lifespan differences, we analyzed a public transcriptomic dataset consisting of four different tissues in addition to embryos. We focused on the GRZ and the MZM0410 captive strains, which show a near twofold difference in lifespan, but similar growth and maturation and validated the results in a newly-generated dataset from a third longer-lived strain. The two strains show distinct transcriptome expression patterns already as embryos and the genotype has a larger effect than age on gene expression, both in terms of number of differentially expressed genes and magnitude of regulation. Network analysis detected RNA processing and histone modifications as the most prominent categories upregulated in GRZ that also showed idiosyncratic expression patterns such as high expression of DND is somatic tissues. The short-lived GRZ strain shows transcriptional aging signatures already at sexual maturity (anticipated aging) in all four tissues suggesting that short lifespan is the results of events that occur early in life rather than the progressive accumulation of strain-dependent differences. The GRZ strain is the most commonly used N. furzeri strain in intervention studies and our results warrant replication of at least key intervention studies in longer-lived strains.

18F]SF51, a novel 18F-labeled PET radioligand for translocator protein 18kDa (TSPO) in brain, works well in monkeys but fails in humans.

[18F]SF51 is a novel radioligand for imaging translocator protein 18 kDa (TSPO) that previously displayed excellent imaging properties in nonhuman primates. This study assessed its performance in human brain and its dosimetry. Seven healthy participants underwent brain PET imaging to measure TSPO binding using a two-tissue compartment model (2TCM) to calculate total distribution volume (VT). This cohort included two high-affinity binders (HABs), three mixed-affinity binders (MABs), and two low-affinity binders (LABs). Two other participants received whole-body scans to assess radiation exposure. Peak brain radioactivity reached a standardized uptake value (SUV) of 1.4 at 3 minutes post-injection, diminishing to 30% of peak by 120 minutes. The average VT for all genotype groups was notably low (<1 mL·cm-3), emphasizing the radioligand's poor binding in brain. [18F]SF51 remained sensitive to the TSPO polymorphism in vivo, as shown by a two-fold difference in VT between HABs and LABs. VT stabilization by 80 minutes post-injection suggested minimal radiometabolite accumulation in brain. The average effective dose was 13.8 ± 0.9 µSv/MBq. Contrary to previously published animal data, [18F]SF51 showed low binding to human TSPO, with uptake remaining influenced by the rs6971 polymorphism. These findings highlight the challenges of developing TSPO radioligands and underscore the significant species differences that may influence translational outcomes.ClinicalTrials.gov identifier: NCT05564429; registered 10/03/2022.

Physiologically-based pharmacokinetic model of in vitro porcine ear skin permeation for drug delivery research.

In silico techniques, such as physiologically based pharmacokinetic modeling (PBKP), are recently gaining importance. Computational methods in drug discovery and development and the generic drugs industry enhance research effectiveness by saving time and money and avoiding ethical issues. One key advantage is the ability to conduct toxicology studies without risking harm to living beings. This study aimed to repurpose the multi-phase multi-layer mechanistic dermal absorption (MPML MechDermA) PBPK model for simulation permeation through porcine ear skin under in vitro conditions. The work was divided into four steps: (1) the development of a pig ear skin model based on a previously collected dataset; (2) testing the model's ability to discriminate permeation between pig ear, human abdomen, and human back skin; (3) development of a caffeine permeation model; and (4) testing the caffeine model's performance against in vitro generated data sourced from the scientific literature. Data from 31 manuscripts were used for the development of the pig skin model. Based on these data, values specific to pig skin were found for 22 parameters of the MPML MechDermA model. The model was able to discriminate permeation between pig and human skin. A caffeine model was developed and used to simulate seven experiments identified in the literature. The model's performance was assessed by comparing simulated to observed results. Based on a visual check, all simulations were considered acceptable, whereas three out of seven experiments met the twofold difference criterion. The variability of the experimental data was considered the biggest challenge for reliable model assessment.

