RESUMEN
Influenza B viruses (IBVs) comprise a substantial portion of the circulating seasonal human influenza viruses. Here, we describe the isolation of human monoclonal antibodies (mAbs) that recognized the IBV neuraminidase (NA) glycoprotein from an individual following seasonal vaccination. Competition-binding experiments suggested the antibodies recognized two major antigenic sites. One group, which included mAb FluB-393, broadly inhibited IBV NA sialidase activity, protected prophylactically in vivo, and bound to the lateral corner of NA. The second group contained an active site mAb, FluB-400, that broadly inhibited IBV NA sialidase activity and virus replication in vitro in primary human respiratory epithelial cell cultures and protected against IBV in vivo when administered systemically or intranasally. Overall, the findings described here shape our mechanistic understanding of the human immune response to the IBV NA glycoprotein through the demonstration of two mAb delivery routes for protection against IBV and the identification of potential IBV therapeutic candidates.
Asunto(s)
Anticuerpos Monoclonales , Anticuerpos Antivirales , Virus de la Influenza B , Gripe Humana , Neuraminidasa , Neuraminidasa/inmunología , Humanos , Virus de la Influenza B/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Antivirales/inmunología , Gripe Humana/inmunología , Gripe Humana/prevención & control , Vacunas contra la Influenza/inmunología , Ratones , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/prevención & control , Proteínas Virales/inmunología , Replicación Viral/efectos de los fármacosRESUMEN
The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs1-3 and revealed how quickly viral escape can curtail effective options4,5. When the SARS-CoV-2 Omicron variant emerged in 2021, many antibody drug products lost potency, including Evusheld and its constituent, cilgavimab4-6. Cilgavimab, like its progenitor COV2-2130, is a class 3 antibody that is compatible with other antibodies in combination4 and is challenging to replace with existing approaches. Rapidly modifying such high-value antibodies to restore efficacy against emerging variants is a compelling mitigation strategy. We sought to redesign and renew the efficacy of COV2-2130 against Omicron BA.1 and BA.1.1 strains while maintaining efficacy against the dominant Delta variant. Here we show that our computationally redesigned antibody, 2130-1-0114-112, achieves this objective, simultaneously increases neutralization potency against Delta and subsequent variants of concern, and provides protection in vivo against the strains tested: WA1/2020, BA.1.1 and BA.5. Deep mutational scanning of tens of thousands of pseudovirus variants reveals that 2130-1-0114-112 improves broad potency without increasing escape liabilities. Our results suggest that computational approaches can optimize an antibody to target multiple escape variants, while simultaneously enriching potency. Our computational approach does not require experimental iterations or pre-existing binding data, thus enabling rapid response strategies to address escape variants or lessen escape vulnerabilities.
Asunto(s)
Anticuerpos Monoclonales , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Simulación por Computador , Diseño de Fármacos , SARS-CoV-2 , Animales , Femenino , Humanos , Ratones , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/química , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/química , Anticuerpos Antivirales/inmunología , COVID-19/inmunología , COVID-19/virología , Mutación , Pruebas de Neutralización , SARS-CoV-2/clasificación , SARS-CoV-2/genética , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Análisis Mutacional de ADN , Deriva y Cambio Antigénico/genética , Deriva y Cambio Antigénico/inmunología , Diseño de Fármacos/métodosRESUMEN
When faced with starvation, the bacterium Bacillus subtilis transforms itself into a dormant cell type called a "spore". Sporulation initiates with an asymmetric division event, which requires the relocation of the core divisome components FtsA and FtsZ, after which the sigma factor σF is exclusively activated in the smaller daughter cell. Compartment-specific activation of σF requires the SpoIIE phosphatase, which displays a biased localization on one side of the asymmetric division septum and associates with the structural protein DivIVA, but the mechanism by which this preferential localization is achieved is unclear. Here, we isolated a variant of DivIVA that indiscriminately activates σF in both daughter cells due to promiscuous localization of SpoIIE, which was corrected by overproduction of FtsA and FtsZ. We propose that the core components of the redeployed cell division machinery drive the asymmetric localization of DivIVA and SpoIIE to trigger the initiation of the sporulation program.
