Antimicrobial Defined Daily Dose in Neonatal Population: Validation in the Clinical Practice

Antimicrobial consumption; Daily-defined dosage; Neonatal antimicrobial prescriptionConsum d'antimicrobians; Dosi diària definida; Prescripció antimicrobiana neonatalConsumo de antimicrobianos; Dosis diaria definida; Prescripción antimicrobiana neonatalBackground: Currently, there is no validated method for estimating antimicrobial consumption in the neonatal population, as it exists for adults using Defined Daily Doses (DDD). In neonatology, although there are different methods, each one with advantages and disadvantages, there is no unified criterion for use. The aim of this study is to validate the neonatal DDD designed as a new standardised form of antimicrobial consumption over this population. Methods: The validation of the neonatal DDD, Phase II of the research project, was carried out through a descriptive observational study. Periodic cut-offs were performed to collect antimicrobial prescriptions of neonates admitted to the neonatology and intensive care units of nine Spanish hospitals. The data collected included demographic variables (gestational age, postnatal age, weight and sex), antimicrobial dose, frequency and route of administration. The selection of the optimal DDD value takes into account power value, magnitude obtained from the differences in the DDD, statistical significance obtained by the Wilcoxon test and degree of agreement in the stipulated doses. Results: Set of 904 prescriptions were collected and finally 860 were analysed based on the established criteria. The antimicrobials were mostly prescribed in the intensive care unit (63.1%). 32 different antimicrobials were collected, and intravenous administration was the most commonly used route. Neonatal DDD were defined for 11 different antimicrobials. A potency > 80% was obtained in 7 antibiotics. The 57.1% of the selected DDD correspond to phase I and 21.4% from phase II. Conclusion: DDD validation has been achieved for the majority of intravenously administered antimicrobials used in clinical practice in the neonatal population. This will make it possible to have an indicator that will be used globally to estimate the consumption of antimicrobials in this population, thus confirming its usefulness and applicability.M.M.-T. received financial support from the Subprograma Río Hortega, Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spain (CM21/00115). The project has been carried out without financial funding but is supported by the Spanish Society of Hospital Pharmacy (SEFH), the Working Group on Pharmaceutical Care in Infectious Diseases of the SEFH (Afinf) and Spanish working group on paediatric pharmacy of the SEFH (gefp)