PATH-33. THE IMPACT OF THE MOLECULAR CLASSIFICATION IN HISTOLOGICALLY DIAGNOSED GLIOBLASTOMAS

Abstract OBJECTIVE Glioblastomas have been diagnosed based on traditional histological findings (necrosis, microvascular proliferation) and molecular genetic findings (IDH-wildtype, H3-wildtype, TERT promoter mutation, EGFR amplification, +7/−10 chromosome copy-number changes). Thus, IDH-wildtype and H3-wildtype glioblastomas can be classified into those with molecular genetic findings (defined as molecular glioblastoma) and those with only histological findings (defined as non-molecular glioblastoma). We re-evaluated the molecular genetics of patients diagnosed histologically with glioblastoma at our institution and examined their characteristics. METHODS A total of 275 cases diagnosed histologically as glioblastoma between December 2000 and March 2022 were included. Sanger sequencing (IDH1/2, Histone H3, TERTp) and MLPA for copy number analysis (PDGFRA, EGFR, CDKN2A, PTEN, MDM2, CDK4, TP53) were performed. The genetic analysis results and survival periods were analyzed. RESULTS Among the 275 cases, 151 initial glioblastomas met the criteria of IDH wild-type and H3 wild-type. Genetic analysis results that could be evaluated were obtained in 89 of these cases. TERT promoter mutation was present in 43 cases (48%), with 37% (16 cases) showing EGFR amplification and 19% (8 cases) showing EGFR gain/PTEN loss (+7/-10) simultaneously. On the other hand, TERT promoter wild-type was found in 45 cases (51%), with EGFR amplification in only 1 case (2%) and EGFR ain/PTEN loss in 4 cases (9%), and these 5 cases were judged to correspond to molecular glioblastoma. Adding one case with TERT promoter evaluation failure but EGFR amplification, the integrated molecular/non-molecular glioblastoma cases were 49 (55%)/40 (45%), revealing that both tumor types exist in nearly equal proportions. Survival curve analysis showed that median overall survivals of molecular and non-molecular glioblastoma were 17 and 29 months, respectively, showing a two-fold difference, and non-molecular glioblastoma had significantly better prognosis (P=0.0136). CONCLUSION It was revealed that tumors diagnosed as glioblastoma based on conventional histological findings can be broadly classified into molecular and non-molecular glioblastoma, with significant differences in prognosis.

Nitrogen and Carbon Mineralization from Organic Amendments and Fertilizers Using Incubations with Sandy Soils

Synthetic fertilizers are the main nitrogen (N) input used in specialty crop systems established on sandy soils of Florida, although organic amendments and fertilizers can be used as a substitute. Organic N contained in these products must be mineralized before crop uptake, which is affected by amendment properties, soil properties, and temperature. A better method for predicting N release can help maximize the nutrient cycling benefits of organic amendments and fertilizers while avoiding negative environmental impacts. The main objective of this study was to measure N release and CO2 emissions from two poultry manure-based amendments (PMA) and two processed organic fertilizers (OF) made from livestock byproducts (e.g., feather meal). We conducted an 8-week incubation using two sandy Florida soils belonging to two soil orders (Entisol and Spodosol) and with a greater than two-fold difference in soil organic C. We incubated these soils at 10 °C, 17 °C, 24 °C, and 30 °C, measured plant-available N at 0, 1, 4, and 8 weeks, and measured CO2 emissions weekly. In both soils, OF released more inorganic N and at a faster rate compared with PMA, but CO2 emissions were greater from PMA than OF. Nitrogen mineralization and CO2 emissions increased with temperature, but temperature effects were less important than expected. These results on the mineralization of PMA and OF in sandy soils are key to optimize their use and management in Florida and other areas dominated by sandy soils.

Evaluation of Tritium Ingestion Dose in the Republic of Korea Using Environmental Impact Assessment Methodologies from Three Organizations

This study performed a comparative analysis using data from Republic of Korea’s nuclear power plants and applied methodologies from Republic of Korea, IAEA TRS-472, and CSA N288.1-14 to assess environmental impact doses. The research primarily centered on estimating the effective doses received from consuming crops and fish affected by tritiums’s atmospheric and marine discharge from nuclear facilities. It has been confirmed that significant differences exist in the effective dose due to various influencing factors such as the moisture content ratio, the weight ratio of the measurement target parameters, and the calculation methods of Organically Bound Tritium (OBT). In the context of crops, the effective dose for Republic of Korea was represented as 1.297 μSv. Conversely, the TRS-472 and N288.1-14 revealed doses of 2.684 μSv and 2.284 μSv, respectively, demonstrating an approximate two-fold difference in the effective dose values. This study highlights the essential need for technological advancements in environmental dose impact assessments, urging the development of customized evaluation models that consider each country’s unique characteristics while advocating for enhanced international standardization in dose evaluations.