Asunto(s)
Bacillus subtilis , Proteínas Bacterianas , Bacillus subtilis/metabolismo , Activación Transcripcional , Proteínas Bacterianas/metabolismo , Esporas Bacterianas/genética , Esporas Bacterianas/metabolismo , División Celular/genética , Factor sigma/genética , Factor sigma/metabolismoRESUMEN
SignificanceWhile most small, regulatory RNAs are thought to be "noncoding," a few have been found to also encode a small protein. Here we describe a 164-nucleotide RNA that encodes a 28-amino acid, amphipathic protein, which interacts with aerobic glycerol-3-phosphate dehydrogenase and increases dehydrogenase activity but also base pairs with two mRNAs to reduce expression. The coding and base-pairing sequences overlap, and the two regulatory functions compete.
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Carbono/metabolismo , Escherichia coli/metabolismo , ARN Bacteriano/fisiología , Medios de Cultivo , Escherichia coli/crecimiento & desarrollo , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Galactosa/metabolismo , Glicerol/metabolismo , Glicerolfosfato Deshidrogenasa/metabolismo , Proteínas de la Membrana/química , Proteínas de la Membrana/metabolismo , Biosíntesis de Proteínas , ARN Bacteriano/química , ARN Bacteriano/metabolismo , ARN Mensajero/metabolismoRESUMEN
Human activity changes multiple factors in the environment, which can have positive or negative synergistic effects on organisms. However, few studies have explored the causal effects of multiple anthropogenic factors, such as urbanization and invasive species, on animals and the mechanisms that mediate these interactions. This study examines the influence of urbanization on the detrimental effect of invasive avian vampire flies (Philornis downsi) on endemic Darwin's finches in the Galápagos Islands. We experimentally manipulated nest fly abundance in urban and non-urban locations and then characterized nestling health, fledging success, diet, and gene expression patterns related to host defense. Fledging success of non-parasitized nestlings from urban (79%) and non-urban (75%) nests did not differ significantly. However, parasitized, non-urban nestlings lost more blood, and fewer nestlings survived (8%) compared to urban nestlings (50%). Stable isotopic values (δ15 N) from urban nestling feces were higher than those from non-urban nestlings, suggesting that urban nestlings are consuming more protein. δ15 N values correlated negatively with parasite abundance, which suggests that diet might influence host defenses (e.g., tolerance and resistance). Parasitized, urban nestlings differentially expressed genes within pathways associated with red blood cell production (tolerance) and pro-inflammatory response (innate immunological resistance), compared to parasitized, non-urban nestlings. In contrast, parasitized non-urban nestlings differentially expressed genes within pathways associated with immunoglobulin production (adaptive immunological resistance). Our results suggest that urban nestlings are investing more in pro-inflammatory responses to resist parasites but also recovering more blood cells to tolerate blood loss. Although non-urban nestlings are mounting an adaptive immune response, it is likely a last effort by the immune system rather than an effective defense against avian vampire flies since few nestlings survived.
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Pinzones , Muscidae , Parásitos , Animales , Humanos , Pinzones/parasitología , EcuadorRESUMEN
We report a novel homozygous 49.6 kb deletion of chromosome 18q12.1 involving the last exon of DSG3 in dizygotic twins with phenotype consistent with acantholytic blistering of the oral and laryngeal mucosa (ABOLM). The twin siblings presented predominantly with friability of the laryngeal and respiratory mucosa. This is only the second report in the literature of this unusual autosomal recessive blistering disorder. The diagnosis explains the mucosal phenotype of a pemphigus-like disorder without evidence of autoimmune dysfunction. The exclusion of an autoimmune basis has management implications. The deletion also involved the DSG2 gene, which is associated with arrhythmogenic right ventricular dysplasia (ARVD). The affected siblings and heterozygous parents do not show any cardiac phenotype at this time. Functional studies would further clarify how deletions resulting in loss of function of DSG3 may cause the reported phenotypes of DSG3-related ABOLM.
