Prospective characterization of intestinal MRI intravoxel incoherent motion in pediatric and young adult patients with newly diagnosed small bowel Crohn's disease.

BACKGROUND: MRI diffusion-weighted imaging (DWI) is commonly used in MR enterography protocols for assessment of intestinal inflammation in patients with Crohn's disease. The intravoxel incoherent motion (IVIM) approach to DWI has been proposed as a more objective approach, providing quantitative parameters that reflect water diffusivity (D), blood flow (D*), and perfusion fraction (f). PURPOSE: We aimed to determine if DWI-IVIM metrics from the terminal ileum in patients with newly diagnosed Crohn's disease differ from healthy participants and change in response to biologic medical therapy. METHODS: In this prospective case-control study, 20 consecutive pediatric patients (mean age = 14 years ± 2 [SD]; eight females) with newly diagnosed ileal Crohn's disease and 15 pediatric healthy participants (mean age = 18 years ± 4 [SD]; eight females) underwent research MRI examinations of the small bowel between 12/2018 and 10/2021. Participants with Crohn's disease underwent MR studies at baseline, 6 weeks, and 6 months following initiation of anti-TNF-alpha therapy, whereas control participants underwent one research MRI examination. The MRI protocol included a DWI-IVIM sequence with nine b-values and the IVIM parameters (D, D*, and f) were extracted. Unpaired t-tests and mixed-effects models were used for analyses. RESULTS: Mean IVIM D (P < 0.001), D* (P = 0.004), and f (P = 0.001) metrics were lower for Crohn's patients at the time of diagnosis compared to healthy participants. Mean IVIM f value increased over time in response to medical therapy (mean f at baseline, 22% ± 6%; 6 weeks, 25% ± 7%; 6 months, 29% ± 10%; P = 0.016). Mean IVIM D* value increased over time in response to treatment (mean D* at baseline, 10.9 ± 3.0 × 10-3 mm2/s; 6 weeks, 11.8 ± 2.8 × 10-3 mm2/s; 6 months, 13.3 ± 3.3 × 10-3 mm2/s; P = 0.047), while there was no significant change in mean IVIM D value (P = 0.10). CONCLUSION: MRI DWI-IVIM metrics in patients with ileal Crohn's disease change over time in response to biological therapy and help discriminate these patients from healthy participants.

Cyclin-Dependent Kinase 4/6 Inhibitors Plus Endocrine Therapy versus Endocrine Therapy Alone for HR-Positive, HER-2-Negative Early Breast Cancer: Meta-Analysis of Phase III Randomized Clinical Trials.

BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are approved for advanced breast cancer combined with endocrine therapy (ET). The efficacy of CDK4/6 inhibitors plus ET in hormone estrogen-positive, human epidermal growth factor 2-negative (HR+/HER2-) early-stage breast cancer (esBC) is still to be confirmed. METHODS: We performed a systematic review and a meta-analysis to investigate the efficacy of CDK4/6i plus ET in esBC. Main outcomes included invasive disease-free survival (iDFS), distant relapse-free survival (DRFS), and overall survival (OS). We included only phase III randomized controlled trials. We used RStudio version 4.2.3, and we considered p < 0.05 to be statistically significant. RESULTS: Four studies were selected, including 14,168 patients, of which 7089 were treated with CDK4/6i plus ET and 7079 received ET monotherapy. Regarding patient characteristics, 6828 (48.2%) were premenopausal. Compared with ET alone, iDFS rates (HR 0.81; 95% CI: 0.67, 0.98; p = 0.034) were significantly in favor of CDK4/6 inhibitors plus ET. However, there were no significant differences in DRFS (HR 0.79; 95% CI: 0.58, 1.07; p = 0.132) nor OS (HR 0.96; 95% CI: 0.69, 1.35; p = 0.829). CONCLUSIONS: Our results show that the addition of CDK4/6 inhibitors is associated with a significant benefit for HR+/HER2- esBC patients in iDFS. More studies and longer follow-up are needed to assess overall survival benefits.

Enhancing hERG Risk Assessment with Interpretable Classificatory and Regression Models.

