Dietary habits, traveling and the living situation potentially influence the susceptibility to SARS-CoV-2 infection: results from healthcare workers participating in the RisCoin Study.

PURPOSE: To explore occupational and non-occupational risk and protective factors for the coronavirus disease 2019 (COVID-19) in healthcare workers (HCWs). METHODS: Serum specimens and questionnaire data were obtained between October 7 and December 16, 2021 from COVID-19-vaccinated HCWs at a quaternary care hospital in Munich, Germany, and were analyzed in the RisCoin Study. RESULTS: Of 3,696 participants evaluated, 6.6% have had COVID-19 at least once. Multivariate logistic regression analysis identified working in patient care occupations (7.3% had COVID-19, 95% CI 6.4-8.3, Pr = 0.0002), especially as nurses, to be a potential occupation-related COVID-19 risk factor. Non-occupational factors significantly associated with high rates of the disease were contacts to COVID-19 cases in the community (12.8% had COVID-19, 95% CI 10.3-15.8, Pr < 0.0001), being obese (9.9% had COVID-19, 95% CI 7.1-13.5, Pr = 0.0014), and frequent traveling abroad (9.4% had COVID-19, 95% CI 7.1-12.3, Pr = 0.0088). On the contrary, receiving the basic COVID-19 immunization early during the pandemic (5.9% had COVID-19, 95% CI 5.1-6.8, Pr < 0.0001), regular smoking (3.6% had COVID-19, 95% CI 2.1-6.0, Pr = 0.0088), living with the elderly (3.0% had COVID-19, 95% CI 1.0-8.0, Pr = 0.0475), and frequent consumption of ready-to-eat meals (2.6% had COVID-19, 95% CI 1.1-5.4, Pr = 0.0045) were non-occupational factors potentially protecting study participants against COVID-19. CONCLUSION: The newly discovered associations between the living situation, traveling as well as dietary habits and altered COVID-19 risk can potentially help refine containment measures and, furthermore, contribute to new mechanistic insights that may aid the protection of risk groups and vulnerable individuals.

Mixed Metal Amide-Hydride Solid Solutions for Potential Energy Storage Applications.

Mixed solid solutions have played an important role in improving the kinetics and performance of hydrogen storage materials, as reported for the Li-Mg-N-H, K-Mg-N-H, and Rb-Mg-N-H systems. Besides, the formation of a homogeneous solid solution, mostly due to partial ionic substitution, is known to be an effective approach to improve the ionic conductivity of a material, which is an important property in electrochemical applications. We have reported a series of solid solutions based on mixed amide-hydride materials of the Group 1 elements, e.g., K(NH2)xH1-x, Rb(NH2)xH1-x, and Cs(NH2)xH1-x, via the exchange of NH2-/H- anions with the change of the lattice cell of the solid solution. Extending the research in this direction, we study the M-N-H solid solution in the MNH2-MH systems (M = K, Rb, Cs, and their combinations), i.e., KNH2-RbH, RbNH2-KH, RbNH2-CsH, and CsNH2-RbH via ex situ/in situ XRD, IR, and 1H 2D solid-state NMR. The results obtained confirm the formation of mixed metal amide-hydride solid solutions associated with an exchange between both anionic (NH2- and H-) and cationic species (K+, Rb+, and Cs+). With this study, we aim to create an accessible library of M-N-H solid solutions for further studies as additives for hydrogen storage materials or ionic conductors.

Reemergence of Marburgvirus disease: Update on current control and prevention measures and review of the literature.

In 1967, the very first case of the Marburgvirus disease (MVD) was detected in Germany and Serbia sequentially. Since then, MVD has been considered one of the most serious and deadly infectious diseases in the world with a case-fatality rate between 23% and 90% and a substantial number of recorded deaths. Marburgvirus belongs to the family of Filoviridae (filoviruses), which causes severe viral hemorrhagic fever (VHF). Some major risk factors for human infections are close contact with African fruit bats, MVD-infected non-human primates, and MVD-infected individuals. Currently, there is no vaccine or specific treatment for MVD, which emphasizes the seriousness of this disease. In July 2022, the World Health Organization reported outbreaks of MVD in Ghana after two suspected VHF cases were detected. This was followed in February and March 2023 with the emergence of the virus in two countries new to the virus: Equatorial Guinea and Tanzania, respectively. In this review, we aim to highlight the characteristics, etiology, epidemiology, and clinical symptoms of MVD, along with the current prevention measures and the possible treatments to control this virus.

