Nanoscale Dodecahedral and Fullerene-Type Organoboroxine and Borazine Cages from Planar Building Units.

Boroxine- and borazine-cage analogs to C20, C60, and C70 were calculated and compared in terms of structure, strain indicators, and physical properties relevant to nanoscale applications. The results show C60 and C70 type cages are less strained than the smaller congener, primarily due to minimized bending in the B-arylene-B segments. The smallest cage calculated has a diameter of 2.4 nm, which increases up to 4.9 nm by either variation of the polyhedron (C20 < C60 < C70-type cage) or organic spacer elongation between boron centers. All calculated cages are porous (apertures ranging from 0.6 to 1.9 nm). Molecular electrostatic potential and Hirshfeld population analysis revealed both nucleophilic and electrophilic sites in the interior and exterior cage surfaces. HOMO-LUMO gaps range from 3.98 to 4.89 eV and 5.10-5.18 eV for the boroxine- and borazine-cages, respectively. Our findings provide insights into the design and properties of highly porous boroxine and borazine cages for nanoscience.

Discontinuation versus continuation of imatinib in patients with advanced gastrointestinal stromal tumours (BFR14): exploratory long-term follow-up of an open-label, multicentre, randomised, phase 3 trial.

BACKGROUND: The long-term impact of tyrosine kinase inhibitor (TKI) discontinuation on resistance and survival in patients with advanced gastrointestinal stromal tumours (GIST) is unclear. We report the exploratory long-term outcomes of patients with advanced GIST stopping imatinib in the BFR14 trial. METHODS: BFR14, an open-label, randomised, phase 3 trial, was done in 17 comprehensive cancer centres or hospitals across France. Patients with advanced GIST aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-3, no previous treatment with imatinib, and no previous malignancy were eligible. Patients were treated with oral imatinib 400 mg daily. Patients with a complete or partial response, or stable disease, according to Response Evaluation Criteria in Solid Tumours (1.0) at 1 year, 3 years, and 5 years from the start of treatment were randomly assigned (1:1) to treatment discontinuation until progression (interruption group) or treatment continuation until progression (continuation group). Randomisation was done centrally with computer-generated permuted blocks of two and six patients stratified by participating centre and presence or absence of residual disease on CT scan. The primary endpoint was progression-free survival. Secondary endpoints included time to imatinib resistance and overall survival. Analyses were conducted on an intention-to-treat basis in all randomly assigned patients who were not lost to follow-up. This trial is registered with ClinicalTrial.gov, NCT00367861. FINDINGS: Between May 12, 2003, and March 16, 2004, after 1 year of imatinib, 32 patients were randomly assigned to the interruption group and 26 to the continuation group. Between June 13, 2005, and May 30, 2007, after 3 years of imatinib, 25 patients were randomly assigned to the interruption group and 25 to the continuation group. Between Nov 9, 2007, and July 12, 2010, after 5 years of imatinib, 14 patients were randomly assigned to the interruption group and 13 to the continuation group. Median follow-up was 235·2 months (IQR 128·8-236·6) after the 1-year randomisation, 200·9 months (190·2-208·4) after the 3-year randomisation, and 164·5 months (134·4-176·4) after the 5-year randomisation. Median progression-free survival in the interruption group versus the continuation group after 1 year of imatinib was 6·1 months (95% CI 2·5-10·1) versus 27·8 months (19·5-37·9; hazard ratio [HR] 0·36 [95% CI 0·20-0·64], log-rank p=0·0003), after 3 years of imatinib was 7·0 months (3·5-11·7) versus 67·0 months (48·8-85·6; 0·15 [0·07-0·32], log-rank p<0·0001), and after 5 years of imatinib was 12·0 months (9·0-16·6) versus not reached (NR; NR-NR; 0·13 [0·03-0·58], log-rank p=0·0016). The median time to imatinib resistance after 1 year of imatinib was 28·7 months (95% CI 18·1-39·1) versus 90·6 months (25·3-156·1; HR 0·93 [95% CI 0·51-1·71], log-rank p=0·82), after 3 years was 66·2 months (43·0-89·6) versus 127·3 months (15·0-239·7; 0·35 [0·17-0·72, log-rank p=0·0028), and after 5 years was 58·6 months (0·0-167·4) versus NR (NR-NR; 0·24 [0·05-1·12], log-rank p=0·049). Median overall survival after 1 year of imatinib was 56·0 months (95% CI 30·3-82·9) versus 105·0 months (20·6-189·6; HR 0·84 [95% CI 0·46-1·54], log-rank p=0·57), after 3 years was 104·0 months (90·7-118·7) versus 134·0 months (89·7-178·3; 0·40 [0·20-0·82], log-rank p=0·0096), and after 5 years was NR (NR-NR) versus 110·4 months (82·7-154·1; 1·28 [0·41-3·99]; log-rank p=0·67), INTERPRETATION: Imatinib interruption in patients with GIST without progressive disease is not recommended. Imatinib interruption in non-progressing patients with GIST was associated with rapid progression, faster resistance to imatinib, and shorter overall survival in the long-term follow-up when compared with imatinib continuation in patients after 3 years and 5 years of imatinib. FUNDING: Centre Léon Bérard, INCa, CONTICANET, Ligue Contre le Cancer, and Novartis.

