Identification of Nifurtimox metabolites in urine of pediatric Chagas disease patients by UHPLC-MS/MS

Background Nifurtimox (NFX) is one of the only 2 available drugs for the treatment of Chagas disease, a parasitic disease endemic to Latin America. In spite of widespread use of this medication, little is known regarding its metabolism, particularly in children.The objective of this study was to develop a method to identify NFX metabolites in human samples, and apply it to the discovery of NFX metabolites in urine from pediatric patients undergoing treatment for Chagas disease.Methods Urine was collected from 12 pediatric patients and 8 healthy volunteers (controls), and anonymized before analysis. Informed consent was obtained from all participants. Samples were aliquoted, deproteinized with ACN (BNZ as internal standard) and centrifuged in cold. 10% of supernatant in water was injected into a 1.8 µm C18 column and chromatographed in 3.5 min under a water/ACN gradient at 0.4 mL/min in a Shimadzu Nexera X2 UHPLC equipment. Species were positively ionized by a Turbo IonSpray source. Metabolites were identified and characterized by an ABSciex 6500 QTRAP spectrometer through Enhanced-Mass-Screening (EMS), Neutral-Loss (NL), Precursor-Ion (PREC), Enhanced-Product-Ion (EPI) and MS3 experiments. For chromatographic monitoring, parameters were optimized and the three most intense Multiple-Reaction-Monitoring (MRM) transitions were selected.Results Denitrated NFX conjugated with cysteine (M1) and N-acetyl-cysteine (M2), as well as other phase I metabolites like saturated nitrile (M3), hydroxyamide (M4), carboxylic acid (M5) or aldehyde (M6) were identified in most samples. The final MS/MS detection method was high reproducible and sensitive for all metabolites.Conclusions We found the main NFX metabolites in pediatric urine using a fast MS/MS method that can allow us to efficiently study the role of NFX and its metabolites in pediatric treatment response and the adverse drug reactions, and in combination with PK/PD experiments will facilitate future clinical trials, and possibly develop new therapeutic drug monitoring strategies.Fil: Pérez Montilla, Carlos Alberto. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; ArgentinaFil: Moroni, Samanta. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; ArgentinaFil: Gonzalez, N.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; ArgentinaFil: Moscatelli, Guillermo. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; ArgentinaFil: Altcheh, Jaime Marcelo. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; ArgentinaFil: García Bournissen, Facundo. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; ArgentinaEuropean Society for Developmental Perinatal and Paediatric Pharmacology CongressBaselSuizaEuropean Society for Perinatal and Paediatric Pharmacolog

The physics potential of a reactor neutrino experiment with Skipper CCDs: Measuring the weak mixing angle

We analyze in detail the physics potential of an experiment like the one recently proposed by the vIOLETA collaboration: a kilogram-scale Skipper CCD detector deployed 12 meters away from a commercial nuclear reactor core. This experiment would be able to detect coherent elastic neutrino nucleus scattering from reactor neutrinos, capitalizing on the exceptionally low ionization energy threshold of Skipper CCDs. To estimate the physics reach, we elect the measurement of the weak mixing angle as a case study. We choose a realistic benchmark experimental setup and perform variations on this benchmark to understand the role of quenching factor and its systematic uncertainties,background rate and spectral shape, total exposure, and reactor antineutrino flux uncertainty. We take full advantage of the reactor flux measurement of the Daya Bay collaboration to perform a data driven analysis which is, up to a certain extent, independent of the theoretical uncertainties on the reactor antineutrino flux. We show that, under reasonable assumptions, this experimental setup may provide a competitive measurement of the weak mixing angle at few MeV scale with neutrino-nucleus scattering.Comment: 11 pages, 6 figure