Peripheral Fusion of Carbon-Based Aromatic Rings to B4N4-Heteropentalene Leading to Close π-Stacking in the Solid State.

π-Electronic molecules with a BN-heterocyclic and carbon-based aromatic hybrid ring system (h-CBN) are interesting in that they potentially exhibit synergistic properties arising from the two different π-systems. Here we report the synthesis and properties of a h-CBN-type molecule (1) having a bicyclic B4N4-heteropentalene core fused with extended aromatic rings. This molecule exhibits excellent chemical stability despite the absence of bulky substituents for kinetic protection, which in turn provides effective stacking of the π-system upon crystallization. Depending on the crystallization solvent, 1 forms two polymorphs, i. e., the α- and β-phases. While both phases have one-dimensional columnar structures, the π-stacking geometries associated with the transfer integrals of the frontier orbitals are different, resulting in a twofold difference in the electrical conducting properties. We also found that upon thermal vacuum deposition, 1 gives an amorphous film, which serves as a host material for a red phosphorescent OLED device (maximum external quantum efficiency: 15.5 and 13.3 % at 0.1 and 2.5 mA, respectively).

Future sick leave, disability pension, and unemployment among patients with cancer after returning to work: Swedish register-based matched prospective cohort study.

Despite increasing numbers of working-age cancer survivors, evidence on their future work-related circumstances is limited. This study examined their future sick leave, disability pension, and unemployment benefits compared to matched cancer-free individuals. A matched cohort study was conducted using nationwide Swedish registers. In total, 94,411 individuals aged 25 to 59 years when diagnosed with incident cancer in 2001-2012 and who returned to work after cancer were compared with their matched cancer-free individuals (N = 354,814). Follow-up started from the year before cancer diagnosis and continued up to 14 years. Generalized estimating equations were used to calculate incidence rate ratios (IRR) and odds ratios for the difference between cancer survivors and matched cancer-free individuals. Compared with cancer-free individuals, cancer survivors had six times higher sick-leave days per year after cancer (IRR 6.25 [95% CI, 5.97-6.54] for men; IRR, 5.51 [5.39-5.64] for women). This higher number of sick-leave days declined over time but a two-fold difference persisted. An approximate 1.5 times higher risk of receiving disability pension remained during follow-up. The unemployment days tended to be lower for cancer survivors (IRR, 0.84 [0.75-0.94] for men; IRR, 0.91 [0.86-0.96] for women). Risk of sick leave and disability pension was higher among those with leukemia, colorectal, and breast cancer than skin and genitourinary cancers. Cancer survivors who returned to work experienced a high and persisting sick leave and disability pension for over a decade. Prolonged receipt of a high amount of benefits may have long-term adverse impacts on financial circumstances; more knowledge to promote the environment that encourages returning to and remaining in work is needed.

Comparative evaluation of Sensititre YeastOne and CLSI M38-Ed3 reference method for determining echinocandin minimum effective concentrations against Aspergillus isolates.

The minimum inhibitory concentration (MIC) of echinocandins against Aspergillus spp. does not represent the actual inhibition threshold of echinocandins. Therefore, the recommended method to evaluate their activity is determining the minimum effective concentration (MEC) in broth microdilution, a method that is less common in clinical settings. This study aimed to assess a user-friendly commercial method, Sensititre YeastOne (SYO), to determine the effectiveness of echinocandins (caspofungin, anidulafungin and micafungin) against Aspergillus spp. Echinocandins MEC was determined against 23 isolates of Aspergillus spp. using SYO and the reference Clinical and Laboratory Standards Institute (CLSI) method. MECs were read with an inverted microscope and a reading mirror. Essential agreement (EA) between the tested methods was defined as a ±twofold dilution difference. There was a high EA (91%-100%) between the reference method and SYO in determining echinocandins MEC against Aspergillus isolates using inverted microscopy. A high EA was also observed between SYO MEC determined by inverted microscopy and a reading mirror, but different incubation times were required. SYO is a reliable, simple method for determining the MEC of echinocandins against Aspergillus isolates, preferably with an inverted microscope, and can be easily used in clinical laboratories when echinocandin susceptibility testing is required.IMPORTANCEUsing a commercial method such as Sensititre YeastOne (SYO) to determine the minimum effective concentration (MEC) of echinocandins against Aspergillus spp. has been shown to be a reliable alternative to the Clinical and Laboratory Standards Institute (CLSI) reference method. This makes it more suitable for high-volume clinical laboratories. SYO provides accurate results comparable to the standard method and could potentially improve patient care by guiding more optimal antifungal treatment choices for patients with Aspergillus infections.