Improved cognition after rifaximin treatment is associated with changes in intra- and inter-brain network functional connectivity.

BACKGROUND: Rifaximin is a non-reabsorbable antibiotic which acts at gut level, and improves cognition and inflammatory parameters in minimal hepatic encephalopathy (MHE) patients, but not all patients show the same level of response. This study aims to assess brain activity, both within and between brain networks, following rifaximin treatment, considering the differences between response groups as well. METHODS: Twenty-two healthy controls and 53 patients with cirrhosis (22 without and 31 with MHE, diagnosed by Psychometric Hepatic Encephalopathy Score, PHES) performed psychometric, attention and coordination tests, and blood inflammatory parameters were measured. Resting-state functional magnetic resonance imaging (fMRI) acquisitions were performed on controls and MHE patients. Eighteen MHE patients underwent a rifaximin treatment for 6 months, after which all measures were repeated. fMRI images were analysed and changes after treatment were assessed. RESULTS: After rifaximin treatment, 13 patients improved their PHES score (Responder patients) while 5 did not (Non-responder patients). No significant decrease in blood ammonia was observed after rifaximin treatment, but there was a decrease in plasma inflammatory cytokines in responder patients. A global effect of rifaximin was detected on the sensorimotor and fronto-parietal networks. Responder patients showed a relative increase of thalamic network connectivity in comparison to non-responder patients. Before treatment, responder and non-responder patients showed connectivity differences in basal ganglia network. The connection of the sensorimotor and thalamic networks between them and with other networks suffered changes after treatment. These connections between networks mostly decreased after treatment. All changes and differences showed a significant level of correlation with the performance of psychometric tests and the blood levels of inflammatory biomarkers. CONCLUSIONS: There was an improvement of the communication between executive, motor and attention-related brain areas, and their functional independence following rifaximin treatment. Patients who respond also show a less deteriorated connection involved in these functions before treatment. Results suggest that the improved inflammatory state of MHE patients, following rifaximin treatment would favour the observed changes in brain function and enhanced cognitive performance.

CD59 gene: 143 haplotypes of 22,718 nucleotides length by computational phasing in 113 individuals from different ethnicities.

