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Macrophages serve as a first line of defense against microbial pathogens. Exposure to interferon-γ (IFNγ) increases interferon-stimulated gene (ISG) expression in these cells, resulting in enhanced antimicrobial and proinflammatory activity. Although this response must be sufficiently vigorous to ensure the successful clearance of pathogens, it must also be carefully regulated to prevent tissue damage. This is controlled in part by CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2), a transcriptional coregulator that limits ISG expression by inhibiting STAT1 and IRF1. Here, we show that the closely related Cited1 is an ISG, which is expressed in a STAT1-dependent manner, and that IFNγ stimulates the nuclear accumulation of CITED1 protein. In contrast to CITED2, ectopic CITED1 enhanced the expression of a subset of ISGs, including Ccl2, Ifit3b, Isg15 and Oas2. This effect was reversed in a Cited1-null cell line produced by CRISPR-based genomic editing. Collectively, these data show that CITED1 maintains proinflammatory gene expression during periods of prolonged IFNγ exposure and suggest that there is an antagonistic relationship between CITED proteins in the regulation of macrophage inflammatory function. This article has an associated First Person interview with the first author of the paper.
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Interferon gama , Proteínas Nucleares , Humanos , Interferon gama/farmacologia , Interferon gama/genética , Interferon gama/metabolismo , Proteínas Nucleares/metabolismo , Regulação da Expressão Gênica , Macrófagos/metabolismo , Expressão Gênica , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transativadores/genética , Transativadores/metabolismoRESUMO
SignificanceKarrikins are chemicals in smoke that stimulate regrowth of many plants after fire. However, karrikin responses are not limited to species from fire-prone environments and can affect growth after germination. Putatively, this is because karrikins mimic an unknown signal in plants, KAI2 ligand (KL). Karrikins likely require modification in plants to become bioactive. We identify a gene, KUF1, that appears to negatively regulate biosynthesis of KL and metabolism of a specific karrikin. KUF1 expression increases in response to karrikin or KL signaling, thus forming a negative feedback loop that limits further activation of the signaling pathway. This discovery will advance understanding of how karrikins are perceived and how smoke-activated germination evolved. It will also aid identification of the elusive KL.
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Proteínas de Arabidopsis/genética , Arabidopsis/efeitos dos fármacos , Arabidopsis/genética , Furanos/farmacologia , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Genes de Plantas , Hidrolases/genética , Piranos/farmacologia , Arabidopsis/metabolismo , Plântula/genética , Plântula/metabolismo , Transdução de SinaisRESUMO
Fragile Xassociated tremor/ataxia syndrome (FXTAS) is a debilitating late-onset neurodegenerative disease in premutation carriers of the expanded CGG repeat in FMR1 that presents with a spectrum of neurological manifestations, such as gait ataxia, intention tremor, and parkinsonism [P. J. Hagerman, R. J. Hagerman, Ann. N. Y. Acad. Sci. 1338, 5870 (2015); S. Jacquemont et al., JAMA 291, 460469 (2004)]. Here, we performed whole-genome sequencing (WGS) on male premutation carriers (CGG55200) and prioritized candidate variants to screen for candidate genetic modifiers using a Drosophila model of FXTAS. We found 18 genes that genetically modulate CGG-associated neurotoxicity in Drosophila, such as Prosbeta5 (PSMB5), pAbp (PABPC1L), e(y)1 (TAF9), and CG14231 (OSGEPL1). Among them, knockdown of Prosbeta5 (PSMB5) suppressed CGG-associated neurodegeneration in the fly as well as in N2A cells. Interestingly, an expression quantitative trait locus variant in PSMB5, PSMB5rs11543947-A, was found to be associated with decreased expression of PSMB5 and delayed onset of FXTAS in human FMR1 premutation carriers. Finally, we demonstrate evidence that PSMB5 knockdown results in suppression of CGG neurotoxicity via both the RAN translation and RNA-mediated toxicity mechanisms, thereby presenting a therapeutic strategy for FXTAS.
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Ataxia , Síndrome do Cromossomo X Frágil , Complexo de Endopeptidases do Proteassoma , Tremor , Animais , Ataxia/genética , Modelos Animais de Doenças , Drosophila melanogaster , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Humanos , Masculino , Complexo de Endopeptidases do Proteassoma/genética , Tremor/genéticaRESUMO
Wheat is a widely grown food crop that suffers major yield losses due to attack by pests and pathogens. A better understanding of biotic stress responses in wheat is thus of major importance. The recently assembled bread wheat genome coupled with extensive transcriptomic resources provides unprecedented new opportunities to investigate responses to pathogen challenge. Here, we analyze gene coexpression networks to identify modules showing consistent induction in response to pathogen exposure. Within the top pathogen-induced modules, we identify multiple clusters of physically adjacent genes that correspond to six pathogen-induced biosynthetic pathways that share a common regulatory network. Functional analysis reveals that these pathways, all of which are encoded by biosynthetic gene clusters, produce various different classes of compoundsnamely, flavonoids, diterpenes, and triterpenes, including the defense-related compound ellarinacin. Through comparative genomics, we also identify associations with the known rice phytoalexins momilactones, as well as with a defense-related gene cluster in the grass model plant Brachypodium distachyon. Our results significantly advance the understanding of chemical defenses in wheat and open up avenues for enhancing disease resistance in this agriculturally important crop. They also exemplify the power of transcriptional networks to discover the biosynthesis of chemical defenses in plants with large, complex genomes.