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Desmogleína 3 , Mucosa Laríngea , Humanos , Homocigoto , Desmogleína 3/genética , Eliminación de Secuencia/genética , Exones/genéticaRESUMEN
OBJECTIVE: Delirium is an under-recognized problem in critically ill children. Although delirium is common in adults hospitalized with COVID-19, the relationship between pediatric COVID-19 and delirium has not been described. To address this gap, we characterized delirium in critically ill children with different manifestations of COVID-19 and investigated associations among demographic, disease, and treatment factors. We hypothesized that multisystem inflammatory syndrome in children (MIS-C) would be associated with a higher incidence of delirium given its underlying pathophysiology of hyperinflammation. DESIGN: Retrospective, single-center cohort study. SETTING: Quaternary-care pediatric intensive care unit (PICU). PATIENTS: Children less than 18 years of age hospitalized in the PICU between March 2020 and March 2023 with either active SARS-CoV-2 infection or serological evidence of prior infection. MEASUREMENTS AND MAIN RESULTS: The cohort included 149 PICU hospitalizations among children with evidence of COVID-19. Patients were categorized by reason for PICU admission: 75 (50%) for COVID-19 respiratory disease, 36 (24%) MIS-C, and 38 (26%) any other primary reason with positive COVID-19 testing. Delirium was diagnosed in 43 (29%) patients. Delirium incidence was highest in patients requiring invasive mechanical ventilation (IMV) (56% vs 7.5% in patients who did not require IMV, p < .001). Patients who were exposed to opioids, dexmedetomidine, paralytics or benzodiazepines more frequently experienced delirium compared to those unexposed (p < .001, p < .001, p < .001 and p = .001, respectively). After multivariable adjustment, delirium was associated with IMV (HR 3 [95% CI 1.5-5.7]), female sex (HR 2.4 [1.2-4.7]), and developmental disability (HR 3.4 [95% CI 1-11.1]). There was no association between delirium and reason for PICU hospitalization. CONCLUSIONS: Delirium was common among children hospitalized with COVID-19. The overall incidence was much less than has been reported in adults with COVID-19. Delirium reduction efforts should focus on children with developmental disability and minimizing ongoing risks during IMV.
RESUMEN
The cause of changes in atmospheric carbon dioxide (CO2) during the recent ice ages is yet to be fully explained. Most mechanisms for glacial-interglacial CO2 change have centred on carbon exchange with the deep ocean, owing to its large size and relatively rapid exchange with the atmosphere1. The Southern Ocean is thought to have a key role in this exchange, as much of the deep ocean is ventilated to the atmosphere in this region2. However, it is difficult to reconstruct changes in deep Southern Ocean carbon storage, so few direct tests of this hypothesis have been carried out. Here we present deep-sea coral boron isotope data that track the pH-and thus the CO2 chemistry-of the deep Southern Ocean over the past forty thousand years. At sites closest to the Antarctic continental margin, and most influenced by the deep southern waters that form the ocean's lower overturning cell, we find a close relationship between ocean pH and atmospheric CO2: during intervals of low CO2, ocean pH is low, reflecting enhanced ocean carbon storage; and during intervals of rising CO2, ocean pH rises, reflecting loss of carbon from the ocean to the atmosphere. Correspondingly, at shallower sites we find rapid (millennial- to centennial-scale) decreases in pH during abrupt increases in CO2, reflecting the rapid transfer of carbon from the deep ocean to the upper ocean and atmosphere. Our findings confirm the importance of the deep Southern Ocean in ice-age CO2 change, and show that deep-ocean CO2 release can occur as a dynamic feedback to rapid climate change on centennial timescales.