The human Ether-à-go-go-Related Gene (hERG) is a transmembrane protein that regulates cardiac action potential, and its inhibition can induce a potentially deadly cardiac syndrome. In vitro tests help identify hERG blockers at early stages; however, the high cost motivates searching for alternative, cost-effective methods. The primary goal of this study was to enhance the Pred-hERG tool for predicting hERG blockage. To achieve this, we developed new QSAR models that incorporated additional data, updated existing classificatory and multiclassificatory models, and introduced new regression models. Notably, we integrated SHAP (SHapley Additive exPlanations) values to offer a visual interpretation of these models. Utilizing the latest data from ChEMBL v30, encompassing over 14,364 compounds with hERG data, our binary and multiclassification models outperformed both the previous iteration of Pred-hERG and all publicly available models. Notably, the new version of our tool introduces a regression model for predicting hERG activity (pIC50). The optimal model demonstrated an R2 of 0.61 and an RMSE of 0.48, surpassing the only available regression model in the literature. Pred-hERG 5.0 now offers users a swift, reliable, and user-friendly platform for the early assessment of chemically induced cardiotoxicity through hERG blockage. The tool provides versatile outcomes, including (i) classificatory predictions of hERG blockage with prediction reliability, (ii) multiclassificatory predictions of hERG blockage with reliability, (iii) regression predictions with estimated pIC50 values, and (iv) probability maps illustrating the contribution of chemical fragments for each prediction. Furthermore, we implemented explainable AI analysis (XAI) to visualize SHAP values, providing insights into the contribution of each feature to binary classification predictions. A consensus prediction calculated based on the predictions of the three developed models is also present to assist the user's decision-making process. Pred-hERG 5.0 has been designed to be user-friendly, making it accessible to users without computational or programming expertise. The tool is freely available at http://predherg.labmol.com.br.

Deep-Learning Models for Abdominal CT Organ Segmentation in Children: Development and Validation in Internal and Heterogeneous Public Datasets.

Background: Deep-learning abdominal organ segmentation algorithms have shown excellent results in adults; validation in children is sparse. Objective: To develop and validate deep-learning models for liver, spleen, and pancreas segmentation on pediatric CT examinations. Methods: This retrospective study developed and validated deep-learning models for liver, spleen, and pancreas segmentation using 1731 CT examinations (1504 training, 221 testing), derived from three internal institutional pediatric (age ≤18) datasets (n=483) and three public datasets comprising pediatric and adult examinations with various pathologies (n=1248). Three deep-learning model architectures (SegResNet, DynUNet, and SwinUNETR) from the Medical Open Network for AI (MONAI) framework underwent training using native training (NT), relying solely on institutional datasets, and transfer learning (TL), incorporating pre-training on public datasets. For comparison, TotalSegmentator (TS), a publicly available segmentation model, was applied to test data without further training. Segmentation performance was evaluated using mean Dice similarity coefficient (DSC), with manual segmentations as reference. Results: For internal pediatric data, DSC for normal liver was 0.953 (TS), 0.964-0.965 (NT models), and 0.965-0.966 (TL models); normal spleen, 0.914 (TS), 0.942-0.945 (NT models), and 0.937-0.945 (TL models); normal pancreas, 0.733 (TS), 0.774-0.785 (NT models), and 0.775-0.786 (TL models); pancreas with pancreatitis, 0.703 (TS), 0.590-0.640 (NT models), and 0.667-0.711 (TL models). For public pediatric data, DSC for liver was 0.952 (TS), 0.876-0.908 (NT models), and 0.941-0.946 (TL models); spleen, 0.905 (TS), 0.771-0.827 (NT models), and 0.897-0.926 (TL models); pancreas, 0.700 (TS), 0.577-0.648 (NT models), and 0.693-0.736 (TL models). For public primarily adult data, DSC for liver was 0.991 (TS), 0.633-0.750 (NT models), and 0.926-0.952 (TL models); spleen, 0.983 (TS), 0.569-0.604 (NT models), and 0.923-0.947 (TL models); pancreas, 0.909 (TS), 0.148-0.241 (NT models), and 0.699-0.775 (TL models). DynUNet-TL was selected as the best-performing NT or TL model and was made available as an opensource MONAI bundle (https://github.com/cchmc-dll/pediatric_abdominal_segmentation_bundle.git). Conclusion: TL models trained on heterogeneous public datasets and fine-tuned using institutional pediatric data outperformed internal NT models and TotalSegmentator across internal and external pediatric test data. Segmentation performance was better in liver and spleen than in pancreas. Clinical Impact: The selected model may be used for various volumetry applications in pediatric imaging.

Pharmacokinetics Profiler (PhaKinPro): Model Development, Validation, and Implementation as a Web Tool for Triaging Compounds with Undesired Pharmacokinetics Profiles.