BACKGROUND: CD59 deficiency due to rare germline variants in the CD59 gene causes disabilities, ischemic strokes, neuropathy, and hemolysis. CD59 deficiency due to common somatic variants in the PIG-A gene in hematopoietic stem cells causes paroxysmal nocturnal hemoglobinuria. The ISBT database lists one nonsense and three missense germline variants that are associated with the CD59-null phenotype. To analyze the genetic diversity of the CD59 gene, we determined long-range CD59 haplotypes among individuals from different ethnicities. METHODS: We determined a 22.7 kb genomic fragment of the CD59 gene in 113 individuals using next-generation sequencing (NGS), which covered the whole NM_203330.2 mRNA transcript of 7796 base pairs. Samples came from an FDA reference repository and our Ethiopia study cohorts. The raw genotype data were computationally phased into individual haplotype sequences. RESULTS: Nucleotide sequencing of the CD59 gene of 226 chromosomes identified 216 positions with single nucleotide variants. Only three haplotypes were observed in homozygous form, which allowed us to assign them unambiguously as experimentally verified CD59 haplotypes. They were also the most frequent haplotypes among both cohorts. An additional 140 haplotypes were imputed computationally. DISCUSSION: We provided a large set of haplotypes and proposed three verified long-range CD59 reference sequences, based on a population approach, using a generalizable rationale for our choice. Correct long-range haplotypes are useful as template sequences for allele calling in high-throughput NGS and precision medicine approaches, thus enhancing the reliability of clinical diagnostics. Long-range haplotypes can also be used to evaluate the influence of genetic variation on the risk of transfusion reactions or diseases.

Effect of COVID-19 on infections associated with medical devices in critical care.

OBJECTIVES: This study explores the hypothesis that COVID-19 patients are at a heightened risk of healthcare-associated infections (HAIs) associated with medical device usage compared to non-COVID-19 patients. Our primary objective was to investigate the correlation between COVID-19 infection in ICU patients and subsequent HAIs following invasive medical device insertion. Additionally, we aim to assess the impact of SARS-CoV-2 infection on onset times concerning specific microorganisms and the type of medical device, providing valuable insights into this intricate relationship in intensive care settings. METHODOLOGY: A retrospective cohort study was conducted using ICU patient records at our hospital from 2020 to 2022. This investigation entailed evaluating the timing of HAIs while distinguishing between patients with and without SARS-CoV-2 infection. We identified and analyzed the type of isolation and infection attributed to the medical device while controlling for ICU duration and ventilator days using Cox regression. RESULTS: Our study included 127 patients without SARS-CoV-2 infection and 140 patients with SARS-CoV-2 infection. The findings indicated a higher incidence of HAI caused by various microorganisms associated with any medical device in patients with SARS-CoV-2 (HR = 6.86; 95% CI-95%: 3.26-14.43; p < 0.01). After adjusting for ICU duration and ventilator days, a heightened frequency of HAIs persisted in SARS-CoV-2-infected individuals. However, a detailed examination of HAIs revealed that only ventilation-associated pneumonia (VAP) displayed a significant association (HR = 6.69; 95% CI: 2.59-17.31; p < 0.01). A statistically significant correlation between SARS-CoV-2 infection and the isolation of S. aureus was also observed (p = 0.034). The prevalence of S. aureus infection was notably higher in patients with SARS-CoV-2 (RR = 8.080; 95% CI: 1.052-62.068; p < 0.01). CONCLUSIONS: The frequency of pathogen isolates in invasive medical devices exhibited an association with SARS-CoV-2 infection. Critically ill patients with SARS-CoV-2 are more prone to developing early-onset VAP than those without SARS-CoV-2 infection.

Chemical Constituents from Agave applanata and Its Antihyperglycemic, Anti-inflammatory, and Antimicrobial Activities Associated with Its Tissue Repair Capability.