Awareness, referral and age at Kasai surgery for biliary atresia in Europe: A survey of the Quality-of-Care Task Force of ESPGHAN.

OBJECTIVES: To identify infants with biliary atresia (BA), European Society of Paediatric Gastroenteroloy and Nutrition (ESPGHAN)/North American Society of Pediatric Gastroenteroloy and Nutrition (NASPGHAN) guidelines recommend measurement of conjugated/direct bilirubin in infants with prolonged jaundice and using a stool colour card (SCC). The 'Quality of Care' Task Force of ESPGHAN performed two surveys to assess current case finding for BA and age at Kasai portoenterostomy (KPE). METHODS: The first survey approached 26 European hepatology centres to report age at referral and age at KPE of all infants diagnosed with BA from 2015 to 2019. The second survey targeted paediatricians in France to assess awareness and compliance with the recently introduced SCC. RESULTS: Data from 785 patients with BA from 18 centres in 15 countries revealed a mean age at referral to tertiary centre of 55 days (median 53, IQR 48-60) (n = 636). The mean age at KPE was 61 days (median 60; IQR 54-67) (n = 772). For 6% of patients, cirrhosis was too advanced for surgery. Of 392 paediatricians answering the second survey, 53% felt familiar with the target diseases, 80% correctly identified cholestasis and 59% always inquired about the infant's stool colour. If abnormal, 93% would order blood tests and 85% call for advice. The SCC screening was considered helpful for case finding and improving knowledge of cholestatic diseases by 62% and 45% paediatricians, respectively. CONCLUSIONS: Referral of infants for KPE remains late, indicating low adherence to search for cholestasis in icteric infants by age 2-3 weeks. Knowledge and structures need improvement to allow earlier guideline conform case finding, diagnosis and therapy.

Anthropometric assessment: ESPGHAN quality of care survey from paediatric hospitals in 28 European countries.

OBJECTIVES: Assessment of anthropometric data is essential for paediatric healthcare. We surveyed the implementation of European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) evidence-based guidelines and practical recommendations on nutritional care, particularly regarding anthropometric measurements. METHODS: Paediatric hospitals from 28 European countries provided pseudonymized data through online questionnaires on hospital characteristics and their standards of nutritional care. Practical tasks assessed an unbiased collection and reporting of anthropometric measurements in random patients' files and discharge letters. RESULTS: Of 114 hospitals (67% academic), 9% have no nutritionist/dietitian available, 18% do not provide standard policy to assess weight and height and 15% lack training for nursing staff for accurate performance. A wall-mounted stadiometer to measure standing height and equipment for sitting weight is unavailable in 9% and 32%, respectively. Infant length is measured by one instead of two healthcare professionals and with a tape instead of a rigid length measuring board in 58% and 15% of hospitals, respectively. The practical tasks reviewed 1414 random patients, thereof 446 younger than 2 years of age. Missing documentation occurred significantly more often for height versus weight and their percentiles in infants ≤2 years versus older children, and in general paediatric versus gastrointestinal patients, with no difference between academic and nonacademic hospitals. Review of documented anthropometric data in discharge letters disclosed that consultants significantly underestimated the deficits in their units compared to documented data. CONCLUSIONS: The survey revealed significant gaps in performance and documentation of anthropometry in the participating hospitals. A resurvey will assess changes in quality of care over time.

Substrate-induced strain and exchange field effects on the electronic and thermal properties of monolayer ß12-borophene.

The recently uncovered two-dimensional materials serve as versatile building blocks for electronic devices. In this study, we methodically investigate the impact of substrate-induced strain and exchange field effects on the electronic density of states (EDOS) and electronic heat capacity (EHC) of single-layer ß12-borophene. Utilizing the Green's function approach, we compute these functions. The van Hove singularities in EDOS are observed to shift with strain, and depending on the direction and strength of the exchange field, the number of singularities increases. All these responses can be attributed to the renormalization of the velocity of electronic bands. Additionally, the inherent Schottky anomaly (an unusual peak at low temperatures) in the EHC undergoes a notable shift to higher and lower temperatures and variations in the intensity of the EHC due to substrate effects.

Management of Helicobacter pylori infection in paediatric patients in Europe: results from the EuroPedHp Registry.