Influence of significant difference in diameters of ureters on the possibility and effectiveness of ureteroureterostomy in the treatment of obstructive uropathies of the duplicated kidney

BACKGROUND: Laparoscopic ureteroureterostomy is increasingly used as a surgical correction method for obstructive uropathies of the duplicated kidney. A complicating factor for this technique may be a significant difference between the diameters of the ureters. AIM: This study aimed to analyze the effectiveness and safety of laparoscopic ureteroureterostomy in patients with obstructive uropathies of the duplicated kidney with a twofold or more difference in ureter diameters. MATERIALS AND METHODS: Among 14 children who underwent laparoscopic ureteroureterostomy for obstructive uropathies of the duplicated kidney at Almazov National Medical Research Centre between 2021 and 2023, in 10 patients (71.4%), the diameter of the “donor” ureter exceeded the diameter of the “recipient” ureter two times or more. RESULTS: In most patients, the indication for surgery was obstructive megaureter of the segment. All patients underwent laparoscopic ureteroureterostomy, proximal in 90% of cases and distal in one child. One of five patients underwent transurethral resection of the ureterocele as the first stage of operative treatment. The only complication observed in the postoperative period in the presented patients was a stent-associated urinary tract infection, which was treated conservatively. One child (10%) required ureter reimplantation with stump resection after ureteroureterostomy. CONCLUSIONS: Laparoscopic ureteroureterostomy is a safe and effective method for surgical correction of obstructive uropathies of the duplicated kidney although a significant difference is noted between the diameters of the “donor” and “recipient” ureters. This factor does not reduce the effectiveness of ureteroureterostomy and does not lead to an increased risk of postoperative complications and reoperations. Thus, laparoscopic ureteroureterostomy can be used in patients with obstructive uropathies of the duplicated kidney.

The interaction of the azetidine thiazole side chain with the active site loop (ASL) 3 drives the evolution of IMP metallo-β-lactamase against tebipenem.

Imipenemase (IMP) metallo-β-lactamases (MBLs) hydrolyze almost all available β-lactams including carbapenems and are not inhibited by any commercially available β-lactamase inhibitor. Tebipenem (TP) pivoxil is the first orally available carbapenem and possesses a unique bicyclic azetidine thiazole moiety located at the R2 position. TP has potent in vitro activity against Enterobacterales producing extended-spectrum and/or AmpC β-lactamases. Thus far, the activity of TP against IMP-producing strains is understudied. To address this knowledge gap, we explored the structure activity relationships of IMP MBLs by investigating whether IMP-6, IMP-10, IMP-25, and IMP-78 [MBLs with expanded hydrolytic activity against meropenem (MEM)] would demonstrate enhanced activity against TP. Most of the Escherichia coli DH10B strains expressing IMP-1 variants displayed a ≥twofold MIC difference between TP and MEM, while those expressing VIM or NDM variants demonstrated comparable MICs. Catalytic efficiency (kcat/KM) values for the TP hydrolysis by IMP-1, IMP-6, IMP-10, IMP-25, and IMP-78 were significantly lower than those obtained for MEM. Molecular dynamic simulations reveal that V67F and S262G substitutions (found in IMP-78) reposition active site loop 3, ASL-3, to better accommodate the bicyclic azetidine thiazole side chain, allowing microbiological/catalytic activity to approach that of comparison MBLs used in this study. These findings suggest that modifying the R2 side chain of carbapenems can significantly impact hydrolytic stability. Furthermore, changes in conformational dynamics due to single amino acid substitutions should be used to inform drug design of novel carbapenems.