Dosis diaria definida de antimicrobianos en la población neonatal

Consumo de antimicrobianos; Prescripción de antimicrobianos en neonatos; NeonatologíaAntimicrobial consumption; Neonatal antimicrobial prescription; NeonatologyConsum d'antimicrobians; Prescripció d'antimicrobians a nounats; NeonatologiaBackground Antimicrobial defined daily dose (DDD), a standardized metric to assess antimicrobial consumption in adult population, has limitations hampering its use in neonatal patients. This study proposes an alternative DDD design applicable for neonates. Methods Neonates (<1 month-old) from 6 Spanish hospitals during a 12-months period were included. Weight and weeks gestational age of each neonate were the variables collected. DDD (g) for each antimicrobial was calculated by multiplying the obtained weight times the recommended dose (mg/kg) of the antimicrobial for the most common infectious indication selected by the Delphi method. Results A total of 4820 neonates were included. Mean age was 36.72 weeks of gestational age and Mean weight was 2.687 kg. Standardized DDD (intravenous; oral route) for representative antimicrobials were: Amoxicillin (0.08; 0.08), amoxicillin-clavulanic acid (0.27; 0.08), ampicillin (0.27; x), cloxacillin (0.13; 0.13), penicillin G sodium (0.12), cefazolin (0.13), cefuroxime (0.27; x), cefotaxime (0.27), ceftazidime (0.27), ceftriaxone (0.13), cefepime (0.27) piperacillin-tazobactam (0.54), aztreonam (0.24), azithromycin (0.03; 0.03), clindamycin (0.04; 0.04), amikacin (0.04), gentamicin (0.01), metronidazole (0.04; 0.08), ciprofloxacin (0.04; 0.05), levofloxacin (x;x), fluconazole (0.02; 0.02), itraconazole (0.01; 0.01), fosfomycin (0.27). Restricted antimicrobials: meropenem (0.11), teicoplanin (0.02), vancomycin (0.08; 0.11), linezolid (0.08; 0.08), daptomycin (x), amphotericin B liposomal (0.01). Conclusions A useful method for antimicrobial DDD measurement in neonatology has been designed to monitor antimicrobial consumption in hospital settings. It should be validated in further studies and thereby included in the design for neonatal antimicrobial stewardship programs in the future.Antecedentes La dosis diaria definida de antimicrobianos (DDD), un método estandarizado para evaluar el consumo de antimicrobianos en la población adulta, tiene limitaciones que dificultan su uso en la población neonatal. Este estudio propone un diseño alternativo de la DDD aplicable a los recién nacidos. Métodos Se incluyeron neonatos (< 1 mes) de 6 hospitales españoles durante un período de 12 meses. El peso y las semanas de edad gestacional de cada recién nacido fueron las variables recogidas. Las DDD (g) de cada antimicrobiano se calcularon multiplicando el peso obtenido por la dosis recomendada (mg/kg) del antimicrobiano para la indicación infecciosa más común seleccionada por el método Delphi. Resultados Se incluyeron un total de 4.820 recién nacidos. La edad media fue de 36,72 semanas de edad gestacional y el peso medio fue de 2,687 kg. La DDD estandarizado (intravenoso; oral) para antimicrobianos seleccionados fueron: amoxicilina (0,08; 0,08), amoxicilina-ácido clavulánico (0,27; 0,08), ampicilina (0,27; x), cloxacilina (0,13; 0,13), penicilina G sódica (0,12), cefazolina (0,13), cefuroxima (0,27; x), cefotaxima (0,27), ceftazidima (0,27), ceftriaxona (0,13), cefepima (0,27) piperacilina-tazobactam (0,54), aztreonam (0,24), azitromicina (0,03; 0,03) clindamicina (0,04; 0,04), amikacina (0,04), gentamicina (0,01), metronidazol (0,04; 0,08), ciprofloxacina (0,04; 0,05), levofloxacina (x; x), fluconazol (0,02; 0,02), itraconazol (0,01; 0,01), fosfomicina (0,27). Antimicrobianos restringidos: meropenem (0,11), teicoplanina (0,02), vancomicina (0,08; 0,11), linezolid (0,08; 0,08), daptomicina (x), anfotericina B liposomal (0, 01). Conclusiones Se ha diseñado un método útil para la medición de las DDD de antimicrobianos en neonatología para controlar el consumo de antimicrobianos en entornos hospitalarios. Debería validarse en estudios posteriores para incluirse en el diseño de los programas de administración de antimicrobianos neonatales en el futuro

Epigenetic loss of RNA‑methyltransferase NSUN5 in glioma targets ribosomes to drive stress adaptive translational program

Tumors have aberrant proteomes that often do not match their corresponding transcriptome profiles. One possible cause of this discrepancy is the existence of aberrant RNA modification landscapes in the so-called epitranscriptome. Here, we report that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate RNA methyltransferase for 5-methylcytosine. In this setting, NSUN5 exhibits tumor-suppressor characteristics in vivo glioma models. We also found that NSUN5 loss generates an unmethylated status at the C3782 position of 28S rRNA that drives an overall depletion of protein synthesis, and leads to the emergence of an adaptive translational program for survival under conditions of cellular stress. Interestingly, NSUN5 epigenetic inactivation also renders these gliomas sensitive to bioactivatable substrates of the stress-related enzyme NQO1. Most importantly, NSUN5 epigenetic inactivation is a hallmark of glioma patients with long-term survival for this otherwise devastating disease

Antimicrobial Defined Daily Dose in Neonatal Population: Validation in the Clinical Practice

Paediatric Antimicrobial Defined Daily Dose Study Group KiDDDs.Currently, there is no validated method for estimating antimicrobial consumption in the neonatal population, as it exists for adults using Defined Daily Doses (DDD). In neonatology, although there are different methods, each one with advantages and disadvantages, there is no unified criterion for use. The aim of this study is to validate the neonatal DDD designed as a new standardised form of antimicrobial consumption over this population.M.M.-T. received financial support from the Subprograma Río Hortega, Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spain (CM21/00115). The project has been carried out without financial funding but is supported by the Spanish Society of Hospital Pharmacy (SEFH), the Working Group on Pharmaceutical Care in Infectious Diseases of the SEFH (Afinf) and Spanish working group on paediatric pharmacy of the SEFH (gefp).Peer reviewe

Epigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program

Altres ajuts: This work was supported by the Obra Social "La Caixa" (to M. Esteller).Tumors have aberrant proteomes that often do not match their corresponding transcriptome profiles. One possible cause of this discrepancy is the existence of aberrant RNA modification landscapes in the so-called epitranscriptome. Here, we report that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate RNA methyltransferase for 5-methylcytosine. In this setting, NSUN5 exhibits tumor-suppressor characteristics in vivo glioma models. We also found that NSUN5 loss generates an unmethylated status at the C3782 position of 28S rRNA that drives an overall depletion of protein synthesis, and leads to the emergence of an adaptive translational program for survival under conditions of cellular stress. Interestingly, NSUN5 epigenetic inactivation also renders these gliomas sensitive to bioactivatable substrates of the stress-related enzyme NQO1. Most importantly, NSUN5 epigenetic inactivation is a hallmark of glioma patients with long-term survival for this otherwise devastating disease

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Diseño y validación de las dosis diaria definida de antimicrobianos en neonatología

Los antimicrobianos (ATB) son unos de los fármacos más utilizados en la población neonatal, de hecho, el 30-50% de los neonatos ingresados en las unidades de cuidados intensivos neonatales reciben uno o varios ciclos de antimicrobianos. Sin embargo, son numerosos los estudios que muestran un uso inadecuado de los ATB, especialmente en este grupo de población donde las infecciones tienen una expresión clínica inespecífica, y conllevan a la introducción de tratamientos de amplio espectro y sus consecuencias. Actualmente son numerosas las estrategias orientadas a mejorar el uso adecuado de ATB a nivel local, nacional e internacional, como son los programas de optimización de uso de antimicrobianos (PROA) propios de cada centro, sistema nacional de vigilancia de infecciones relacionadas con la asistencia sanitaria (IRAS) o proyectos específicos liderados por la Organización Mundial de la Salud (OMS). Dentro de estas estrategias, uno de los indicadores que se monitorizan es el consumo de los antimicrobianos, Sin embargo, y a diferencia de lo que ocurre en adultos, no existe un método de medición internacional validado en la población neonatal, que permita establecer diferencias de los consumos entre unidades de un mismo hospital y comparativas entre diferentes centros. Por ello, el objetivo de esta tesis es diseñar y validar la Dosis Diaria Definida (DDD) de los ATB en la población neonatal como indicador de consumo de antimicrobianos y, secundariamente, establecer un factor de conversión respecto a las DDD de adultos para agilizar el cálculo y utilizar las plataformas y bases de datos que tienen disponibles los hospitales. Esta Tesis muestra los resultados de un proyecto multidisciplinar que cuenta con la colaboración de neonatologos, farmacéuticos y pediatras de diferentes centros a nivel nacional y referentes en sus áreas, así como con el apoyo del Grupo de Atención Farmacéutica de Enfermedades Infecciosas (Afinf) y el Grupo Español de Farmacia Pediátrica (gefp) de la Sociedad Española de Farmacia Hospitalaria. El proyecto, liderado y coordinado desde el Servicio de Farmacia del Hospital Universitario Virgen del Rocío, se ha desarrollado en dos Fases. La primera fase que tiene como objetivo el diseño de las DDD y consistió, por un lado, en un estudio descriptivo con 4820 neonatos para la recogida de variable peso y, por otro lado, seleccionar las dosis de cada uno de los ATB mediante la metodología Delphi tras constituir un grupo de expertos. La segunda fase, validación de las DDD, consistió en la recogida de más de 900 prescripciones reales de neonatos ingresados en los centros participantes con el fin de calcular el valor de DDD en práctica clínica real (DDD Fase II) y posteriormente comparar dicho valor con las DDD diseñadas en la Fase I. En la primera fase, se determinó un peso medio de 2,687Kg, y se seleccionaron las dosis de ATB consiguiendo consenso por el grupo de expertos en el 95% de los ATB seleccionados. Gracias a ello, se han definido las DDD neonatales de 47 ATB, 31 ATB de administración intravenosa y 16 ATB de administración oral. Además, en la segunda fase, se han conseguido validar las DDD para los ATB intravenosos más utilizados en práctica clínica en neonatología: Amikacina, Amoxicilina, Amoxicilina-Clavulánico, Ampicilina, Cefazolina, Cefotaxima, Cloxacilina, Gentamicina, Linezolid, Meropenem y Vancomicina; así como establecer el correspondiente factor de conversión respecto a las DDD de adultos. El estudio ha diseñado y validado las DDD neonatales para los ATB intravenosos más empleados en neonatología, que serán utilizadas para pilotar el consumo de antimicrobianos entre diferentes hospitales a nivel nacional, evaluar tendencias de consumo de antimicrobianos y establecer nuevas estrategias, con el objetivo de hacer frente a la lucha contra las resistencias a los antimicrobianos

Life cycle assessment to address the environmental impacts of tourism in a Spanish tourist destination: The case of Rias Baixas (Galicia) holidays