Asunto(s)
Atmósfera/química , Dióxido de Carbono/análisis , Secuestro de Carbono , Agua de Mar/química , Animales , Regiones Antárticas , Antozoos/química , Boro , Dióxido de Carbono/metabolismo , Clima , Groenlandia , Historia Antigua , Concentración de Iones de Hidrógeno , Hielo/análisis , Isótopos , Modelos Teóricos , Océanos y Mares , Factores de TiempoRESUMEN
Food systems comprise interconnected webs of processes that together transform inputs (land, labour, water, nutrients and genetics, to mention just a few) into outputs such as nutrition and revenue for human societies. Perfect systems do not exist; rather, global food systems operate in the presence of hazards, biotic and abiotic alike, and under the constraint of limited resources to mitigate these hazards. There are, therefore, inefficiencies in these systems, which lead to losses in terms of monetary, nutritional, health and environmental values and create additional negative externalities in the health, social and environmental spaces. Health hazards in the food system do not respect arbitrary distinctions between the crop and livestock sectors, which are highly interconnected. These linkages exist where one sector provides inputs to another or through substitution effects where supply in one sector influences demand in another. The One Health approach advocates investigating the intersectoral hazards in a highly interdisciplinary manner. This article provides a conceptual framework for integrating the methodologies developed by the Global Burden of Crop Loss and Global Burden of Animal Diseases initiatives to generate burden estimates for hazards in food systems that better account for interconnectivity and foster an improved understanding of food systems that is aligned with the interdisciplinary nature of the One Health approach. A case study related to maize and poultry sector linkages in the wider context of public and environmental health is presented.
Les systèmes alimentaires sont des réseaux de processus interconnectés qui concourent à transformer des intrants (terre, main-d'oeuvre, eau, nutriments et génétique, pour n'en mentionner que quelques-uns) en extrants tels que des aliments et des revenus pour les sociétés humaines. Il n'existe pas de système parfait ; les systèmes alimentaires mondiaux sont exposés en permanence à des dangers de nature tant biotique qu'abiotique et contraints par les ressources limitées consacrées à l'atténuation de ces dangers. Les problèmes d'efficacité sont donc inéluctables ; ils entraînent des pertes de valeur tant monétaire que nutritionnelle, sanitaire et environnementale, et génèrent de nouvelles externalités négatives dans le domaine de la santé ainsi que dans l'espace social et dans l'environnement. Les dangers sanitaires présents dans le système alimentaire ignorent les distinctions arbitraires entre les secteurs agricole et d'élevage, lesquels sont fortement interconnectés. Ces liens se manifestent lorsqu'un secteur fournit des intrants à l'autre et, par l'effet de substitutions, lorsque l'offre dans un secteur influence la demande dans l'autre. L'approche " Une seule santé " préconise d'adopter une méthode fondée sur l'interdisciplinarité pour enquêter sur les dangers intersectoriels. Les auteurs décrivent le cadre conceptuel de l'intégration des méthodes des initiatives " Fardeau mondial des pertes agricoles " et " Impact mondial des maladies animales " dans le but de produire des estimations de la charge induite par les dangers des systèmes alimentaires qui prennent davantage en compte leur inter-connectivité et donnent lieu à une meilleure compréhension des systèmes alimentaires, en cohérence avec le caractère interdisciplinaire de l'approche " Une seule santé ". Est également présentée une étude de cas portant sur les liens entre la culture du maïs et l'élevage de volailles dans le contexte plus large de la santé publique et environnementale.
Los sistemas alimentarios comprenden redes interconectadas de procesos que, conjuntamente, transforman insumos (tierra, mano de obra, agua, nutrientes y genética, por mencionar solo algunos) en productos como alimentos e ingresos para las sociedades humanas. No existen sistemas perfectos; más bien, los sistemas alimentarios mundiales funcionan en un entorno de peligros, tanto bióticos como abióticos, y con las restricciones impuestas por los limitados recursos disponibles para mitigarlos. En estos sistemas se observan, por tanto, ineficiencias, que provocan pérdidas en términos monetarios, nutricionales, sanitarios y ambientales y que crean externalidades negativas adicionales en los ámbitos sanitario, social y ambiental. Los peligros para la salud en los sistemas alimentarios no atienden a distinciones arbitrarias entre los sectores agrícola y ganadero, que están muy interconectados. Estos vínculos surgen cuando un sector proporciona insumos a otro o a través de efectos de sustitución en los que la oferta de un sector influye en la demanda de otro. El enfoque de "Una sola salud" aboga por investigar los peligros intersectoriales de manera eminentemente interdisciplinaria. En este artículo se ofrece un marco teórico para la integración de las metodologías desarrolladas por las iniciativas dedicadas al impacto global de las pérdidas de cosechas y al impacto global de las enfermedades animales a fin de obtener estimaciones de los peligros en los sistemas alimentarios que tengan más en cuenta la interconexión y fomenten una mejor comprensión de los sistemas alimentarios acorde con el carácter interdisciplinario del enfoque de "Una sola salud". En este sentido, se presenta un estudio de caso relacionado con los vínculos entre los sectores del maíz y las aves de corral en el contexto más amplio de la salud pública y ambiental.
