Explore the vast range of titles available.

Background The study aimed to assess the efficacy and safety of Natamycin + Lactulose vaginal suppositories (100 mg natamycin and 300 mg lactulose) (AVVA RUS JSC, Russia) in adult females with vulvovaginal candidiasis. Methods and Results An international, randomized, controlled, assessor-blinded clinical trial enrolled 218 females randomly distributed into three groups: Natamycin + Lactulose (92 patients), Lactulose (36 patients), and Pimafucin® (90 patients). The study drug and comparator drugs had an identical dosing regimen (one suppository intravaginally once a day at bedtime for six days). The study involved four visits to the study site with examination at Visits 2 and 3. The fixed-dose combination of Natamycin + Lactulose was superior to both comparator drugs in terms of the primary efficacy endpoint defined as the percentage of patients achieving a clinical recovery: the absence of symptoms of vulvovaginal candidiasis. At Visit 2, clinical recovery was reported in 81.6% of females in the Natamycin + Lactulose group compared to 42.9% and 62.3% of patients in the Lactulose and Pimafucin groups, respectively. The difference in proportions was 38.8% and 18.4%. In the Natamycin + Lactulose group, microscopic recovery was observed in 75.9% of patients at Visit 2 and in 90.8% of patients at Visit 3. In the Lactulose group, 45.7% and 74.3% subjects responded positively at Visits 2 and 3. In Pimafucin group, microscopic recovery was reported in 71.3% and 88.5% of patients at Visits 2 and 3, respectively, while no differences were observed between the Natamycin + Lactulose and Pimafucin groups at both visits. At Visit 3, the number of vaginal lactobacilli was significantly higher in the Natamycin + Lactulose group. In females with the low baseline content of vaginal lactobacilli, the combination drug under investigation increased the vaginal lactobacilli content to the reference values in 15.4% and 20.9% of patients at Visit 2 and Visit 3, respectively. Conclusions The fixed-dose combination Natamycin + Lactulose 100 mg + 300 mg vaginal suppositories (AVVA RUS JSC, Russia) demonstrated superior efficacy compared to 1) Pimafucin 100 mg and 2) Lactulose 300 mg vaginal suppositories in adult females with vulvovaginal candidiasis. Trial registration NCT06411314, retrospectively registered on May, the 13th, 2024.

The United States Transuranium and Uranium Registries’ (USTUR) female whole body tissue donor studied here was occupationally exposed to highly enriched uranium for 17 years. One hundred and twenty-nine tissue samples were collected at the time of death, 31 years post-exposure. These samples were radiochemically analyzed for uranium. The highest uranium concentration of 16.5 ± 2.0 µg kg−1 was measured in the lungs, and the lowest concentration of 0.11 ± 0.01 µg kg−1 in the liver. The thyroid had the highest concentration of 6.3 ± 2.9 µg kg−1 among systemic tissues. Mass-weighted average concentration in the entire skeleton was estimated to be 1.60 ± 0.19 µg kg−1. In the skeleton, uranium was non-uniformly distributed among different bones. Thirty-one years after the intake, approximately 40% of occupational uranium was still retained in the skeleton, followed by the kidneys (~ 30%), and the brain and liver (~ 10%). Systemic uranium was equally distributed between the skeleton and soft tissues. Uranium content in systemic organs followed the pattern: skeleton >  > brain ≈ kidneys > heart ≈ liver > thyroid ≈ spleen. Uranium distribution in this female was compared to previously published USTUR data for male tissue donors. It is concluded that no difference in uranium systemic distribution was observed between female and male individuals. It is demonstrated that dose assessment based on the current ICRP biokinetic model overestimated the dose to the brain by 20%.

The United States Transuranium and Uranium Registries (USTUR) is a unique resource of data and materials for studying biokinetics of uranium in the human body. In this study, bioassay data and post-mortem organ activities from a female whole-body USTUR donor who was exposed to highly enriched uranium were analyzed using the IMBA Professional Plus® software to derive the best estimate of the total intake. The resulting radiation doses delivered to this individual’s whole body and major target organs were calculated from estimated intake based on case-specific dose coefficients derived using the AIDE® software. Both intake and dose calculations were carried out using the biokinetic and dosimetric models recommended by the International Commission on Radiological Protection (ICRP) in its Occupational Intakes of Radionuclides publication series. Different exposure scenarios including chronic and acute inhalation intakes were tested. A combination of a chronic inhalation intake and two acute inhalation intakes appears to best describe the bioassay data. To fit this female individual’s autopsy data, the transfer rate from the liver to the blood was increased by a factor of 8 and the transfer rate from the kidneys to the blood was decreased by a factor of 2.2. This resulted in the best fit to all data (p = 0.519). The total intake was estimated to be 44.1 kBq, and the committed effective dose was 211 mSv with 96.8% contributed by 234U. 96.6% of the committed effective dose was contributed by the lungs. The remaining 3.4% of the committed effective dose was contributed by all systemic tissues and organs with the highest contribution (0.40%) from the red bone marrow. It is concluded that the current ICRP models, with the adjustment for smoking status, adequately describe uranium biokinetics for this individual except retention in the liver and kidneys. However, this study was based on a single case and may not be sufficient to identify any apparent sex-specific differences in uranium biokinetics.