Toxicity of rare earth elements (REEs) to marine organisms: Using species sensitivity distributions to establish water quality guidelines for protecting marine life

A lack of chronic rare earth element (REE) toxicity data for marine organisms has impeded the establishment of numerical REE water quality benchmarks (e.g., guidelines) to protect marine life and assess ecological risk. This study determined the chronic no (significant) effect concentrations (N(S)ECs) and median-effect concentrations (EC50s) of eight key REEs (yttrium (Y), lanthanum (La), cerium (Ce), praseodymium (Pr), neodymium (Nd), gadolinium (Gd), dysprosium (Dy) and lutetium (Lu)) for 30 coastal marine organisms (encompassing 22 phyla and five trophic levels from temperate and tropical habitats). Organisms with calcifying life stages were most vulnerable to REEs, which competitively inhibit calcium uptake. The most sensitive organism was a sea urchin, with N(S)ECs ranging from 0.64 μg/L for Y to 1.9 μg/L for La and Pr, and EC50s ranging from 4.3 μg/L for Y to 14.4 μg/L for Pr. Conversely, the least sensitive organism was a cyanobacterium, with N(S)ECs ranging from 121 μg/L for Y to 469 μg/L for Pr, and EC50s ranging from 889 μg/L for Y to 3000 μg/L for Pr. Median sensitivity varied 215-fold across all organisms. The two-fold difference in median toxicity (μmol/L EC50) among REEs (Y ∼ Gd > Lu ∼ Nd ∼ Dy ∼ Ce > La ∼ Pr) was attributed to offset differences in binding affinity (log K) to cell surface receptors and the percentage of free metal ion (REE3+) in the test waters. The toxicity (EC50) of the remaining REEs (samarium, europium, terbium, holmium, thulium and ytterbium) was predicted using a combination of physicochemical data and measured EC50s for the eight tested REEs, with good agreement between predicted and measured EC50s for selected organisms. Numerical REE water quality guidelines to protect marine life were established using species sensitivity distributions (e.g., for 95 % species protection, values ranged from 1.1 μg/L for Y to 3.0 μg/L for La, Pr or Lu).

Comparative Analysis of Hulless Barley Transcriptomes to Regulatory Effects of Phosphorous Deficiency.

Hulless barley is a cold-resistant crop widely planted in the northwest plateau of China. It is also the main food crop in this region. Phosphorus (P), as one of the important essential nutrient elements, regulates plant growth and defense. This study aimed to analyze the development and related molecular mechanisms of hulless barley under P deficiency and explore the regulatory genes so as to provide a basis for subsequent molecular breeding research. Transcriptome analysis was performed on the root and leaf samples of hulless barley cultured with different concentrations of KH2PO4 (1 mM and 10 μM) Hoagland solution. A total of 46,439 genes were finally obtained by the combined analysis of leaf and root samples. Among them, 325 and 453 genes had more than twofold differences in expression. These differentially expressed genes (DEGs) mainly participated in the abiotic stress biosynthetic process through Gene Ontology prediction. Moreover, the Kyoto Encyclopedia of Genes and Genomes showed that DEGs were mainly involved in photosynthesis, plant hormone signal transduction, glycolysis, phenylpropanoid biosynthesis, and synthesis of metabolites. These pathways also appeared in other abiotic stresses. Plants initiated multiple hormone synergistic regulatory mechanisms to maintain growth under P-deficient conditions. Transcription factors (TFs) also proved these predictions. The enrichment of ARR-B TFs, which positively regulated the phosphorelay-mediated cytokinin signal transduction, and some other TFs (AP2, GRAS, and ARF) was related to plant hormone regulation. Some DEGs showed different values in their FPKM (fragment per kilobase of transcript per million mapped reads), but the expression trends of genes responding to stress and phosphorylation remained highly consistent. Therefore, in the case of P deficiency, the first response of plants was the expression of stress-related genes. The effects of this stress on plant metabolites need to be further studied to improve the relevant regulatory mechanisms so as to further understand the importance of P in the development and stress resistance of hulless barley.

Association between Group B Streptococcus and Clinical Chorioamnionitis by Gestational Week at Delivery-A Multicenter Cohort Study.