Asunto(s)
Enfermedades de los Animales , Productos Agrícolas , Abastecimiento de Alimentos , Animales , Humanos , Enfermedades de los Animales/epidemiología , Enfermedades de los Animales/prevención & control , Salud Global , Aves de Corral , Salud ÚnicaRESUMEN
Ophthalmomyiasis is the result of fly larvae feeding on the tissues of the eye. Commonly associated with poor hygiene and open wounds, this condition is rare and often stigmatized. Treatment can be straightforward, and full recovery is common. Identifying the species responsible for ophthalmomyiasis is important for the medical, forensic, and entomological communities. Here, we present a case of ophthalmomyiasis where 30-40 blow fly (Diptera: Calliphoridae) larvae were removed from the eye of a human male. A representative subsample of five larvae was used for taxonomic identification via two approaches (a) DNA analysis, via sequencing of the complete mitochondrial genome (mtGenome) and comparison of the mtGenome and mitochondrial COI barcode region to GenBank, and (b) morphology, examination of the posterior spiracles using microscopy, and comparison to published larval descriptions of blow flies. Two species of blow flies were identified from the DNA analysis: Lucilia coeruleiviridis and Phormia regina. Morphological examination could only confirm L. coeruleiviridis as being present. To our knowledge, finding two blow fly species causing ophthalmomyiasis in a single individual has not been previously reported in the scientific literature. Neither P. regina nor L. coeruleiviridis prefers living tissue for larva development, but since they fill similar ecological niches, perhaps this was a show of competition rather than a normal feeding habit. Knowing these blow fly species can resort to this behavior, and that it can affect human populations, is valuable to the education of patients and providers.
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Calliphoridae , Larva , Animales , Calliphoridae/genética , Masculino , Humanos , Miasis/parasitología , Miasis/diagnóstico , América del Norte , Filogenia , Dípteros/parasitología , Genoma MitocondrialRESUMEN
BACKGROUND: It is now understood that it is the quality rather than the absolute amount of adipose tissue that confers risk for obesity-associated disease. Adipose-derived stem cells give rise to adipocytes during the developmental establishment of adipose depots. In adult depots, a reservoir of progenitors serves to replace adipocytes that have reached their lifespan and for recruitment to increase lipid buffering capacity under conditions of positive energy balance. MAIN: The adipose tissue expandability hypothesis posits that a failure in de novo differentiation of adipocytes limits lipid storage capacity and leads to spillover of lipids into the circulation, precipitating the onset of obesity-associated disease. Since adipose progenitors are specified to their fate during late fetal life, perturbations in the intrauterine environment may influence the rapid expansion of adipose depots that occurs in childhood or progenitor function in established adult depots. Neonates born to mothers with obesity or diabetes during pregnancy tend to have excessive adiposity at birth and are at increased risk for childhood adiposity and cardiometabolic disease. CONCLUSION: In this narrative review, we synthesize current knowledge in the fields of obesity and developmental biology together with literature from the field of the developmental origins of health and disease (DOHaD) to put forth the hypothesis that the intrauterine milieu of pregnancies complicated by maternal metabolic disease disturbs adipogenesis in the fetus, thereby accelerating the trajectory of adipose expansion in early postnatal life and predisposing to impaired adipose plasticity.