Computational models that predict pharmacokinetic properties are critical to deprioritize drug candidates that emerge as hits in high-throughput screening campaigns. We collected, curated, and integrated a database of compounds tested in 12 major end points comprising over 10,000 unique molecules. We then employed these data to build and validate binary quantitative structure-activity relationship (QSAR) models. All trained models achieved a correct classification rate above 0.60 and a positive predictive value above 0.50. To illustrate their utility in drug discovery, we used these models to predict the pharmacokinetic properties for drugs in the NCATS Inxight Drugs database. In addition, we employed the developed models to predict the pharmacokinetic properties of all compounds in the DrugBank. All models described in this paper have been integrated and made publicly available via the PhaKinPro Web-portal that can be accessed at https://phakinpro.mml.unc.edu/.

Cardiovascular benefits of statin plus ezetimibe combination therapy versus statin monotherapy in acute coronary syndrome: a meta-analysis of randomized controlled trials

BACKGROUND: The efficacy of adding ezetimibe to statin therapy for event reduction in patients with acute coronary syndromes (ACS) remains a topic of ongoing debate. METHODS: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing ezetimibe plus statin versus statin monotherapy in patients with ACS. We searched PubMed, Embase, and Cochrane for eligible trials. Random-effects model was used to calculate the risk ratios (RRs), with 95% confidence intervals (CIs). Statistical analyses were performed using RStudio version 4.2.3. RESULTS: Six RCTs comprising 20,574 patients with ACS were included, of whom 10,259 (49.9%) were prescribed ezetimibe plus statin. The patient population had an average age of 63.8 years and 75.1% were male. Compared with statin monotherapy, ezetimibe plus statin significantly reduced major adverse cardiovascular events (MACE) (RR 0.93; 95% CI 0.90-0.97; p<0.01) and non-fatal myocardial infarction (RR 0.88; 95% CI 0.81-0.95; p<0.01). There was no significant difference between groups for revascularization (RR 0.94; 95% CI 0.88-1.01; p=0.07), all-cause death (RR 0.87; 95% CI 0.63-1.21; p=0.42), or unstable angina (RR 1.05; 95% CI 0.86-1.27; p=0.64). CONCLUSION: In this meta-analysis of patients with ACS, the combination of ezetimibe plus statin was associated with a reduction in MACE and non-fatal myocardial infarction, compared with statin monotherapy.

ATP-P2X7 signaling mediates brain pathology while contributing to viral control in perinatal Zika virus infection.

Zika virus (ZIKV), the causative agent of Zika fever, is a flavivirus transmitted by mosquitoes of the Aedes genus. Zika virus infection has become an international concern due to its association with severe neurological complications such as fetal microcephaly. Viral infection can induce the release of ATP in the extracellular environment, activating receptors sensitized by extracellular nucleotides, such as the P2X7 receptor. This receptor is the primary purinergic receptor involved in neuroinflammation, neurodegeneration, and immunity. In this work, we investigated the role of ATP-P2X7 receptor signaling in Zika-related brain abnormalities. Wild-type mice (WT) and P2X7 receptor-deficient (P2X7-/-) C57BL/6 newborn mice were subcutaneously inoculated with 5 × 106plaque-forming units of ZIKV or mock solution. P2X7 receptor expression increased in the brain of Zika virus-infected mice compared to the mock group. Comparative analyses of the hippocampi from WT and P2X7-/-mice revealed that the P2X7 receptor increased hippocampal damage in CA1/CA2 and CA3 regions. Doublecortin expression decreased significantly in the brains of ZIKV-infected mice. WT ZIKV-infected mice showed impaired motor performance compared to P2X7-/- infected mice. WT ZIKV-infected animals showed increased expression of glial markers GFAP (astrocytes) and IBA-1 (microglia) compared to P2X7-/- infected mice. Although the P2X7 receptor contributes to neuronal loss and neuroinflammation, WT mice were more efficient in controlling the viral load in the brain than P2X7 receptor-deficient mice. This result was associated with higher induction of TNF-α, IFN-ß, and increased interferon-stimulated gene expression in WT mice than P2X7-/-ZIKV-infected. Finally, we found that the P2X7 receptor contributes to inhibiting the neuroprotective signaling pathway AKT/mTOR while stimulating the caspase-3 activation, possibly two distinct pathways contributing to neurodegeneration. These findings suggest that ATP-P2X7 receptor signaling contributes to the antiviral response in the brain of ZIKV-infected mice while increasing neuronal loss, neuroinflammation, and related brain abnormalities.