In the era of group B Streptococcus (GBS) screening and intrapartum antibiotic prophylaxis (IAP), GBS colonization has been associated with a lower risk of chorioamnionitis, possibly due to a protective effect of IAP. We sought to confirm this finding and assess whether this association varies by gestational week at delivery. We performed a retrospective cohort study of term (37.0-42.6 weeks), singleton parturients with known GBS status who delivered from 2005 to 2021 at two academic medical centers in Israel. We excluded patients who underwent planned cesarean, out of hospital birth, or had a fetal demise. Patients received GBS screening and IAP for GBS positivity as routine clinical care. The primary outcome was a diagnosis of clinical chorioamnionitis as determined by the International Classification of Diseases 10th Revision code, compared between GBS-positive and -negative groups, and assessed by gestational week at delivery. Of 292,126 deliveries, 155,255 met inclusion criteria. In total, 30.1% were GBS positive and 69.9% were negative. GBS-positive patients were 21% less likely to be diagnosed with clinical chorioamnionitis than GBS-negative patients, even after controlling for confounders (1.5 vs. 2.2%, adjusted odds ratio: 0.79, 95% confidence interval: 0.68-0.92). When assessed by gestational week at delivery, there was a significantly greater difference in rates of clinical chorioamnionitis between GBS-positive versus GBS-negative groups with advancing gestational age: 1.5-fold difference at 38 to 40 weeks, but a twofold difference at 42 weeks. The risk of clinical chorioamnionitis remained stable in the GBS-positive group, but increased significantly in the GBS-negative group at 41- and 42-week gestation (2.0 vs. 2.9%, p < 0.01 at 41 weeks; up to 3.9% at 42 weeks, p < 0.01). In a large multicenter cohort with universal GBS screening and IAP, GBS positivity was associated with a lower risk of chorioamnionitis, driven by an increasing rate of chorioamnionitis among GBS-negative patients after 40 weeks. · GBS positivity and IAP may be associated with lower risk of chorioamnionitis.. · GBS-positive patients were less likely to be diagnosed with chorioamnionitis.. · This difference increased with advancing gestational age after 40 weeks..

Recommendations for the Prevention and Management of Deep Brain Stimulation Infections Based on 26-Year Single-Center Experience

Introduction: Infections related to deep brain stimulation (DBS) can lead to discontinuation of the treatment and increased morbidity. Various measures of reducing infection rates have been proposed in the literature, but scientific consensus is lacking. The aim of this study was to report a 26-year single center experience of DBS infections and provide recommendations for the prevention and management of them. Methods: The retrospective analysis consisted of 978 DBS surgeries performed at Oulu University Hospital (OUH) from 1997 to 2022. This included 342 primary or reimplantations of DBS electrodes and 559 primary or reimplantations of implantable pulse generator (IPG). Infections within approximately 1 year after the surgery without secondary cause were considered surgical-site infections (SSIs). χ2 test was used to compare infection rates before and after 2013, when the systematic implementation of infection prevention measures was started. Results: A total of 35 DBS implants were found to be infected. The number of SSIs was 30, of which 29 were originally operated in OUH leading to a center-specific infection rate of 3.1%. Of the SSIs, 17.2% occurred after IPG replacement. Staphylococcus aureus was found in 75.0% of cultures and 32.1% were mixed infections. The treatment of SSIs included aggressive surgical revision combined with cefuroxime and vancomycin antibiotics, as most patients in the initial conservative treatment group eventually required surgical revision. A statistically significant difference in infection rates before and after the implementation of preventative measures was not observed (risk ratio 2.20, 95% confidence interval 0.94–5.75, p = 0.051), despite over two-fold difference in the incidence of SSIs. Conclusion: Our findings show that the rates of surgical infections are low in modern DBS, but due to their serious consequences, preventative measures should be implemented. We highlight that mixed infections should be accounted for in the antibiotic selection. Furthermore, our treatment recommendation includes aggressive surgical revision combined with antibiotic treatment.

Baseline characteristics, reperfusion treatment secondary prevention and outcome after acute ischemic stroke in three different socioeconomic environments in Europe.