PURPOSE: The EuroPedHp-registry aims to monitor guideline-conform management, antibiotic resistance, and eradication success of 2-week triple therapy tailored to antibiotic susceptibility (TTT) in Helicobacter pylori-infected children. METHODS: From 2017 to 2020, 30 centres from 17 European countries reported anonymized demographic, clinical, antibiotic susceptibility, treatment, and follow-up data. Multivariable logistic regression identified factors associated with treatment failure. RESULTS: Of 1605 patients, 873 had follow-up data (53.2% female, median age 13.0 years, 7.5% with ulcer), thereof 741 (85%) treatment naïve (group A) and 132 (15%) after failed therapy (group B). Resistance to metronidazole was present in 21% (A: 17.7%, B: 40.2%), clarithromycin in 28.8% (A: 25%, B: 51.4%), and both in 7.1% (A: 3.8%, B: 26.5%). The majority received 2-week tailored triple therapy combining proton pump inhibitor (PPI), amoxicillin with clarithromycin (PAC) or metronidazole (PAM). Dosing was lower than recommended for PPI (A: 49%, B: 41%) and amoxicillin (A: 6%, B: 56%). In treatment naïve patients, eradication reached 90% (n = 503, 95% CI 87-93%) and 93% in compliant children (n = 447, 95% CI 90-95%). Tailored triple therapy cured 59% patients after failed therapy (n = 69, 95% CI 48-71%). Treatment failure was associated with PAM in single clarithromycin resistance (OR = 2.47, 95% CI 1.10-5.53), with PAC in single metronidazole resistance (OR = 3.44, 95% CI 1.47-8.08), and with low compliance (OR = 5.89, 95% CI 2.49-13.95). CONCLUSIONS: Guideline-conform 2-weeks therapy with PPI, amoxicillin, clarithromycin or metronidazole tailored to antibiotic susceptibility achieves primary eradication of ≥ 90%. Higher failure rates in single-resistant strains despite tailored treatment indicate missed resistance by sampling error.

Experience of Peripheral Blood CD34+ Stem Cells Collection in Autoimmune Patients.

BACKGROUND: Autologous Hematopoietic Stem Cell Transplantation with or without CD34+ selection is being used successfully to treat patients with severe and refractory autoimmune disease. This study describes our experience of CD34+ stem cell mobilization, harvesting and selection in autoimmune patients based on conditions in Vietnam - the developing country. METHODS: Eight autoimmune patients (four patients with Myasthenia Gravis and four patients with Systemic Lupus Erythematosus) underwent PBSC mobilization with granulocyte colony-stimulating factor (G-CSF) and cyclophosphamide. The apheresis was performed on a Terumo BCT Spectra Optia machine. CD34+ hematopoetic stem cells were collected from the leukapheresis by CliniMACS Plus device using CD34 Enrichment KIT. CD34+ cells, T and B lymphocytes were counted on a FACS BD Canto II device. RESULTS: Eight patients (4 MG and 4 SLE) including 5 females and 3 males were involved in this study. The mean age of the patients was 33.13 ± 16.64 years (ranging from 13 to 58 years). The average number of days for mobilization was 7.9 ± 1.6 days, whereas the average number of days for harvesting was 1.5 ± 0.5 days. There was no difference in the number of days for mobilization and harvesting between the MG and SLE groups. The number of CD34+ cells in peripheral blood (PB) on the day of harvesting was 108.37 ± 59.64 x 106 cells/L. There was a significant difference in white blood cell (WBC), neutrophil, monocyte, and platelet cell counts between before and after mobilization. On the day of stem cell harvesting, variables such as WBC, neutrophil, lymphocyte, monocyte, platelet, CD34+ cell counts, and hemoglobin were not different between the MG and SLE groups. The CD34+ recovery percentage following the CD34+ selection procedure was 68.8%, whereas almost 99.9% of the T and B lymphocytes, and NK cells in the PBSC products were eliminated. CONCLUSIONS: Very first attempts in mobilizing, harvesting, and selecting CD34+ stem cells were successful, paving the way for autoimmune patients to have autologous hematopoietic stem cell transplantation in Vietnam.

Time Series Electrical Motor Drives Forecasting Based on Simulation Modeling and Bidirectional Long-Short Term Memory.