Incidental Thalamic Lesions Identified on Brain MRI in Pediatric and Young Adult Patients: Imaging Features and Natural History.

BACKGROUND AND PURPOSE: Nonspecific, localized thalamic signal abnormalities of uncertain significance are occasionally found on pediatric brain MR imaging. The goal of this study is to describe the MR imaging appearance and natural history of these lesions in children and young adults. MATERIALS AND METHODS: This retrospective study evaluated clinically acquired brain MR imaging examinations obtained from February 1995 to March 2022 at a large, tertiary care pediatric hospital. Examinations with non-mass-like and nonenhancing thalamic lesions were identified based on term search of MR imaging reports. A total of 221 patients formed the initial group for imaging assessment. Additional exclusions during imaging review resulted in 171 patients. Imaging appearance and size changes were assessed at baseline and at follow-up examinations. RESULTS: A total of 171 patients (102 male) at a median age of 11 years (range: 1-23 years), 568 MR imaging examinations, and 180 thalamic lesions were included. Median time from baseline to the last follow-up MR imaging was 542 days (range: 46-5730 days). No lesion enhanced at any time point. On imaging follow-up, 11% of lesions (18/161) became smaller, 10% (16/161) resolved, 73% (118/161) remained stable, and 6% (9/161) increased in size at some point during evaluation. Median time interval from baseline to enlargement was 430 days (range: 136-1074 days). CONCLUSIONS: Most incidental, non-mass-like thalamic signal abnormalities were stable, decreased in size, or resolved on follow-up imaging and are likely of no clinical significance. Surveillance strategies with longer follow-up intervals may be adequate in the management of such findings.

Reduced count pediatric whole-body 18F-FDG PET imaging reconstruction with a Bayesian penalized likelihood algorithm.

BACKGROUND: Advanced positron emission tomography (PET) image reconstruction methods promise to allow optimized PET/CT protocols with improved image quality, decreased administered activity and/or acquisition times. OBJECTIVE: To evaluate the impact of reducing counts (simulating reduced acquisition time) in block sequential regularized expectation maximization (BSREM) reconstructed pediatric whole-body 18F-fluorodeoxyglucose (FDG) PET images, and to compare BSERM with ordered-subset expectation maximization (OSEM) reconstructed reduced-count images. MATERIALS AND METHODS: Twenty children (16 male) underwent clinical whole-body 18F-FDG PET/CT examinations using a 25-cm axial field-of-view (FOV) digital PET/CT system at 90 s per bed (s/bed) with BSREM reconstruction (ß=700). Reduced count simulations with varied BSREM ß levels were generated from list-mode data: 60 s/bed, ß=800; 50 s/bed, ß=900; 40 s/bed, ß=1000; and 30 s/bed, ß=1300. In addition, a single OSEM reconstruction was created at 60 s/bed based on prior literature. Qualitative (Likert scores) and quantitative (standardized uptake value [SUV]) analyses were performed to evaluate image quality and quantitation across simulated reconstructions. RESULTS: The mean patient age was 9.0 ± 5.5 (SD) years, mean weight was 38.5 ± 24.5 kg, and mean administered 18F-FDG activity was 4.5 ± 0.7 (SD) MBq/kg. Between BSREM reconstructions, no qualitative measure showed a significant difference versus the 90 s/bed ß=700 standard (all P>0.05). SUVmax values for lesions were significantly lower from 90 s/bed, ß=700 only at a simulated acquisition time of 30 s/bed, ß=1300 (P=0.001). In a side-by-side comparison of BSREM versus OSEM reconstructions, 40 s/bed, ß=1000 images were generally preferred over 60 s/bed TOF OSEM images. CONCLUSION: In children who undergo whole-body 18F-FDG PET/CT on a 25-cm FOV digital PET/CT scanner, reductions in acquisition time or, by corollary, administered radiopharmaceutical activity of >50% from a clinical standard of 90 s/bed may be possible while maintaining diagnostic quality when a BSREM reconstruction algorithm is used.

Carbohydrate metabolism evaluation of terrestrial snail Subulina octona (Gastropoda, Subulinidae) experimentally infected by the Paratanaisia bragai digenetic trematode (Digenea, Eucotylidae).