The differences in vascular risk factors' and stroke burden across Europe are notable, however there is limited understanding of the influence of socioeconomic environment on the quality of secondary prevention and outcome after acute ischemic stroke. In this observational multicenter cohort study, we analyzed baseline characteristics, reperfusion treatment, outcome and secondary prevention in patients with acute ischemic stroke from three tertiary-care teaching hospitals with similar service population size in different socioeconomic environments: Bern/CH/n = 293 (high-income), Gdansk/PL/n = 140 (high-income), and Lutsk/UA/n = 188 (lower-middle-income). We analyzed 621 patients (43.2% women, median age = 71.4 years), admitted between 07 and 12/2019. Significant differences were observed in median BMI (CH = 26/PL = 27.7/UA = 27.8), stroke severity [(median NIHSS CH = 4(0-40)/PL = 11(0-33)/UA = 7(1-30)], initial neuroimaging (CT:CH = 21.6%/PL = 50.7%/UA = 71.3%), conservative treatment (CH = 34.1%/PL = 38.6%/UA = 95.2%) (each p < 0.001), in arterial hypertension (CH = 63.8%/PL = 72.6%/UA = 87.2%), atrial fibrillation (CH = 28.3%/PL = 41.4%/UA = 39.4%), hyperlipidemia (CH = 84.9%/PL = 76.4%/UA = 17%) (each p < 0.001) and active smoking (CH = 32.2%/PL = 27.3%/UA = 10.2%) (p < 0.007). Three-months favorable outcome (mRS = 0-2) was seen in CH = 63.1%/PL = 50%/UA = 59% (unadjusted-p = 0.01/adjusted-p CH-PL/CH-UA = 0.601/0.981), excellent outcome (mRS = 0-1) in CH = 48.5%/PL = 32.1%/UA = 27% (unadjusted-p < 0.001/adjusted-p CH-PL/CH-UA = 0.201/0.08 and adjusted-OR CH-UA = 2.09). Three-months mortality was similar between groups (CH = 17.2%/PL = 15.7%/UA = 4.8%) (unadjusted-p = 0.71/adjusted-p CH-PL/CH-UA = 0.087/0.24). Three-months recurrent stroke/TIA occurred in CH = 3.1%/PL = 10.7%/UA = 3.1%, adjusted-p/OR CH-PL = 0.04/0.32). Three-months follow-up medication intake rates were the same for antihypertensives. Statin/OAC intake was lowest in UA = 67.1%/25.5% (CH = 87.3%/39.2%/unadjusted-p < 0.001/adjusted-p CH-UA = 0.02/0.012/adjusted-OR CH-UA = 2.33/2.18). Oral intake of antidiabetics was lowest in CH = 10.8% (PL = 15.7%/UA = 16.1%/unadjusted-p = 0.245/adjusted-p CH-PL/CH-UA = 0.061/0.002/adjusted-OR CH-UA = 0.25). Smoking rates decreased in all groups during follow-up. Substantial differences in presentation, treatment and secondary prevention measures, are linked to a twofold difference in adjusted 3-months excellent outcome between Switzerland and Ukraine. This underscores the importance of socioeconomic factors that influence stroke outcomes, emphasizing the necessity for targeted interventions to address disparities in treatment and secondary prevention strategies.

Integrated high-throughput drug screening microfluidic system for comprehensive ocular toxicity assessment

Traditional experimental methodologies suffer from a few limitations in the toxicological evaluation of the preservatives added to eye drops. In this study, we overcame these limitations by using a microfluidic device. We developed a microfluidic system featuring a gradient concentration generator for preservative dosage control with microvalves and micropumps, automatically regulated by a programmable Arduino board. This system facilitated the simultaneous toxicological evaluation of human corneal epithelial cells against eight different concentrations of preservatives, allowing for quadruplicate experiments in a single run. In our study, the IC50 values for healthy eyes and those affected with dry eyes syndrome showed an approximately twofold difference. This variation is likely attributable to the duration for which the preservative remained in contact with corneal cells before being washed off by the medium, suggesting the significance of exposure time in the cytotoxic effect of preservatives. Our microfluidic system, automated by Arduino, simulated healthy and dry eye environments to study benzalkonium chloride toxicity and revealed significant differences in cell viability, with IC50 values of 0.0033% for healthy eyes and 0.0017% for dry eyes. In summary, we implemented the pinch-to-zoom feature of an electronic tablet in our microfluidic system, offering innovative alternatives for eye research.

Energy expenditure and physiological markers during a city mountain hike in the heat: A case study.