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Síndrome Metabólico , Obesidad Materna , Obesidad Infantil , Recién Nacido , Adulto , Femenino , Humanos , Embarazo , Obesidad Materna/metabolismo , Adipocitos/metabolismo , Tejido Adiposo/metabolismo , LípidosRESUMEN
Temporal patterns in spawning and juvenile recruitment can have major effects on population size and the demographic structure of coral reef fishes. For harvested species, these patterns are crucial in determining stock size and optimizing management strategies such as seasonal closures. For the commercially important coral grouper (Plectropomus spp.) on the Great Barrier Reef, histological studies indicate peak spawning around the summer new moons. Here we examine the timing of spawning activity for P. maculatus in the southern Great Barrier Reef by deriving age in days for 761 juvenile fish collected between 2007 and 2022, and back-calculating settlement and spawning dates. Age-length relationships were used to estimate spawning and settlement times for a further 1002 juveniles collected over this period. Unexpectedly, our findings indicate year-round spawning activity generates distinct recruitment cohorts that span several weeks to months. Peak spawning varied between years with no clear association with environmental cues, and little to no alignment with existing seasonal fisheries closures around the new moon. Given the variability and uncertainty in peak spawning times, this fishery may benefit from additional and longer seasonal closures, or alternative fisheries management strategies, to maximize the recruitment contribution from periods of greatest reproductive success.
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Antozoos , Lubina , Animales , Estaciones del Año , Peces , Arrecifes de Coral , Explotaciones Pesqueras , EnvejecimientoRESUMEN
Splitting bioactive proteins into conditionally reconstituting fragments is a powerful strategy for building tools to study and control biological systems. However, split proteins often exhibit a high propensity to reconstitute, even without the conditional trigger, limiting their utility. Current approaches for tuning reconstitution propensity are laborious, context-specific or often ineffective. Here, we report a computational design strategy grounded in fundamental protein biophysics to guide experimental evaluation of a sparse set of mutants to identify an optimal functional window. We hypothesized that testing a limited set of mutants would direct subsequent mutagenesis efforts by predicting desirable mutant combinations from a vast mutational landscape. This strategy varies the degree of interfacial destabilization while preserving stability and catalytic activity. We validate our method by solving two distinct split protein design challenges, generating both design and mechanistic insights. This new technology will streamline the generation and use of split protein systems for diverse applications.
Asunto(s)
Sondas Moleculares/química , Ingeniería de Proteínas/métodos , Factores de Transcripción/genética , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Endopeptidasas/química , Endopeptidasas/metabolismo , Genes Reporteros , Células HEK293 , Humanos , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Sondas Moleculares/genética , Sondas Moleculares/metabolismo , Mutación , Multimerización de Proteína , Proteolisis , Sirolimus/metabolismo , Sirolimus/farmacología , Proteínas de Unión a Tacrolimus/genética , Proteínas de Unión a Tacrolimus/metabolismo , Factores de Transcripción/metabolismo , Activación TranscripcionalRESUMEN
BACKGROUND: CONCISE is an internationally agreed minimum set of outcomes for use in nutritional and metabolic clinical research in critically ill adults. Clinicians and researchers need to be aware of the clinimetric properties of these instruments and understand any limitations to ensure valid and reliable research. This systematic review and meta-analysis were undertaken to evaluate the clinimetric properties of the measurement instruments identified in CONCISE. METHODS: Four electronic databases were searched from inception to December 2022 (MEDLINE via Ovid, EMBASE via Ovid, CINAHL via Healthcare Databases Advanced Search, CENTRAL via Cochrane). Studies were included if they examined at least one clinimetric property of a CONCISE measurement instrument or recognised variation in adults ≥ 18 years with critical illness or recovering from critical illness in any language. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist for systematic reviews of Patient-Reported Outcome Measures was used. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses were used in line with COSMIN guidance. The COSMIN checklist was used to evaluate the risk of bias and the quality of clinimetric properties. Overall certainty of the evidence was rated using a modified Grading of Recommendations, Assessment, Development and Evaluation approach. Narrative synthesis was performed and where possible, meta-analysis was conducted. RESULTS: A total of 4316 studies were screened. Forty-seven were included in the review, reporting data for 12308 participants. The Short Form-36 Questionnaire (Physical Component Score and Physical Functioning), sit-to-stand test, 6-m walk test and Barthel Index had the strongest clinimetric properties and certainty of evidence. The Short Physical Performance Battery, Katz Index and handgrip strength had less favourable results. There was limited data for Lawson Instrumental Activities of Daily Living and the Global Leadership Initiative on Malnutrition criteria. The risk of bias ranged from inadequate to very good. The certainty of the evidence ranged from very low to high. CONCLUSIONS: Variable evidence exists to support the clinimetric properties of the CONCISE measurement instruments. We suggest using this review alongside CONCISE to guide outcome selection for future trials of nutrition and metabolic interventions in critical illness. TRIAL REGISTRATION: PROSPERO (CRD42023438187). Registered 21/06/2023.