The U.S. Transuranium and Uranium Registries performs autopsies on each of its deceased Registrants as a part of its mission to follow up occupationally-exposed individuals. This provides a unique opportunity to explore death certificate misclassification errors, and the factors that influence them, among this small population of former nuclear workers. Underlying causes of death from death certificates and autopsy reports were coded using the 10 th revision of the International Classification of Diseases (ICD-10). These codes were then used to quantify misclassification rates among 268 individuals for whom both full autopsy reports and death certificates with legible underlying causes of death were available. When underlying causes of death were compared between death certificates and autopsy reports, death certificates correctly identified the underlying cause of death’s ICD-10 disease chapter in 74.6% of cases. The remaining 25.4% of misclassified cases resulted in over-classification rates that ranged from 1.2% for external causes of mortality to 12.2% for circulatory disease, and under-classification rates that ranged from 7.7% for external causes of mortality to 47.4% for respiratory disease. Neoplasms had generally lower misclassification rates with 4.3% over-classification and 13.3% under-classification. A logistic regression revealed that the odds of a match were 2.8 times higher when clinical history was mentioned on the autopsy report than when it was not. Similarly, the odds of a match were 3.4 times higher when death certificates were completed using autopsy findings than when autopsy findings were not used. This analysis excluded cases where it could not be determined if autopsy findings were used to complete death certificates. The findings of this study are useful to investigate the impact of death certificate misclassification errors on radiation risk estimates and, therefore, improve the reliability of epidemiological studies.

The biokinetic and dosimetry models recommended by the International Commission on Radiological Protection do not incorporate dosimetric uncertainty. Recently, Bayesian approach—offering distribution of dose estimates rather than a single point value—has been applied in epidemiological risk modeling. Although the true dose is unknown, Bayesian analysis is assumed to provide information on the true dose through a posterior distribution. This study presents a unique opportunity to validate that assumption. Radiation dose is directly related to the time-dependent radionuclide activity deposited or retained in organs and tissues. Therefore, uncertainties in organ activity predictions derived from biokinetic modeling can serve as proxies for the uncertainties in dose estimation. In this study, uncertainties in model predictions of 239 Pu organ activities were evaluated for 20 former nuclear workers with known plutonium inhalation. Ten individuals from Los Alamos were primarily exposed to soluble Pu-nitrate, while ten from Rocky Flats were exposed to insoluble PuO 2 . All individuals were volunteer tissue donors to the United States Transuranium and Uranium Registries. Urine bioassay data and post-mortem measurements of 239 Pu in the liver, skeleton and respiratory tract were used in the analysis. Latin hypercube sampling was employed to generate parameter sets for each realization, varying only two parameters of the human respiratory tract model: the rapidly dissolved fraction, f r and slow dissolution rate, s s . For each realization: (i) intake was estimated using maximum likelihood fitting of the urine bioassay data, and (ii) post-mortem organ activities, used as surrogates of true doses, were predicted based on the estimated intake. Predicted distributions of 239 Pu organ activities were compared to point estimates based on default parameters for soluble and insoluble plutonium, as well as to the measured post-mortem values. Results showed that in most cases, the predicted distributions did not cover the measured values (75% for liver, 90% for skeleton, and 50% for the respiratory tract), indicating a need to improve current biokinetic models. Additionally, in some cases, the model predictions were not conservative, which raises concerns from a radiation protection standpoint.

Deep eutectic solvents (DESs) are one of the most rapidly evolving types of solvents, appearing in a broad range of applications, such as nanotechnology, electrochemistry, biomass transformation, pharmaceuticals, membrane technology, biocomposite development, modern 3D-printing, and many others. The range of their applicability continues to expand, which demands the development of new DESs with improved properties. To do so requires an understanding of the fundamental relationship between the structure and properties of DESs. Computer simulation and machine learning techniques provide a fruitful approach as they can predict and reveal physical mechanisms and readily be linked to experiments. This review is devoted to the computational research of DESs and describes technical features of DES simulations and the corresponding perspectives on various DES applications. The aim is to demonstrate the current frontiers of computational research of DESs and discuss future perspectives.

Death certificates are commonly used in epidemiological studies investigating the relationship between exposure and health outcomes. It is known that death certificates may misclassify the underlying causes of death, and it is commonly understood that if misclassification is non-differential, it will bias dose-response relationships toward the null or underestimate the association. This simulation study explores the probability that results of an individual study may contradict the general understanding by addressing two key questions: (1) what is the probability that misclassification of disease mortality moves measures of dose-response associations away from the null? and (2) what is the probability that misclassification moves measures of dose-response associations away from the null sufficiently to change the conclusion of a study from statistically non-significant to significant? As the starting point, this simulation study used a small group of radiation-exposed nuclear workers for whom both death certificates and autopsy reports were available. Results suggest that nominally non-differential misclassification can lead to an odds ratio that moves away from the null. For datasets where the initial p -values were slightly non-significant, the percentage of odds ratios that moved away from the null generally decreased with higher levels of misclassification, and the probability that the p -values associated with these odds ratios would change to significant decreased with increasing misclassification rates. The traditional heuristic is more likely to be true when: (1) there is a larger misclassification rate, and (2) there is a high association between dose and disease mortality. This has implications for environmental epidemiology, such as low-dose radiation epidemiology, where estimated effects are often small and conclusions may hinge on marginal statistical significance. As another implication, these findings apply broadly to various health outcomes, even if the outcome misclassification rate is low.