Emergence of methicillin resistance predates the clinical use of antibiotics

The discovery of antibiotics more than 80 years ago has led to considerable improvements in human and animal health. Although antibiotic resistance in environmental bacteria is ancient, resistance in human pathogens is thought to be a modern phenomenon that is driven by the clinical use of antibiotics(1). Here we show that particular lineages of methicillin-resistant Staphylococcus aureus-a notorious human pathogen-appeared in European hedgehogs in the pre-antibiotic era. Subsequently, these lineages spread within the local hedgehog populations and between hedgehogs and secondary hosts, including livestock and humans. We also demonstrate that the hedgehog dermatophyte Trichophyton erinacei produces two beta-lactam antibiotics that provide a natural selective environment in which methicillin-resistant S. aureus isolates have an advantage over susceptible isolates. Together, these results suggest that methicillin resistance emerged in the pre-antibiotic era as a co-evolutionary adaptation of S. aureus to the colonization of dermatophyte-infected hedgehogs. The evolution of clinically relevant antibiotic-resistance genes in wild animals and the connectivity of natural, agricultural and human ecosystems demonstrate that the use of a One Health approach is critical for our understanding and management of antibiotic resistance, which is one of the biggest threats to global health, food security and development

Emergence of methicillin resistance predates the clinical use of antibiotics.

The discovery of antibiotics more than 80 years ago has led to considerable improvements in human and animal health. Although antibiotic resistance in environmental bacteria is ancient, resistance in human pathogens is thought to be a modern phenomenon that is driven by the clinical use of antibiotics1. Here we show that particular lineages of methicillin-resistant Staphylococcus aureus-a notorious human pathogen-appeared in European hedgehogs in the pre-antibiotic era. Subsequently, these lineages spread within the local hedgehog populations and between hedgehogs and secondary hosts, including livestock and humans. We also demonstrate that the hedgehog dermatophyte Trichophyton erinacei produces two β-lactam antibiotics that provide a natural selective environment in which methicillin-resistant S. aureus isolates have an advantage over susceptible isolates. Together, these results suggest that methicillin resistance emerged in the pre-antibiotic era as a co-evolutionary adaptation of S. aureus to the colonization of dermatophyte-infected hedgehogs. The evolution of clinically relevant antibiotic-resistance genes in wild animals and the connectivity of natural, agricultural and human ecosystems demonstrate that the use of a One Health approach is critical for our understanding and management of antibiotic resistance, which is one of the biggest threats to global health, food security and development

Sähkönlaadun ja energiankulutuksen tutkimus

Opinnäytetyössä tutkitaan sähkönlaadun ja energiankulutusta Raute Oyj:n rakentamissa vaneri- ja LVL-viilupalkkikoneissa. Opinnäytetyön tarkoituksena on selvittää esiintyykö Raute Oyj:n valmistamissa koneissa sähkönlaatua heikentäviä tekijöitä, kuten harmonisia yliaaltoja. Sähkönlaatua heikentävien tekijöiden lisäksi opinnäytetyössä selvitetään mahdollisuutta moottorikeskusten mitoituksessa käytettävän korjauskertoimen tarkentamiselle. Opinnäytetyön teoriaosassa esitellään sähkönlaatuun vaikuttavia tekijöitä, sekä niiden vaikutuksia sähköverkkoon ja verkonkäyttäjälle. Lisäksi teoriaosassa käydään läpi ratkaisuja, joilla esimerkiksi sähköverkossa esiintyvien yliaaltojen pitoisuutta voidaan vähentää tai poistaa kokonaan. Verkossa esiintyville häiriöille kuten harmonisille yliaalloille, taajuuden ja jännitteen vaihteluille on määritelty rajoituksia standardilla SFS-EN 50160, myös näitä rajoituksia ja niiden vaikutuksia sähkönlaatuun käydään läpi opinnäytetyön teoriaosassa. Sähkönlaatua ja energiankulutusta mitattiin kahdessa Raute Oyj:n koneessa, ja näiden mittaukseen käytettiin Fluken power quality analyzer mallia olevaa mittalaitetta. Mittaustuloksissa huomattiin sähkönlaadun olevan yleisesti hyvällä tasolla ja täyttävän standardissa SFS-EN 50160 sähkönlaadulle määritellyt raja-arvot. Tulosten perusteella huomattiin myös, että joissakin tapauksissa keskusten mitoituksessa käytettäviä korjauskertoimia pystyy tarkentamaan.The study researches the quality of electricity and the energy consumption on plywood and laminated veneer lumber (LVL) machines manufactured by Raute Plc. The Thesis aims to examine the potential existence of factors reducing the quality of electric, such as harmonic waves, on machines manufactured by Raute Plc. In addition to examine the electricity quality and consumption of energy, the thesis looks into the possibility of elaboration of motorcabin’s equalisation. The theory part of the Thesis presents factors that influence electric quality, as well as their influences on the electricity network and network’s users. Additionally, the theory part discusses solutions, which for instance reduce or eliminate harmonic waves in electric network. SFS-EN 50160 standard defines restrictions for disturbance in electric network such as harmonic waves, frequency and voltage variation, these restrictions are also presented in the theory part of the Thesis. In this study, electric quality and energy consumption were measured in two different machines manufactured by Raute Plc, and the measurements were conducted by Fluke power quality analyser measuring device. Electric quality was generally high according to the measurements, and it meets the electric quality standards defined in SFS-EN 50160. The measurements also indicated that in some cases the equalisation is possible to elaborate