Agave applanata is a Mexican agave whose fresh leaves are employed to prepare an ethanol tonic used to relieve diabetes. It is also applied to skin to relieve varicose and diabetic foot ulcers, including wounds, inflammation, and infections. In this study, the chemical composition of this ethanol tonic is established and its association with antihyperglycemic, anti-inflammatory, antimicrobial, and wound healing activities is discussed. The fresh leaves of A. applanata were extracted with ethanol : H2O (85 : 15). A fraction of this extract was lyophilized, and the remainder was partitioned into CH2Cl2, n-BuOH, and water. CH2Cl2 and n-BuOH fractions were subjected to a successive open column chromatography process. The structure of the isolated compounds was established using nuclear magnetic resonance and mass spectrometry spectra. The antihyperglycemic activity was evaluated through in vivo sucrose and glucose tolerance experiments, as well as ex vivo intestinal absorption and hepatic production of glucose. Wound healing and edema inhibition were assayed in mice. The minimum inhibitory concentrations (MICs) of the hydroalcoholic extract, its fractions, and pure compounds were determined through agar microdilution against the most isolated pathogens from diabetic foot ulcers. Fatty acids, ß-sitosterol, stigmasterol, hecogenin (1: ), N-oleyl-D-glucosamine, ß-daucosterol, sucrose, myo-inositol, and hecogenin-3-O-α-L-rhamnopyranosyl-(1 → 3)-ß-D-xylopyranosyl-(1 → 2)-[ß-D-xylopyranosyl-(1 → 3)-ß-D-glucopyranosyl-(1 → 3)]-ß-D-glucopyranosyl-(1 → 4)-ß-D-galactopyranoside (2: ) were characterized. This research provides evidence for the pharmacological importance of A. applanata in maintaining normoglycemia, showing anti-inflammatory activity and antimicrobial effects against the microorganisms frequently found in diabetic foot ulcers. This plant plays an important role in wound healing and accelerated tissue reparation.

Optimizing patient outcomes: a comprehensive evaluation of protocolized sedation in intensive care settings: a systematic review and meta-analysis.

INTRODUCTION: Amidst the routine utilization of protocolized sedation in ventilated ICU patients, existing management guidelines exhibit a lack of unanimous recommendations for its widespread adoption. This study endeavors to comprehensively assess the effectiveness and safety of protocolized sedation in critically ill ventilated patients. OBJECTIVE: The primary objective of this study was to systematically review and conduct a meta-analysis of clinical trials comparing protocolized sedation with standard management in critically ill ventilated patients. Key outcomes under scrutiny include ICU and hospital mortality, ventilation days, duration of ICU stay, and incidents of self-extubation. The evaluation incorporates the Risk of Bias 2 (RoB2) tool to assess the quality of included studies. Data analysis utilizes a random-effects model for relative risk (RR) and mean differences. Subgroup analysis categorizes sedation protocols into algorithmic or daily interruption, addressing potential heterogeneity. Additionally, a GRADE evaluation is performed to ascertain the overall certainty of the evidence. RESULTS: From an initial pool of 1504 records, 10 studies met the inclusion criteria. Protocolized sedation demonstrated a reduced RR for mortality (RR: 0.80, 95% CI 0.68-0.93, p < 0.01, I2 = 0%) and a decrease in ventilation days (mean difference: - 1.12, 95% CI - 2.11 to - 0.14, p = 0.03, I2 = 84%). Furthermore, there was a notable reduction in ICU stay (mean difference: - 2.24, 95% CI - 3.59 to - 0.89, p < 0.01, I2 = 81%). However, incidents of self-extubation did not exhibit a significant difference (RR: 1.20, 95% CI 0.49-2.94, p = 0.69, I2 = 35%). Subgroup analyses effectively eliminated heterogeneity (I2 = 0%), and the GRADE evaluation yielded moderate results for mortality, ventilation days, and ICU duration. CONCLUSION: Protocolized sedation, whether implemented algorithmically or through daily interruption, emerges as a safe and effective approach when compared to standard management in ventilated ICU patients. The findings from this study contribute valuable insights to inform evidence-based practices in sedation management for this critical patient population.

DNA Reference Reagents for Genotyping RH Variants.