Radionuclide molecular imaging of epidermal growth factor receptor (EGFR) expression might permit the selection of patients for EGFR-targeting therapies. Designed ankyrin repeat protein (DARPin) E01 with a high affinity to the ectodomain III of the EGFR is a possible EGFR imaging probe. The goal of this study was to evaluate the potential of radiolabeled DARPin E01 for in vivo imaging of EGFR. DARPin E01 containing the (HE)3-tag was site-specifically labeled with a residualizing 99mTc (using 99mTc]Tc(CO)3). Two methods providing non-residualizing 123I labels, direct electrophilic radioiodination and indirect radioiodination using [123I]I-para-iodobenzoate (PIB), were tested. [99mTc]Tc-(HE)3-E01 and [123I]I-(HE)3-E01-PIB preserved specific binding to EGFR-expressing cells and affinity in the single-digit nanomolar range. Direct labeling with 123I resulted in a substantial loss of binding. In vitro cellular processing studies showed that both [99mTc]Tc-(HE)3-E01 and [123I]I-(HE)3-E01-PIB had rapid binding and relatively slow internalization. Evaluation of [99mTc]Tc-(HE)3-E01 biodistribution in normal CD1 mice showed that its hepatic uptake was non-saturable, suggesting that this tracer does not bind to murine EGFR. A side-by-side comparison of biodistribution and tumor targeting of [99mTc]Tc-(HE)3-E01 and [123I]I-(HE)3-E01-PIB was performed in Nu/j mice bearing EGFR-positive A-431 and EGFR-negative Ramos human cancer xenografts. Both radiolabeled DARPins demonstrated EGFR-specific tumor uptake. However, [123I]I-(HE)3-E01-PIB had appreciably lower uptake in normal organs compared to [99mTc]Tc-(HE)3-E01, which provided significantly (p < 0.05) higher tumor-to-organ ratios. Gamma-camera imaging confirmed that [123I]I-(HE)3-E01-PIB demonstrated a higher imaging contrast in preclinical models than [99mTc]Tc-(HE)3-E01. In conclusion, DARPin (HE)3-E01 labeled using a non-residualizing [123I]I-para-iodobenzoate (PIB) label is the preferred radiotracer for in vivo imaging of EGFR expression in cancer.

Designed ankyrin repeat protein (DARPin) Ec1, a small scaffold protein (18 kDa), binds with high affinity the epithelial cell adhesion molecule (EpCAM) that is overexpressed in several carcinomas. To enhance the targeted delivery of cytotoxic drugs using Ec1, we investigated the potential of fusing Ec1 with an albumin-binding domain (ABD) to improve its circulation time and decrease renal uptake. Two fusion proteins were created, Ec1-ABD, with the ABD at the C-terminus, and ABD-Ec1, with the ABD at the N-terminus. Both variants were labeled with 111In. ABD-fused variants bound specifically to EpCAM-expressing cells with picomolar affinity. Adding human albumin reduced the affinity. This effect was more pronounced for Ec1-ABD; however, the affinity remained in the subnanomolar range. The position of the ABD did not influence the internalization rate of both variants by human cancer cells. In mouse models with human cancer xenografts, both variants demonstrated over 10-fold lower renal uptake compared to the Ec1. Tumor uptake of the ABD-fused variants was higher than the uptake of Ec1. ABD-Ec1 provided two-fold higher tumor uptake, indicating fusion with an ABD as a promising way to modulate the targeting properties of an Ec1-based construct. However, the effect of fusion depends on the order of the domains.

Designed ankyrin repeat protein (DARPin) G3 is an engineered scaffold protein. This small (14.5 kDa) targeting protein binds with high affinity to human epidermal growth factor receptor 2 (HER2). HER2 is overexpressed in several cancers. The use of the DARPin G3 for radionuclide therapy is complicated by its high renal reabsorption after clearance via the glomeruli. We tested the hypothesis that a fusion of the DARPin G3 with an albumin-binding domain (ABD) would prevent rapid renal excretion and high renal reabsorption resulting in better tumour targeting. Two fusion proteins were produced, one with the ABD at the C-terminus (G3-ABD) and another at the N-terminus (ABD-G3). Both variants were labelled with 177Lu. The binding properties of the novel constructs were evaluated in vitro and their biodistribution was compared in mice with implanted human HER2-expressing tumours. Fusion with the ABD increased the retention time of both constructs in blood compared with the non-ABD-fused control. The effect of fusion with the ABD depended strongly on the order of the domains in the constructs, resulting in appreciably better targeting properties of [177Lu]Lu-G3-ABD. Our data suggest that the order of domains is critical for the design of targeting constructs based on scaffold proteins.