Background: Energy expenditure may be difficult to assess when hiking difficult trails. Case presentation: We measured physical activity exercise energy expenditure (PAEE) directly from oxygen uptake using a mobile device (cardiopulmonary exercise testing, CPET), and by using a formula based on heart rate (HR), or metabolic equivalent values from the Compendium of Physical Activity, and other physiological outcomes. Outcomes and implications: Total PAEE (1342 kcal) using CPET showed a two-fold difference between ascending and descending (887 vs. 455 kcal) during a 124-min hike. For HR, PAEE was 1893kcal (+551 kcal overreporting), while compendium-based scenarios ranged from 1179 to 1446 kcal, which was in closer range (-163 to +104 kcal/min) compared to the CPET data. Fluid consumption was 1300 mL/hour, with 1.1% bodyweight loss, peak skin temperature of 35.2°C and core body temperature of 39.2°C. Recommendations: Tables reasonably predict energy expenditure while not precisely reflecting the actual situation.

Uridine 5'-Diphospho-glucuronosyltransferase 1A3 (UGT1A3) Prediction of Hepatic Clearance of Organic Anion Transporting Polypeptide 1B3 (OATP1B3) Substrate Telmisartan by Glucuronidation Using In Vitro-In Vivo Extrapolation (IVIVE).

The prediction of pharmacokinetic parameters for drugs metabolised by cytochrome P450 enzymes has been the subject of active research for many years, while the application of in vitro-in vivo extrapolation (IVIVE) techniques for non-cytochrome P450 enzymes has not been thoroughly evaluated. There is still no established quantitative method for predicting hepatic clearance of drugs metabolised by uridine 5'-diphospho-glucuronosyltransferases (UGTs), not to mention those which undergo hepatic uptake. The objective of the study was to predict the human hepatic clearance for telmisartan based on in vitro metabolic stability and hepatic uptake results. Telmisartan was examined in liver systems, allowing to estimate intrinsic clearance (CLint, in vitro) based on the substrate disappearance rate with the use of liquid chromatography tandem mass spectrometry (LC-MS/MS) technique. Obtained CLint, in vitro values were corrected for corresponding unbound fractions. Prediction of human hepatic clearance was made from scaled unbound CLint, in vitro data with the use of the well-stirred model, and finally referenced to the literature value of observed clearance in humans, allowing determination of the essential scaling factors. The in vitro scaled CLint, in vitro by UGT1A3 was assessed using three systems, human hepatocytes, liver microsomes, and recombinant enzymes. Obtained values were scaled and hepatic metabolism clearance was predicted, resulting in significant clearance underprediction. Utilization of the extended clearance concept (ECC) and hepatic uptake improved prediction of hepatic metabolism clearance. The scaling factors for hepatocytes, assessing the in vitro-in vivo difference, changed from sixfold difference to only twofold difference with the application of the ECC. The study showed that taking into consideration hepatic uptake of a drug allows us to obtain satisfactory scaling factors, hence enabling the prediction of in vivo hepatic glucuronidation from in vitro data.

Fetch‐Limited, Strongly Forced Wind Waves in Waters With Frazil and Grease Ice – Spectral Modeling and Satellite Observations in an Antarctic Coastal Polynya

AbstractSea ice–wave interactions have been widely studied in the marginal ice zone, at relatively low wind speeds and wave frequencies. Here, we focus on very different conditions typical of coastal polynyas: extremely high wind speeds and locally generated, short, steep waves. We overview available parameterizations of relevant physical processes (nonlinear wave–wave interactions, energy input by wind, whitecapping and ice‐related dissipation) and discuss modifications necessary to adjust them to polynya conditions. We use satellite‐derived data and spectral modeling to analyze waves in 10 polynya events in the Terra Nova Bay, Antarctica. We estimate the wind‐input reduction factor over frazil/grease ice in the wave‐energy balance equation at 0.56. By calibrating the model to satellite observations we show that exact treatment of quadruplet wave–wave interactions (as opposed to the default Discrete Interaction Approximation) is necessary to fit the model to data, and that the power n &gt; 4 in the sea‐ice source term Sice ∼ fn (where f denotes wave frequency) is required to reproduce the strong attenuation of high‐frequency waves observed for frazil streaks. We use a very‐high resolution satellite image of a fragment of one of the polynyas to determine whitecap fraction. We show that there are more than twofold differences in whitecap fraction over ice‐free and ice‐covered regions, and that the model produces realistic whitecap fractions without any tuning of the whitecapping source term. Finally, we estimate the polynya‐area‐integrated wind input, energy dissipation due to whitecapping, and whitecap fraction to be on average below 25%, 10% and 30%, respectively, of the corresponding open‐water values.