Accurately forecasting electrical signals from three-phase Direct Torque Control (DTC) induction motors is crucial for achieving optimal motor performance and effective condition monitoring. However, the intricate nature of multiple DTC induction motors and the variability in operational conditions present significant challenges for conventional prediction methodologies. To address these obstacles, we propose an innovative solution that leverages the Fast Fourier Transform (FFT) to preprocess simulation data from electrical motors. A Bidirectional Long Short-Term Memory (Bi-LSTM) network then uses this altered data to forecast processed motor signals. Our proposed approach is thoroughly examined using a comparative examination of cutting-edge forecasting models such as the Recurrent Neural Network (RNN), Long Short-Term Memory (LSTM), and Gated Recurrent Unit (GRU). This rigorous comparison underscores the remarkable efficacy of our approach in elevating the precision and reliability of forecasts for induction motor signals. The results unequivocally establish the superiority of our method across stator and rotor current testing data, as evidenced by Mean Absolute Error (MAE) average results of 92.6864 and 93.8802 for stator and rotor current data, respectively. Additionally, compared to alternative forecasting models, the Root Mean Square Error (RMSE) average results of 105.0636 and 85.7820 underscore reduced prediction loss.

Flamingo-Optimization-Based Deep Convolutional Neural Network for IoT-Based Arrhythmia Classification.

Cardiac arrhythmia is a deadly disease that threatens the lives of millions of people, which shows the need for earlier detection and classification. An abnormal signal in the heart causing arrhythmia can be detected at an earlier stage when the health data from the patient are monitored using IoT technology. Arrhythmias may suddenly lead to death and the classification of arrhythmias is considered a complicated process. In this research, an effective classification model for the classification of heart disease is developed using flamingo optimization. Initially, the ECG signal from the heart is collected and then it is subjected to the preprocessing stage; to detect and control the electrical activity of the heart, the electrocardiogram (ECG) is used. The input signals collected using IoT nodes are collectively presented in the base station for the classification using flamingo-optimization-based deep convolutional networks, which effectively predict the disease. With the aid of communication technologies and the contribution of IoT, medical professionals can easily monitor the health condition of patients. The performance is analyzed in terms of accuracy, sensitivity, and specificity.

Activity and Crystal Structure of the Adherent-Invasive Escherichia coli Tle3/Tli3 T6SS Effector/Immunity Complex Determined Using an AlphaFold2 Predicted Model.

The type VI secretion system (T6SS) delivers enzymatic effectors into target cells to destroy them. Cells of the same strain protect themselves against effectors with immunity proteins that specifically inhibit effectors. Here, we report the identification and characterization of a Tle3 phospholipase effector and its cognate immunity protein Tli3-an outer membrane lipoprotein from adherent-invasive Escherichia coli (AIEC). Enzymatic assays demonstrate that purified Tle3AIEC has a phospholipase A1, and not A2, activity and that its toxicity is neutralized by the cognate immunity protein Tli3AIEC. Tli3AIEC binds Tle3 in a 1:1 stoichiometric ratio. Tle3AIEC, Tli3AIEC and the Tle3AIEC-Tli3AIEC complex were purified and subjected to crystallization. The Tle3AIEC-Tli3AIEC complex structure could not be solved by SeMet phasing, but only by molecular replacement when using an AlphaFold2 prediction model. Tle3AIEC exhibits an α/ß-hydrolase fold decorated by two protruding segments, including a N-terminus loop. Tli3AIEC displays a new fold of three stacked ß-sheets and a protruding loop that inserts in Tle3AIECcatalytic crevice. We showed, experimentally, that Tle3AIEC interacts with the VgrG AIEC cargo protein and AlphaFold2 prediction of the VgrGAIEC-Tle3AIEC complex reveals a strong interaction between the VgrGAIEC C-terminus adaptor and Tle3AIEC N-terminal loop.

Classification and Explanation for Intrusion Detection System Based on Ensemble Trees and SHAP Method.