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Enfermedad Crítica , Fuerza de la Mano , Adulto , Humanos , Enfermedad Crítica/terapia , Actividades Cotidianas , Resultado del Tratamiento , Evaluación de Resultado en la Atención de SaludRESUMEN
The highly structured, cis-encoded RNA elements known as riboswitches modify gene expression upon binding a wide range of molecules. The yybP-ykoY motif was one of the most broadly distributed and numerous bacterial riboswitches for which the cognate ligand was unknown. Using a combination of in vivo reporter and in vitro expression assays, equilibrium dialysis, and northern analysis, we show that the yybP-ykoY motif responds directly to manganese ions in both Escherichia coli and Bacillus subtilis. The identification of the yybP-ykoY motif as a manganese ion sensor suggests that the genes that are preceded by this motif and encode a diverse set of poorly characterized membrane proteins have roles in metal homeostasis.
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Bacillus subtilis/genética , Proteínas de Escherichia coli/genética , Escherichia coli/genética , Manganeso/metabolismo , Proteínas de Transporte de Membrana/genética , Secuencias Reguladoras de Ácido Ribonucleico , Riboswitch/genética , Regiones no Traducidas 5' , Bacillus subtilis/efectos de los fármacos , Bacillus subtilis/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Secuencia de Bases , Escherichia coli/efectos de los fármacos , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Proteínas Fimbrias/genética , Proteínas Fimbrias/metabolismo , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Manganeso/farmacología , Proteínas de Transporte de Membrana/metabolismo , Datos de Secuencia Molecular , Mutación , Regiones Promotoras Genéticas/efectos de los fármacos , ARN Bacteriano/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismoRESUMEN
INTRODUCTION AND HYPOTHESIS: Overactive bladder (OAB) and urinary incontinence (UI) are prevalent in older women. We investigated relations of toileting behaviors and urinary urge cues to OAB and UI in women ≥ 65 years. We tested mediation hypotheses that toileting behaviors lead to higher sensitivity to urinary urge cues (the mediator), which leads to both OAB and UI. METHODS: An e-panel was recruited to respond to an electronic survey that included demographic information, Urinary Cues Scale version 2, Toileting Behaviors-Women's Elimination Behaviors (TB-WEB) scale, and the International Consultation on Incontinence Questionnaire Short Forms for Urinary Incontinence (ICIQ-SF-UI) and Overactive Bladder (ICIQ-SF-OAB). Descriptive statistics were conducted; correlation matrices were created to explore relationships among major variables. Regression analyses were conducted to test our mediation hypotheses. RESULTS: There were 338 respondents with average age 70.9 (SD + 5.55) years. Most were white, overweight or obese, and had UI. Urinary urge cues fully mediated the relationship of TB-WEB with OAB. Urinary urge cues partially mediated the relationship of TB-WEB with UI; the direct effect of toileting behaviors on UI remained significant. Age and body mass index had significant partial correlations with UI but not with OAB. DISCUSSION: Toileting behaviors appear to contribute to sensitivity to urinary cues, which are related to both OAB and UI. Toileting behaviors have indirect effects on OAB and both indirect and direct effects on UI. Interventions to change toileting behaviors and extinguish urinary cues are needed. CONCLUSIONS: Behavioral and conditioning factors contribute to UI in older women.