Tourism has grown steadily in recent decades, becoming a strategic sector for the economy in many countries. However, the environmental impacts associated with tourism have also experienced an upward trend. In this sense, innovation is needed in the tourism sector, to move towards new models and strategies that integrate environmental sustainability with the social aspects of the sector. In this study, a holistic assessment of the environmental impact of tourism has been carried out using the Life Cycle Assessment (LCA) method, considering all stages of tourism activity: transportation from the place of origin to destination and back, accommodation, catering, and activities conducted. For this purpose, a case study has been carried out based on a typical trip made from Madrid to Rías Baixas (Galicia), considering a four-night stay and the performance of two activities (music festival and cultural museum) at the destination. Two alternative transportation scenarios (train or plane) have been defined to analyze the influence of the type of transportation on the overall impact. Other touristic activities such as visiting gardens or thermal baths instead of visiting a cultural museum or attending a music festival have been analyzed and it has been found that the thermal baths and the museum have the greatest environmental impacts. Transportation was the biggest contributor to most of the environmental impacts in the selected categories. On the other hand, the stay at the destination has stood out due to the impact of the consumption of food and energy used at the accommodation facility. The impact of the activities conducted at the destination is also worth highlighting. Finally, alternative scenarios for transportation have shown that the mode of transportation selected is key for lowering the overall environmental impact of the stay at the destination, highlighting the public transportation alternative, such as the train, as the most environmentally friendly option.This research was funded by the INTERREG SUDOE Programme, grant number GREENTOUR: Circular Economy and Sustainable Tourism in Destinations of the SUDOE space (SOE4/P5/E1089). The authors of CESAM acknowledge the Portuguese Foundation for Science and Technology (FCT)/MCTES for the contracts CEECIND/ 02174/2017 and CEECIND/00143/2017, and for the financial support to CESAM (UIDB/50017/2020+UIDP/50017/2020+LA/P/0094/2020), through national funds. The author of the Galician Water Research Foundation (Cetaqua Galicia) belongs to the Galician Competitive Research Group GRC (IN845A-2), program co-funded by FEDE

Smartphone-based ecological momentary assessment for the measurement of the performance status and health-related quality of life in cancer patients under systemic anticancer therapies: Development and acceptability of a mobile app

Background: We have defined a project to develop a mobile app that continually records smartphone parameters which may help define the Eastern Cooperative Oncology Group performance status (ECOG-PS) and the health-related quality of life (HRQoL), without interaction with patients or professionals. This project is divided into 3 phases. Here we describe phase 1. The objective of this phase was to develop the app and assess its usability concerning patient characteristics, acceptability, and satisfaction. Methods: The app eB2-ECOG was developed and installed in the smartphone of cancer patients who will be followed for six months. Criteria inclusion were: age over 18-year-old; diagnosed with unresectable or metastatic lung cancer, gastrointestinal stromal tumor, sarcoma, or head and neck cancer; under systemic anticancer therapies; and possession of a Smartphone. The app will collect passive and active data from the patients while healthcare professionals will evaluate the ECOG-PS and HRQoL through conventional tools. Acceptability was assessed during the follow-up. Patients answered a satisfaction survey in the app between 3-6 months from their inclusion. Results: The app developed provides a system for continuously collecting, merging, and processing data related to patient"s health and physical activity. It provides a transparent capture service based on all the available data of a patient. Currently, 106 patients have been recruited. A total of 36 patients were excluded, most of them (21/36) due to technological reasons. We assessed 69 patients (53 lung cancer, 8 gastrointestinal stromal tumors, 5 sarcomas, and 3 head and neck cancer). Concerning app satisfaction, 70.4% (20/27) of patients found the app intuitive and easy to use, and 51.9% (17/27) of them said that the app helped them to improve and handle their problems better. Overall, 17 out of 27 patients [62.9%] were satisfied with the app, and 14 of them [51.8%] would recommend the app to other patients. Conclusions: We observed that the app's acceptability and satisfaction were good, which is essential for the continuity of the project. In the subsequent phases, we will develop predictive models based on the collected information during this phase. We will validate the method and analyze the sensitivity of the automated results.This work has been partly supported by the Spanish Ministerio de Ciencia, Innovación y Universidades (TEC2017-92552-EXP, RTI2018-099655-B-I00), the Comunidad de Madrid (Y2018/TCS-4705 PRACTICO-CM, IND2018/TIC-9649, IND2017/TIC-7618), and the BBVA Foundation (Deep-DARWiN grant)