Patients who carry Rhesus (RH) blood group variants may develop Rh alloantibodies requiring matched red blood cell transfusions. Serologic reagents for Rh variants often fail to specifically identify variant Rh antigens and are in limited supply. Therefore, red blood cell genotyping assays are essential for managing transfusions in patients with clinically relevant Rh variants. Well-characterized DNA reference reagents are needed to ensure quality and accuracy of the molecular tests. Eight lyophilized DNA reference reagents, representing 21 polymorphisms in RHD and RHCE, were produced from an existing repository of immortalized B-lymphoblastoid cell lines at the Center for Biologics Evaluation and Research/US Food and Drug Administration. The material was validated through an international collaborative study involving 17 laboratories that evaluated each DNA candidate using molecular assays to characterize RHD and RHCE alleles, including commercial platforms and laboratory-developed testing, such as Sanger sequencing, next-generation sequencing, and third-generation sequencing. The genotyping results showed 99.4% agreement with the expected results for the target RH polymorphisms and 87.9% for RH allele agreement. Most of the discordant RH alleles results were explained by a limited polymorphism coverage in some genotyping methods. Results of stability and accelerated degradation studies support the suitability of these reagents for use as reference standards. The collaborative study results demonstrate the qualification of these eight DNA reagents for use as reference standards for RH blood group genotyping assay development and analytical validation.

Fundoplication with extensive dissection of the esophagogastric junction: Lessons learned and outcomes from 178 consecutives patients.

INTRODUCTION: Antireflux surgery is commonly associated with significant recurrence and complication rates, and several surgical techniques have been proposed to minimize them. The aim of this study is to evaluate the results of a fundoplication with extensive dissection of the esophagogastric junction 1 and 3 years after the procedure. METHODS: Retrospective observational study including 178 patients with gastroesophageal reflux disease or hiatal hernia who underwent fundoplication with extensive dissection of the esophagogastric junction between 2015 and 2020. Hernia recurrence, symptoms and quality of life at 1 and 3 years after surgery were assessed by barium transit, endoscopy and questionnaires for symptoms and quality of life (GERD-HRQL). RESULTS: Heartburn rate was 7.5% and 10.7% at 1 and 3 years respectively, regurgitation 3.8% and 6.9% and dysphagia was 3.7% and 7.6%. The presence of hiatal hernia was evident preoperatively in 55.1% and in 7.8% and 9.6% at follow-up and the median GERD-HRQL scale was 27, 2 and 0 respectively. There were no cases of slippage of the fundoplication or symptoms suggestive of vagal injury. No differences were found when comparing the different types of fundoplication in terms of reflux and recurrence or complications. CONCLUSIONS: Fundoplication with extensive dissection of the esophagogastric junction contributes to correct positioning and better anchorage of the fundoplication, which is associated with low rates of hiatal hernia and reflux recurrence, as well as absence of slippage and lower possibility of vagal injury.

A preliminary report on critical antimicrobial resistance in Escherichia coli, Enterococcus faecalis, and Enterococcus faecium strains isolated from healthy dogs in Chile during 2021-2022.

Antimicrobial Resistance (AMR) represents one of the main current threats to global public health; where production animals, companion animals, humans, and the environment play a significant role in its dissemination. However, little attention has been given to companion animals as reservoirs and disseminators of relevant antimicrobial resistant bacteria, especially in South American countries such as Chile. For this reason, this research aimed to estimate the prevalence of AMR to different critical antibiotics at a screening level in commensal bacteria such as E. coli and Enterococcus spp., isolated from healthy pet dogs in the Metropolitan Region of Chile, studying their geographical distribution and evaluating associations of phenotypic resistance to different antibiotics. Thus, in E. coli we detected AMR to all critical drugs assessed, including 34.1% to amoxicillin, 20.1% to colistin, 15.7% to enrofloxacin, and 9.2% to cefotaxime. On the other hand, AMR prevalence in E. faecalis was 8.1% for ampicillin and 3.4% for vancomycin; while for E. faecium the AMR prevalence was 19.1% for ampicillin and 10.2% for vancomycin. Additionally, significant differences in prevalence of the different possible AMR were detected according to their geographical distribution, suggesting the existence of various risk factors and stressing the need to establish mitigation measures specific to the differences identified.

Dysexecutive symptomatology in everyday functioning and academic achievement in adolescents.