Among the effects of the larval development of digenetic trematodes on their intermediate hosts, changes in the carbohydrate metabolism in the snails stand out. The aim of this study was to analyze, every 10 days after infection (d.p.i.), the effects of Paratanaisia bragai infection on the glycogen content in the digestive gland and cephalopedal mass in Subulina octona snail, and also verify the glucose concentration and the enzyme D- and L-lactate dehydrogenase activity (EC1.1.1.27 and EC1.1.1.28) (LDH) and the concentration of some metabolites(oxalic, succinic, pyruvic and lactic acid) presents in the hemolymph. Histochemical analisys were also performed. We verified a total increase of 54.81% in glucose concentration in infected snails and an oscillating pattern in the glycogen content in the cephalopedal mass and in the digestive gland. LDH activity shows an increase of 10 d.p.i. (+ 74.32%) and 40 d.p.i. (+ 47.81%) and decrease at 20 d.p.i. and 30 d.p.i. The concentrations of oxalic, succinic and pyruvic acids showed significant and progressive reductions; however, lactic acid had a significant increase. Histological and histochemical analysis showed a tissue disorganization in the cephalopedal mass of infected snails and morphological changes in the digestive gland. These results confirm that infection causes metabolic pathway changes in the snails due to activation of an alternative anaerobic pathway for producing energy, indicated by the increased lactic acid content and LDH activity.

Safety and efficacy of sotagliflozin in patients with type II diabetes mellitus and chronic kidney disease: a meta-analysis of randomized controlled trials.

BACKGROUND: Sotagliflozin is a dual sodium-glucose co-transporter 1 and 2 inhibitor that increases glucosuria and natriuresis in patients with type 2 diabetes mellitus (T2DM). However, the safety and efficacy in patients with concomitant chronic kidney disease (CKD) remains unclear. Therefore, we aimed to conduct a meta-analysis to evaluate the current evidence in this regard. METHODS: We searched PubMed, Embase, Cochrane, and Web of Science for randomized controlled clinical trials on the safety and efficacy of Sotagliflozin in patients with T2DM and CKD compared with placebo. Statistical analysis was performed using RevMan 5.4. Heterogeneity was assessed with I2 statistics. The study was recorded in PROSPERO registry (CRD42023449631). RESULTS : We included three studies totaling 11,648 patients followed for 15.7 ± 5.9 months. Reduction in HbA1C (mean difference - 0.33%; 95% CI [- 0.54, - 0.11]; p = 0.003; I2 = 100%) and weight (mean difference - 1.01 kg; 95% CI [- 1.17, - 0.86]; p < 0.00001; I2 = 96%) were significantly higher in the Sotagliflozin group compared with placebo. All-cause mortality (RR 0.98; 95% CI [0.81, 1.20]; p = 0.87; I2 = 0%) and major adverse cardiovascular events (RR 0.70; 95% CI [0.40, 1.21]; p = 0.20; I2 = 39%) were not significantly different between groups. However, estimated glomerular filtration rate reduction (mean difference - 0.95; 95% CI [- 1.32, - 0.58]; p < 0.00001; I2 = 98%), genital mycotic infections (RR 2.73; 95% CI [1.96, 3.79]; p < 0.00001; I2 = 0%), diarrhea (RR 1.42; 95% CI [1.24. 1.63]; p < 0.00001; I2 = 0%) and volume depletion (RR 1.31; 95% CI [1.11, 1.56]; p = 0.002; I2 = 0%) were more common with Sotagliflozin. CONCLUSIONS: In patients with T2DM and CKD, Sotagliflozin appears to be effective for glycemic control and weight loss. Although the medication seemed safe concerning mortality and cardiovascular events, it induced estimated glomerular filtration rate reduction, and was associated with a higher risk of genital mycotic infections, diarrhea, and volume depletion.

Mesenchymal-Epithelial Transition Kinase Inhibitor Therapy in Patients with Advanced Papillary Renal-Cell Carcinoma: A Systematic Review and Meta-Analysis.