In recent years, many methods for intrusion detection systems (IDS) have been designed and developed in the research community, which have achieved a perfect detection rate using IDS datasets. Deep neural networks (DNNs) are representative examples applied widely in IDS. However, DNN models are becoming increasingly complex in model architectures with high resource computing in hardware requirements. In addition, it is difficult for humans to obtain explanations behind the decisions made by these DNN models using large IoT-based IDS datasets. Many proposed IDS methods have not been applied in practical deployments, because of the lack of explanation given to cybersecurity experts, to support them in terms of optimizing their decisions according to the judgments of the IDS models. This paper aims to enhance the attack detection performance of IDS with big IoT-based IDS datasets as well as provide explanations of machine learning (ML) model predictions. The proposed ML-based IDS method is based on the ensemble trees approach, including decision tree (DT) and random forest (RF) classifiers which do not require high computing resources for training models. In addition, two big datasets are used for the experimental evaluation of the proposed method, NF-BoT-IoT-v2, and NF-ToN-IoT-v2 (new versions of the original BoT-IoT and ToN-IoT datasets), through the feature set of the net flow meter. In addition, the IoTDS20 dataset is used for experiments. Furthermore, the SHapley additive exPlanations (SHAP) is applied to the eXplainable AI (XAI) methodology to explain and interpret the classification decisions of DT and RF models; this is not only effective in interpreting the final decision of the ensemble tree approach but also supports cybersecurity experts in quickly optimizing and evaluating the correctness of their judgments based on the explanations of the results.

RealPrice: Blockchain-Powered Real-Time Pricing for Software-Defined Enabled Edge Network.

With the limited Internet bandwidth in a given area, unlimited data plans can create congestion because there is no retribution for transmitting many packets. The real-time pricing mechanism can inform users of their Internet consumption to limit congestion during peak hours. However, implementing real-time pricing is opex-heavy from the network provider side and requires high-integrity operations to gain consumer trust. This paper aims to leverage the software-defined network to solve the opex issues and blockchain technology to solve trust issues. First, the network congestion level in a given area is analyzed. Then, the price is adjusted accordingly. Devices that send a lot of traffic during congestion will be charged more expensive bills than if transmitting traffic during an off-peak period. To prevent over-charging, the consumers can pre-configure a customized Internet profile stating how many data bytes they are willing to send during congestion. The software-defined controller also authenticates consumers and checks whether they have enough token deposits in the blockchain as Internet usage fees. We implement our work using Ethereum and POX controllers. The experiment results show that the proposed real-time pricing can be performed seamlessly, and the network provider can reap up to 72.91% more profits than existing approaches, such as usage-based pricing or time-dependent pricing. The fairness and trustability of real-time pricing is also guaranteed through the proof-of-usage mechanism and the transparency of the blockchain.

Transformation Kinetics of LiBH4-MgH2 for Hydrogen Storage.

The reactive hydride composite (RHC) LiBH4-MgH2 is regarded as one of the most promising materials for hydrogen storage. Its extensive application is so far limited by its poor dehydrogenation kinetics, due to the hampered nucleation and growth process of MgB2. Nevertheless, the poor kinetics can be improved by additives. This work studied the growth process of MgB2 with varying contents of 3TiCl3·AlCl3 as an additive, and combined kinetic measurements, X-ray diffraction (XRD), and advanced transmission electron microscopy (TEM) to develop a structural understanding. It was found that the formation of MgB2 preferentially occurs on TiB2 nanoparticles. The major reason for this is that the elastic strain energy density can be reduced to ~4.7 × 107 J/m3 by creating an interface between MgB2 and TiB2, as opposed to ~2.9 × 108 J/m3 at the original interface between MgB2 and Mg. The kinetics of the MgB2 growth was modeled by the Johnson-Mehl-Avrami-Kolmogorov (JMAK) equation, describing the kinetics better than other kinetic models. It is suggested that the MgB2 growth rate-controlling step is changed from interface- to diffusion-controlled when the nucleation center changes from Mg to TiB2. This transition is also reflected in the change of the MgB2 morphology from bar- to platelet-like. Based on our observations, we suggest that an additive content between 2.5 and 5 mol% 3TiCl3·AlCl3 results in the best enhancement of the dehydrogenation kinetics.

Sustainable and green trends in using plant extracts for the synthesis of biogenic metal nanoparticles toward environmental and pharmaceutical advances: A review.