EXCESS workshop: Descriptions of rising low-energy spectra

International audienceMany low-threshold experiments observe sharply rising event rates of yet unknown origins below a few hundred eV, and larger than expected from known backgrounds. Due to the significant impact of this excess on the dark matter or neutrino sensitivity of these experiments, a collective effort has been started to share the knowledge about the individual observations. For this, the EXCESS Workshop was initiated. In its first iteration in June 2021, ten rare event search collaborations contributed to this initiative via talks and discussions. The contributing collaborations were CONNIE, CRESST, DAMIC, EDELWEISS, MINER, NEWS-G, NUCLEUS, RICOCHET, SENSEI and SuperCDMS. They presented data about their observed energy spectra and known backgrounds together with details about the respective measurements. In this paper, we summarize the presented information and give a comprehensive overview of the similarities and differences between the distinct measurements. The provided data is furthermore publicly available on the workshop’s data repository together with a plotting tool for visualization

Delayed colorectal cancer care during covid-19 pandemic (decor-19). Global perspective from an international survey

Background The widespread nature of coronavirus disease 2019 (COVID-19) has been unprecedented. We sought to analyze its global impact with a survey on colorectal cancer (CRC) care during the pandemic. Methods The impact of COVID-19 on preoperative assessment, elective surgery, and postoperative management of CRC patients was explored by a 35-item survey, which was distributed worldwide to members of surgical societies with an interest in CRC care. Respondents were divided into two comparator groups: 1) ‘delay’ group: CRC care affected by the pandemic; 2) ‘no delay’ group: unaltered CRC practice. Results A total of 1,051 respondents from 84 countries completed the survey. No substantial differences in demographics were found between the ‘delay’ (745, 70.9%) and ‘no delay’ (306, 29.1%) groups. Suspension of multidisciplinary team meetings, staff members quarantined or relocated to COVID-19 units, units fully dedicated to COVID-19 care, personal protective equipment not readily available were factors significantly associated to delays in endoscopy, radiology, surgery, histopathology and prolonged chemoradiation therapy-to-surgery intervals. In the ‘delay’ group, 48.9% of respondents reported a change in the initial surgical plan and 26.3% reported a shift from elective to urgent operations. Recovery of CRC care was associated with the status of the outbreak. Practicing in COVID-free units, no change in operative slots and staff members not relocated to COVID-19 units were statistically associated with unaltered CRC care in the ‘no delay’ group, while the geographical distribution was not. Conclusions Global changes in diagnostic and therapeutic CRC practices were evident. Changes were associated with differences in health-care delivery systems, hospital’s preparedness, resources availability, and local COVID-19 prevalence rather than geographical factors. Strategic planning is required to optimize CRC care