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Vejiga Urinaria Hiperactiva , Incontinencia Urinaria , Humanos , Femenino , Anciano , Señales (Psicología) , Encuestas y CuestionariosRESUMEN
Efficacy of cleaning methods against SARS-CoV-2 suspended in either 5% soil load (SARS-soil) or simulated saliva (SARS-SS) was evaluated immediately (hydrated virus, T0) or 2 hours post-contamination (dried virus, T2). Hard water dampened wiping (DW) of surfaces, resulted in 1.77-3.91 log reduction (T0) or 0.93-2.41 log reduction (T2). Incorporating surface pre-wetting by spraying with a detergent solution (D + DW) or hard water (W + DW) just prior to dampened wiping did not unilaterally increase efficacy against infectious SARS-CoV-2, however, the effect was nuanced with respect to surface, viral matrix, and time. Cleaning efficacy on porous surfaces (seat fabric, SF) was low. W + DW on stainless steel (SS) was as effective as D + DW for all conditions except SARS-soil at T2 on SS. DW was the only method that consistently resulted in > 3-log reduction of hydrated (T0) SARS-CoV-2 on SS and ABS plastic. These results suggest that wiping with a hard water dampened wipe can reduce infectious virus on hard non-porous surfaces. Pre-wetting surfaces with surfactants did not significantly increase efficacy for the conditions tested. Surface material, presence or absence of pre-wetting, and time post-contamination affect efficacy of cleaning methods.
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COVID-19 , Virus , Humanos , SARS-CoV-2 , Desinfección/métodos , Detergentes/farmacología , Tacto , COVID-19/prevención & control , AguaRESUMEN
Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study (GWAS) of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P<3x10-8) with age-of-onset. Forty-five variants had comparable effects on the onset of the three individual diseases and 38 were also associated with allergic disease case-control status in an independent study (n = 222,484). We observed a strong negative genetic correlation between age-of-onset and case-control status of allergic disease (rg = -0.63, P = 4.5x10-61), indicating that cases with early disease onset have a greater burden of allergy risk alleles than those with late disease onset. Subsequently, a multivariate GWAS of age-of-onset and case-control status identified a further 26 associations that were missed by the univariate analyses of age-of-onset or case-control status only. Collectively, of the 76 variants identified, 18 represent novel associations for allergic disease. We identified 81 likely target genes of the 76 associated variants based on information from expression quantitative trait loci (eQTL) and non-synonymous variants, of which we highlight ADAM15, FOSL2, TRIM8, BMPR2, CD200R1, PRKCQ, NOD2, SMAD4, ABCA7 and UBE2L3. Our results support the notion that early and late onset allergic disease have partly distinct genetic architectures, potentially explaining known differences in pathophysiology between individuals.
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Asma/genética , Eccema/genética , Polimorfismo de Nucleótido Simple , Rinitis Alérgica Estacional/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Asma/patología , Niño , Eccema/patología , Femenino , Sitios Genéticos , Estudio de Asociación del Genoma Completo/métodos , Humanos , Masculino , Persona de Mediana Edad , Rinitis Alérgica Estacional/patologíaRESUMEN
Work with deceased human bodies to enhance anatomical education was first documented in the 3rd century BCE. However, the development of body donation programs provided many new opportunities for medical education. The aim of this study was to investigate the work supported by human body donors at academic institutions in the United States and to evaluate the ethical oversight process and the preparation methods used. A questionnaire was developed using Qualtrics and sent to 125 body donation programs in the United States. Representatives from a total of 69 institutions completed the questionnaire. The data showed that human body donations across the United States are used in teaching, clinical skills training, research, and educational outreach. Most institutions worked with hard-fixed donors for teaching and some with soft-preserved and unembalmed donors for clinical skills training. Among the participating programs, only 33 representatives reported an ethical approval process for conducting research involving human body donors. These findings raise ethical concerns related to the operation of body donation programs due to the lack of oversight. Furthermore, some institutions allowed faculty and staff to take photographs of donated bodies for educational purposes, which is often not disclosed on the consent form. The data also showed the need for more discussion on anatomical legacy collections housed at these institutions in the United States.
Asunto(s)
Anatomía , Educación Médica , Humanos , Estados Unidos , Cuerpo Humano , Donantes de Tejidos , Universidades , Docentes , Anatomía/educaciónRESUMEN
This is a comprehensive review of facial fillers including landmark studies and expert commentary spanning the years from 2003 (when the first hyaluronic acid [HA] dermal filler underwent Food and Drug Administration approval in United States) to present.