Papillary subtypes of renal-cell carcinoma (pRCC) represent 10-15% of the cases and commonly have MET alterations. This systematic review and single-arm meta-analysis evaluated MET inhibitor therapy (METi) efficacy and safety in adults with confirmed advanced pRCC. The search strategy included PubMed, Web-of-science, Cochrane, and Scopus. We used the DerSimonian/Laird random effect model for all analyses; p-value < 5% was considered significant, and heterogeneity was assessed with I2. Three clinical trials and six cohort studies were included with 504 patients; 31% were MET-driven. Our pooled analysis demonstrated an objective response rate (ORR) in MET-driven, MET-independent, and overall patients of: 36% (95%CI: 10-62), 0% (95%CI: 0-3), and 21% (95%CI: 1-41), respectively. One-year disease control and progression-free survival rates were, respectively, 70% (95%CI: 52-88) and 15% (95%CI: 10-20). Twelve- and twenty-four-month survival rates were, respectively, 43% (95%CI: 23-64) and 10% (95%CI: 0-30). The prevalence of adverse events of any grade and grades 3-5 were 96% (95%CI: 91-100) and 44% (95%CI: 37-50), respectively. We suggest METi has anti-tumor activity and is tolerable in patients with advanced pRCC.

Influence of exposure Heterorhabditis bacteriophora HP88, (Rhabditida: Heterorhabditidae) on biological and physiological parameters of Pseudosuccinea columella (Basommatophora: Lymnaeidae).

Many studies about fasciolosis control have been carried out, whether acting on the adult parasite or in Pseudosuccinea columella, compromising the development of the larval stages. The present study aimed to evaluate, under laboratory conditions, the susceptibility of P. columella to Heterorhabditis bacteriophora HP88, during for 24 and 48 hours of exposure. The snails were evaluated for 21 days for accumulated mortality; number of eggs laid; hatchability rate; biochemical changes; and histopathological analysis. We found that exposure induced a reduction in glucose and glycogen levels, characterizing a negative energy balance, due to the depletion of energy reserves as a result of the direct competition established by the nematode/endosymbiont bacteria complex in such substrates. A mortality rate of 48.25% and 65.52% was observed in the group exposed for 24 h and 48 h, respectively, along with significant impairment of reproductive biology in both exposed groups in relation to the respective controls. The results presented here show that P. columella is susceptible to the nematode H. bacteriophora, with the potential to be used as an alternative bioagent in the control of this mollusk, especially in areas considered endemic for fascioliasis, in line with the position expressed by the World Health Organization Health.

Comparative Analysis of Capsular and Secreted Polysaccharides Produced by Rhodotorula mucilaginosa and Cryptococcus neoformans.

Fungal infections are a global public health challenge, especially among immunocompromised patients. Basidiomycetous yeasts, such as Rhodotorula mucilaginosa, have emerged as opportunistic pathogens, but have received less attention than Cryptococcus neoformans. This study aimed to characterize the polysaccharides of R. mucilaginosa and compare them with those of C. neoformans, analyzing their clinical implications. Comprehensive physicochemical, mechanical, and ultrastructural analyses of polysaccharides from both species were performed, revealing correlations with virulence and pathogenicity. R. mucilaginosa cells are surrounded by a capsule smaller than that produced by C. neoformans, but with similar polysaccharides. Those polysaccharides are also secreted by R. mucilaginosa. Cross-reactivity with R. mucilaginosa was observed in a diagnostic C. neoformans antigen test, using both in vitro and in vivo samples, highlighting the need for more reliable tests. Some R. mucilaginosa strains exhibited virulence comparable to that of C. neoformans in an invertebrate experimental model (Tenebrio molitor). This study contributes to a deeper understanding of yeast pathogenicity and virulence, highlighting the need for more accurate diagnostic tests to improve the differential diagnosis of infections caused by basidiomycetous yeasts.

Alterations in the metabolism of Pseudosuccinea columella (Mollusca: Gastropoda) caused by Heterorhabditis bacteriophora HP88 (Rhabditida: Heterorhabditidae).

The gastropod Pseudosuccinea columella participates in the dissemination of Fasciola hepatica in the environment, acting as the main intermediate host of this parasite in Brazil. The present study sought to elucidate the possible pathogenic effects of the entomopathogenic nematode (EPN) Heterorhabditis bacteriophora on P. columella, by evaluating the influence of infection on alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as well as the concentrations of total protein, uric acid, and urea in the snail's hemolymph. For this, the snails were exposed to EPNs for 24 and 48 h, and for each exposure time, 20 snails were dissected after 7, 14 and 21 days for hemolymph collection. The primary findings suggest a significant proteolysis alongside elevated levels of uric acid and urea in P. columella infected individuals. These findings reveal that H. bacteriophora HP88 infection induced serious changes in the snail's metabolism, triggering important deleterious effects.

Cheminformatics-driven discovery of hit compounds against Paracoccidioides spp.