Conventionally utilized physical and chemical routes for constructing nanoparticles are not eco-friendly. They are associated with many shortcomings like the requirement of specially designed equipment, templates, extremely high temperature, and pressure. Biosynthesis seems to be drawn unequivocal attention owing to its upsurge of applications in different fields like; energy, nutrition, pharmaceutical, and medicinal sciences. To harness the biological sources, the present review describes an environment-friendly route to generate biogenic nanoparticles from the natural plant extracts and the followed mechanisms for their synthesis, growth, and stabilization. The present review summarizes the recent trends involved in the photosynthesis of metallic nanoparticles and their effective use in controlling malaria, hepatitis, cancer, like various endemic diseases. Also, various characterization approaches, such as UV-visible spectrophotometry, Fourier transform infrared spectroscopy, powder X-ray diffraction, scanning electron microscopy, transmission electron microscopy, and energy-dispersive X-ray spectroscopy, are discussed here examine the properties of as-fabricated nanoparticles. Various plant parts like leaves, stems, barks, fruit, and flowers are rich in flavonoids, phenols, steroids, terpenoids, enzymes, and alkaloids, thereby playing an essential role in reducing metal ions that generate metallic nanoparticles. Herein, the uniqueness of phytofabricated nanoparticles along with their distinctive antibacterial, antioxidant, cytotoxic, and drug delivery properties are featured. Lastly, this work highlights the various challenges and future perspectives to further synthesize biogenic metal nanoparticles toward environmental and pharmaceutical advances in the coming years.

Tetramer formation of Bacillus subtilis YabJ protein that belongs to YjgF/YER057c/UK114 family.

Bacillus subtilis YabJ protein belongs to the highly conserved YjgF/YER057c/UK114 family, which has a homotrimeric quaternary structure. The dominant allele of yabJ gene that is caused by a single amino acid mutation of Ser103Phe enables poly-γ-glutamic acid (γPGA) production of B. subtilis under conditions where the cell-density signal transduction was disturbed by the loss of DegQ function. X-ray crystallography of recombinant proteins revealed that unlike the homotrimeric wild-type YabJ, the mutant YabJ(Ser103Phe) had a homotetrameric quaternary structure, and the structural change appeared to be triggered by an inversion of the fifth ß-strand. The YabJ homotetramer has a hole that is highly accessible, penetrating through the tetramer, and 2 surface concaves as potential ligand-binding sites. Western blot analyses revealed that the conformational change was also induced in vivo by the Ser103Phe mutation.

Development and clinical application of a preimplantation genetic testing for monogenic disease (PGT-M) for beta thalassemia in Vietnam.

PURPOSE: The purpose of this research is to study the clinical outcomes using a next-generation sequencing-based protocol allowing for simultaneous testing of mutations in the beta thalassemia (HBB) gene, including single nucleotide polymorphism (SNP) markers for PGT-M along with low-pass whole genome analysis of chromosome aneuploidies for PGT-A. METHODS: A combined PGT-M (thalassemia) plus PGT-A system was developed for patients undergoing IVF in Vietnam. Here we developed a system for testing numerous thalassemia mutations plus SNP-based testing for backup mutation analysis and contamination control using next-generation sequencing (NGS). Low -pass next-generation sequencing was used to assess aneuploidy in some of the clinical PGT cases. Patients underwent IVF followed by embryo biopsy at the blastocyst stage for combined PGT-A/M. RESULTS: Two cases have completed the entire process including transfer of embryos, while a further nine cases have completed the IVF and PGT-M/A analysis but have not completed embryo transfer. In the two cases with embryo transfer, both patients achieved pregnancy with an unaffected, euploid embryo confirmed through prenatal diagnosis. In the further nine cases, 39 embryos were biopsied and all passed QC for amplification. There were 8 unaffected embryos, 31 carrier embryos, and 11 affected embryos. A subset of 24 embryos also had PGT-A analysis with 22 euploid embryos and 2 aneuploid embryos. CONCLUSIONS: Here we report the development and clinical application of a combined PGT-M for HBB and PGT-A for gross chromosome aneuploidies from 11 patients with detailed laboratory findings along with 2 cases that have completed embryo transfer.

Design, synthesis and evaluation of novel indirubin-based N-hydroxybenzamides, N-hydroxypropenamides and N-hydroxyheptanamides as histone deacetylase inhibitors and antitumor agents.

Several novel indirubin-based N-hydroxybenzamides, N-hydropropenamides and N-hydroxyheptanamides (4a-h, 7a-h, 10a-h) were designed using a fragment-based approach with structural features extracted from several previously reported HDAC inhibitors, such as SAHA (vorinostat), MGCD0103 (mocetinostat), nexturastat A and PXD-101 (belinostat). The biological results reveal that our compounds showed excellent cytotoxicity toward three common human cancer cell lines (SW620, PC-3 and NCI-H23) with IC50 values ranging from 0.09 to 0.007 µM. The cytotoxicity of the compounds was equipotent or even up to 10-times more potent than adriamycin and up to 205-times more potent than SAHA. Among the series of N-hydroxypropenamides, compounds 10a-d were the most potent HDAC inhibitors as well as cytotoxicity toward the cell lines tested. In addition, the strong inhibitory activites toward HDAC of our compounds were observed with IC50 values of below-micromolar range. Especially, compound 4a inhibited HDAC6 with an IC50 value of 29-fold lower than that against HDAC2 isoform. Representative compounds 4a and 7a were found to significantly arrest SW620 cells at G0/G1 phase. Compounds 7a and 10a were found to strongly induce apoptosis in SW620 cells. Docking studies revealed some important features affecting the selectivity against HDAC6 isoform. The results clearly demonstrate the potential of the indirubin-hydroxamic acid hybrids and these compounds should be very promising for further development.