Background: During the educational stage, academic achievement depends on various social, family, and personal factors. Among the latter, executive skills in everyday life play a significant role in dealing with the academic demands of adolescents. Therefore, the aim of this study is to ascertain the effects of executive symptomatology in everyday functioning on academic achievement in adolescents. Method: The study involved 910 students aged between 13 and 15 years (M = 14.09, SD = 0.68) from both public and private schools in the Community of Madrid. The DEX, BDEFS-CA, and BRIEF-SR questionnaires were utilised to assess executive difficulties, while grades in language, mathematics, and natural sciences were used as a measure of academic achievement. Results: The data revealed statistically significant differences in working memory, emotional control, materials organisation, and task completion. In relation to language and natural sciences subjects. In the case of mathematics, emotional control and task completion were significant variables. Conclusion: Our results indicate that certain executive skills that are manifested in everyday life activities can contribute, albeit in a variable way, to academic achievement in the subjects studied. This aspect is relevant insofar as it allows us to develop preventive interventions based on the executive training of these everyday skills.

Efficacy and safety of dynamic arterial elastance for weaning vasopressor support in septic shock patients: a randomised controlled trial protocol.

INTRODUCTION: The dynamic arterial elastance (EaDyn), calculated as pulse pressure variation divided by stroke volume variation, has been studied as a predictor of vasopressor weaning. However, its potential as a haemodynamic tool for tapering off vasopressors in patients with sepsis remains unexplored. Therefore, our study aimed to assess whether using EaDyn for weaning vasopressor support could reduce the duration of vasopressor support in patients with sepsis. METHODS AND ANALYSIS: This pragmatic single-centre controlled clinical trial will take place at Fundación Santa Fe de Bogotá, Colombia. Adult patients diagnosed with septic shock according to the sepsis-3 criteria and a Sequential Organ Failure Assessment score ≥4 will be included. A total of 114 patients (57 per group) will undergo conventional critical care monitoring, and the weaning of vasopressor support will be initiated based on the EaDyn or mean arterial pressure (MAP), depending on the assigned group. EaDyn will be estimated based on the measurements obtained from a PiCCO device connected to a PulsioFlex Monitoring Platform (PULSION Medical Systems SE, Feldkirchen, Germany). Our primary outcome is the difference in vasopressor support duration between the EaDyn and MAP groups.Participants and statisticians performing the statistical analysis will be blinded to the group allocation. Dependent and independent variables will be analysed through univariate and multivariate statistical tests. Since we will perform three repeated measurements for analysis, we will implement a Bonferroni post hoc correction. Additionally, Cox regression and Kaplan-Meier analyses will be conducted to address objectives related to time. ETHICS AND DISSEMINATION: This study was approved by the Ethics Committee at Fundación Santa Fe de Bogotá (CCEI-16026-2024). Written informed consent will be obtained from all participants. The results will be disseminated through publication in peer-reviewed journals and presentations at national and international events. TRIAL REGISTRATION NUMBER: NCT06118775.

Green Enzymatic Synthesis of Geranyl Butyrate: Process Optimization and Mechanistic Insights.

Flavor esters are organic compounds widely used in the food industry to enhance the aroma and taste of products. However, most chemical processes for the production of these flavoring compounds use toxic organic solvents. Some organic solvents derived from petroleum can leave behind residual traces in food products, which may raise concerns about potential health risks and contamination. In this study, we employ Eversa Transform 2.0, a commercial lipase derived from the lipase from Thermomyces lanuginosus, to produce geranyl butyrate in aqueous media. The chemical process was optimized using the Taguchi method, and a conversion of 93% was obtained at the optimal reaction conditions of: 1:5 molar ratio (v/v), 15% biocatalyst load (w/w), at 50 °C, in 6 h. Classic (molecular dynamics) and quantum (density functional theory) simulations unveiled amino acid residues involved in the stabilization of the enzyme-substrate complex. Detailed QM/MM mechanistic studies identified the nucleophilic attack of the deacylation reaction as the rate-limiting step of the entire mechanism, which has a free energy barrier of 14.0 kcal/mol.