Aims: The development of safe and effective therapies for treating paracoccidioidomycosis using computational strategies were employed to discover anti-Paracoccidioides compounds. Materials & methods: We 1) collected, curated and integrated the largest library of compounds tested against Paracoccidioides spp.; 2) employed a similarity search to virtually screen the ChemBridge database and select nine compounds for experimental evaluation; 3) performed an experimental evaluation to determine the minimum inhibitory concentration and minimum fungicidal concentration as well as cytotoxicity; and 4) employed computational tools to identify potential targets for the most active compounds. Seven compounds presented activity against Paracoccidioides spp. Conclusion: These compounds are new hits with a predicted mechanisms of action, making them potentially attractive to develop new compounds.

Effect of rapamycin on Cryptococcus neoformans: cellular organization, biophysics and virulence factors.

Background: Cryptococcus neoformans is an opportunistic fungal pathogen that causes infections mainly in immunosuppressed individuals, such as transplant recipients. Aims: This study investigated the effects of rapamycin, an immunosuppressant drug, on the cellular organization, biophysical characteristics, and main virulence factors of C. neoformans. Methods: Morphological, structural, physicochemical and biophysical analyses of cells and secreted polysaccharides of the reference H99 C. neoformans strain were investigated under the effect of subinhibitory concentrations of rapamycin. Results: Rapamycin at a minimum inhibitory concentration of 2.5 µM reduced C. neoformans cell viability by 53%, decreased capsule, increased cell size, chitin and lipid body formation, and changed peptidase and urease activity. Conclusion: Further studies are needed to assess how rapamycin affects the virulence factors and pathogenicity of C. neoformans.

Cryptococcosis is a fungal infection caused by a type of fungus called Cryptococcus. Among the Cryptococcus group, Cryptococcus neoformans is often linked to fungal infections in people who have a weak immune system (known as being immunosuppressed). The main aim of this work was to look at the effect of an immunosuppressant called rapamycin, which is commonly used to prevent organ transplant rejection, on the ability of C. neoformans to cause infection. The results showed that this drug stopped the growth of the fungus, dampening its ability to cause disease.

Lies and Liabilities: Computational Assessment of High-Throughput Screening Hits to Identify Artifact Compounds.

Hits from high-throughput screening (HTS) of chemical libraries are often false positives due to their interference with assay detection technology. In response, we generated the largest publicly available library of chemical liabilities and developed "Liability Predictor," a free web tool to predict HTS artifacts. More specifically, we generated, curated, and integrated HTS data sets for thiol reactivity, redox activity, and luciferase (firefly and nano) activity and developed and validated quantitative structure-interference relationship (QSIR) models to predict these nuisance behaviors. The resulting models showed 58-78% external balanced accuracy for 256 external compounds per assay. QSIR models developed and validated herein identify nuisance compounds among experimental hits more reliably than do popular PAINS filters. Both the models and the curated data sets were implemented in "Liability Predictor," publicly available at https://liability.mml.unc.edu/. "Liability Predictor" may be used as part of chemical library design or for triaging HTS hits.

Characterization of Auricular Growth within the Pediatric Population Using Computed Tomography Scan Measurements.

Background: In patients with microtia, auricular reconstruction is ideally performed promptly to prevent impaired socialization during formative childhood years. The earliest viable age for reconstruction is widely accepted from 7-10 years of age, as full auricular size is achieved around age 8, with some variability dependent on sex. This retrospective study aims to provide an auricular growth curve that accounts for age and sex, enhancing the individualized approach to ear reconstruction. Methods: A total of 319 images of unaffected patients who underwent computed tomography angiography of the head and neck were reviewed, with bilateral cartilage height and width measured according to a consensus-standardized image measurement protocol. Means and SDs of cartilage height and width were calculated for both sexes, and analysis of ear growth was performed through plotting the mean cartilage height, width, and width:height ratio over time. Results: Cartilage height and width differed significantly between male and female groups. Maximum cartilage height was reached at age 11 for female and at age 12 for male patients, whereas maximum cartilage width was reached at ages 10 and 8, respectively. On average, the width:height ratio for female group was 0.58. For male group, the average width:height ratio was 0.59. Conclusions: An auricular growth map was designed using computed tomography measurements demonstrating maximum auricular size at age 11 and 12 respectively for female and male patients, with both sexes having a width:height ratio maintained at approximately 0.6 throughout growth.