Helicobacter pylori Infection in Pediatric Patients Living in Europe: Results of the EuroPedHP Registry 2013 to 2016.

OBJECTIVES: The aim of the study was to assess clinical presentation, endoscopic findings, antibiotic susceptibility and treatment success of Helicobacter pylori (H. pylori) infected pediatric patients. METHODS: Between 2013 and 2016, 23 pediatric hospitals from 17 countries prospectively submitted data on consecutive H. pylori-infected (culture positive) patients to the EuroPedHP-Registry. RESULTS: Of 1333 patients recruited (55.1% girls, median age 12.6 years), 1168 (87.6%) were therapy naïve (group A) and 165 (12.4%) had failed treatment (group B). Patients resided in North/Western (29.6%), Southern (34.1%) and Eastern Europe (23.0%), or Israel/Turkey (13.4%). Main indications for endoscopy were abdominal pain or dyspepsia (81.2%, 1078/1328). Antral nodularity was reported in 77.8% (1031/1326) of patients, gastric or duodenal ulcers and erosions in 5.1% and 12.8%, respectively. Primary resistance to clarithromycin (CLA) and metronidazole (MET) occurred in 25% and 21%, respectively, and increased after failed therapy. Bacterial strains were fully susceptible in 60.5% of group A, but in only 27.4% of group B. Primary CLA resistance was higher in Southern and Eastern Europe (adjusted odds ratio [ORadj] = 3.44, 95% confidence interval [CI] 2.22-5.32, P < 0.001 and 2.62, 95% CI: 1.63-4.22, P < 0.001, respectively) compared with Northern/Western Europe. Children born outside Europe showed higher primary MET resistance (ORadj = 3.81, 95% CI: 2.25-6.45, P < 0.001). Treatment success in group A reached only 79.8% (568/712) with 7 to 14 days triple therapy tailored to antibiotic susceptibility. CONCLUSIONS: Peptic ulcers are rare in dyspeptic H. pylori-infected children. Primary resistance to CLA and MET is markedly dependent on geographical regions of birth and residence. The ongoing survey will show whether implementation of the updated ESPGHAN/NASPGHAN guidelines will improve the eradication success.

Exploration of certain 1,3-oxazole- and 1,3-thiazole-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents.

Several novel series of hydroxamic acids bearing 2-benzamidooxazole/thiazole (5a-g, 6a-g) or 2-phenylsulfonamidothiazole (8a-c) were designed and synthesized. The compounds were obtained straightforwards via a two step pathway, starting from commercially available ethyl 2-aminooxazole-4-carboxylate or ethyl 2-aminothiazole-4-carboxylate. Biological evaluation showed that these hydroxamic acids generally exhibited good cytotoxicity against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung cancer), with IC50 values in low micromolar range and comparable to that of SAHA. These compounds also comparably inhibited HDACs with IC50 values in sub-micromolar range (0.010-0.131 µM) and some compounds (e.g 5f, IC50, 0.010 µM) were even more potent than SAHA (IC50, 0.025 µM) in HDAC inhibition. Representative compounds 6a and 8a appeared to arrest the SW620 cell cycle at G2 phase and significantly induced both early and late apoptosis of SW620 colon cancer cells. Docking experiments on HDAC2 and HDAC6 isozymes revealed favorable interactions at the tunnel of the HDAC active site which positively contributed to the inhibitory activity of synthesized compound. The binding affinity predicted by docking program showed good correlation with the experimental IC50 values. This study demonstrates that simple 1,3-oxazole- and 1,3-thiazole-based hydroxamic acids are also promising as antitumor agents and HDAC inhibitors and these results should provide valuable information for further design of more potent HDAC inhibitors and antitumor agents.