Long term survival in adult osteosarcoma patients treated with a two-drug regimen: Final results of the OSAD93 phase II study of the FSG-GETO.

RATIONALE: We report a phase II trial (OSAD93) testing CDDP with ifosfamide (IFO), without doxorubicin in neoadjuvant phase, in adult osteosarcoma with a 25 years follow-up. PATIENTS AND METHODS: This is a multicentric phase II study of neoadjuvant chemotherapy with IFO and CDDP in localized high-grade osteosarcoma of patients. Patients received 4 pre-operative courses of IFO 9 g/m2 and CDDP 100 mg/m2 on day 4 (SHOC regimen), followed by local treatment. Doxorubicin was added post-operatively (HOCA regimen) in patients with > 10 % residual tumor cells. A Good Histological Response (GHR), ie ≤ 10 % residual tumor cells in > 30 % of patients, was the primary objective. Disease-free survival (DFS), overall survival (OS) and toxicity were secondary objectives. RESULTS: From Jan 1994 to Jun 1998, 60 patients were included. Median age was 27 (range: 16-63). Primary tumor sites were limbs (76 %), trunk, head or neck (24 %). After neoadjuvant SHOC, grade 3-4 and febrile neutropenia, thrombopenia, and re-hospitalization occurred in 58 %, 17 %, 17 % and 22 % of SHOC courses and in 76 %, 28 %, 47 %, 47 % of HOCA courses, respectively. GHR was obtained in 16/60 (27.5 %) patients. With a median follow-up of 322 months, the DFS and OS were 51.8 % and 64.4 % at 5 years. At 10 years, DFS and OS were 49.9 % and 64.4 %. At 25 years, DFS and OS were 47.8 % and 55.9 %. No long-term cardiac toxicity was observed. Three patients developed a second malignancy (one fatal) after 300 months. CONCLUSION: Though the primary endpoint of OSAD93 was not met, this pre-operative doxorubicin-free regimen led to excellent long-term survival with limited toxicity in localized osteosarcoma.

Mangiferin potentiates the activity of antifungal agents against fluconazole-resistant Candida spp.

Aim: To evaluate the antifungal activity of mangiferin against Candida spp. resistant to fluconazole.Materials & methods: The antifungal activity of mangiferin was assessed using broth microdilution and its interaction with azoles and amphotericin B was evaluated by checkerboard. The activity of mangiferin against Candida spp. biofilms was assessed using the MTT colorimetric assay and its possible mechanism of action was evaluated using flow cytometry.Results: Mangiferin showed activity against Candida albicans, Candida tropicalis and Candida parapsilosis resistant to fluconazole and showed synergism with azoles and amphotericin B. Mangiferin increased the activity of antifungals against Candida biofilms and caused depolarization of the mitochondrial membrane and externalization of phosphatidylserine, suggesting apoptosis.Conclusion: mangiferin combined with antifungals has potential against Candida spp.

Candida is a type of fungus that can make people ill. Over time, many species of Candida have found ways to resist the drugs used to kill them. It is important to find new drugs. We decided to see if a substance called mangiferin works against Candida. We found that mangiferin works against Candida and may help other drugs to work better. We still need to do more studies to find out whether mangiferin can help prevent diseases caused by Candida in the future.

Antimicrobial activity of hydralazine against methicillin-resistant and methicillin-susceptible Staphylococcus aureus.

Background: Staphylococcus aureus is a human pathogen responsible for high mortality rates. The development of new antimicrobials is urgent. Materials & methods: The authors evaluated the activity of hydralazine along with its synergism with other drugs and action on biofilms. With regard to action mechanisms, the authors evaluated cell viability, DNA damage and molecular docking. Results: MIC and minimum bactericidal concentration values ranged from 128 to 2048 µg/ml. There was synergism with oxacillin (50%) and vancomycin (25%). Hydralazine reduced the viability of biofilms by 50%. After exposure to hydralazine 2× MIC, 58.78% of the cells were unviable, 62.07% were TUNEL positive and 27.03% presented damage in the comet assay (p < 0.05). Hydralazine showed affinity for DNA gyrase and TyrRS. Conclusion: Hydralazine is a potential antibacterial.

Staphylococcus aureus is a bacterium that can cause infection. Infections of S. aureus are becoming difficult to treat, but developing new drugs is a challenge. Repurposing them may be easier. This study looks at the possibility of using hydralazine, a type of medicine used to treat high blood pressure, against S. aureus. The authors found that hydralazine can kill S. aureus and can be used with other antibiotics, including oxacillin and vancomycin. Hydralazine interferes with important processes for the multiplication and survival of this bacterium. These results are preliminary but encouraging. Further studies are needed to confirm the use of hydralazine as a new treatment for S. aureus infections.

Predictive value of dynamic arterial elastance for vasopressor withdrawal: a systematic review and meta-analysis.

BACKGROUND: Dynamic arterial elastance (Eadyn) has been investigated for its ability to predict hypotension during the weaning of vasopressors. Our study focused on assessing Eadyn's performance in the context of critically ill adult patients admitted to the intensive care unit, regardless of diagnosis. MAIN BODY: Our study was conducted in accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analysis checklist. The protocol was registered in PROSPERO (CRD42023421462) on May 26, 2023. We included prospective observational studies from the MEDLINE and Embase databases through May 2023. Five studies involving 183 patients were included in the quantitative analysis. We extracted data related to patient clinical characteristics, and information about Eadyn measurement methods, results, and norepinephrine dose. Most patients (76%) were diagnosed with septic shock, while the remaining patients required norepinephrine for other reasons. The average pressure responsiveness rate was 36.20%. The synthesized results yielded an area under the curve of 0.85, with a sensitivity of 0.87 (95% CI 0.74-0.93), specificity of 0.76 (95% CI 0.68-0.83), and diagnostic odds ratio of 19.07 (95% CI 8.47-42.92). Subgroup analyses indicated no variations in the Eadyn based on norepinephrine dosage, the Eadyn measurement device, or the Eadyn diagnostic cutoff to predict cessation of vasopressor support. CONCLUSIONS: Eadyn, evaluated through subgroup analyses, demonstrated good predictive ability for the discontinuation of vasopressor support in critically ill patients.

Relationship between sociodemographic, clinical, and laboratory characteristics and severity of COVID-19 in pediatric patients.

COVID-19 affects children less seriously than adults; however, severe cases and deaths are documented. This study objective is to determine socio-demographic, clinical and laboratory indicators associated with severe pediatric COVID-19 and mortality at hospital entrance. A multicenter, retrospective, cross-sectional study was performed in 13 tertiary hospitals in Bolivia. Clinical records were collected retrospectively from patients less than 18 years of age and positive for SARS-CoV-2 infection. All variables were measured at hospital entrance; outcomes of interest were ICU admission and death. A score for disease severity was developed using a logistic regression model. 209 patients were included in the analysis. By the end of the study, 43 (20.6%) of children were admitted to the Intensive care unit (ICU), and 17 (8.1%) died. Five indicators were independently predictive of COVID-19 severity: age below 10 years OR: 3.3 (CI95%: 1.1-10.4), days with symptoms to medical care OR: 2.8 (CI95%: 1.2-6.5), breathing difficulty OR: 3.4 (CI95%: 1.4-8.2), vomiting OR: 3.3 (CI95%: 1.4-7.4), cutaneous lesions OR: 5.6 (CI95%: 1.9-16.6). Presence of three or more of these risk factors at hospital entrance predicted severe disease in COVID-19 positive children. Age, presence of underlying illness, male sex, breathing difficulty, and dehydration were predictive of death in COVID-19 children. Our study identifies several predictors of severe pediatric COVID-19 and death. Incorporating these predictors, we developed a tool that clinicians can use to identify children at high risk of severe COVID-19 in limited-resource settings.