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Vias Biossintéticas , Interações Hospedeiro-Patógeno , Doenças das Plantas , Triticum , Vias Biossintéticas/genética , Pão , Resistência à Doença/genética , Família Multigênica/genética , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Triticum/genética , Triticum/metabolismo , Triticum/microbiologiaRESUMO
BACKGROUND: Inhibition of kinases is the ever-expanding therapeutic approach to various types of cancer. Typically, assessment of the treatment response is accomplished by standard, volumetric imaging procedures, performed weeks to months after the onset of treatment, given the predominantly cytostatic nature of the kinase inhibitors, at least when used as single agents. Therefore, there is a great clinical need to develop new monitoring approaches to detect the response to kinase inhibition much more promptly. Noninvasive 1H magnetic resonance spectroscopy (MRS) can measure in vitro and in vivo concentration of key metabolites which may potentially serve as biomarkers of response to kinase inhibition. METHODS: We employed mantle cell lymphoma (MCL) cell lines demonstrating markedly diverse sensitivity of inhibition of Bruton's tyrosine kinase (BTK) regarding their growth and studied in-depth effects of the inhibition on various aspects of cell metabolism including metabolite synthesis using metabolomics, glucose and oxidative metabolism by Seahorse XF technology, and concentration of index metabolites lactate, alanine, total choline and taurine by 1H MRS. RESULTS: Effective BTK inhibition profoundly suppressed key cell metabolic pathways, foremost pyrimidine and purine synthesis, the citrate (TCA) cycle, glycolysis, and pyruvate and glutamine/alanine metabolism. It also inhibited glycolysis and amino acid-related oxidative metabolism. Finally, it profoundly and quickly decreased concentration of lactate (a product of mainly glycolysis) and alanine (an indicator of amino acid metabolism) and, less universally total choline both in vitro and in vivo, in the MCL xenotransplant model. The decrease correlated directly with the degree of inhibition of lymphoma cell expansion and tumor growth. CONCLUSIONS: Our results indicate that BTK inhibition exerts a broad and profound suppressive effect on cell metabolism and that the affected index metabolites such as lactate, alanine may serve as early, sensitive, and reliable biomarkers of inhibition in lymphoma patients detectable by noninvasive MRS-based imaging method. This kind of imaging-based detection may also be applicable to other kinase inhibitors, as well as diverse lymphoid and non-lymphoid malignancies.
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Tirosina Quinase da Agamaglobulinemia , Linfoma de Célula do Manto , Inibidores de Proteínas Quinases , Humanos , Linhagem Celular Tumoral , Inibidores de Proteínas Quinases/farmacologia , Animais , Tirosina Quinase da Agamaglobulinemia/metabolismo , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Linfoma de Célula do Manto/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Proliferação de Células/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos , Biomarcadores/metabolismoRESUMO
Maternal, placental, and neonatal factors were compared between infants born at ≤29 weeks of gestational age with admission hyperthermia (>37.5âC) and euthermia (36.5-37.5âC). Admission hyperthermia was associated with longer duration of face-mask positive-pressure ventilation and infant's temperature ≥37.5âC in the delivery room. Infants born preterm with admission hyperthermia had greater odds of developing necrotizing enterocolitis and neurodevelopmental impairment.
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Enterocolite Necrosante , Hipertermia Induzida , Lactente , Recém-Nascido , Humanos , Gravidez , Feminino , Recém-Nascido Prematuro , Placenta , Idade Gestacional , Fatores de RiscoRESUMO
Maternal obesity increases the risk of adverse pregnancy outcomes. The mechanisms that contribute to this elevated risk are unclear but may be related to greater activity of the sympathetic nervous system, which is associated with hypertensive disorders of pregnancy. We hypothesized that resting muscle sympathetic nerve activity (MSNA) would be greater in women with obesity during pregnancy when compared with normal-weight women. Blood pressure, heart rate, and MSNA were recorded during 5 min of supine rest in 14 normal-weight women [body mass index (BMI) 22.1 ± 2.1 (SD) kg/m2] and 14 women with obesity (BMI 33.9 ± 3.5 kg/m2) during (early and late) pregnancy and postpartum. All women had uncomplicated pregnancies. Resting MSNA burst frequency was not different between groups during early (normal weight 17 ± 10 vs. obesity 22 ± 15 bursts/min, P = 0.35) but was significantly greater in the obesity group during late pregnancy (23 ± 13 vs. 35 ± 15 bursts/min, P = 0.031) and not different postpartum (10 ± 6 vs. 9 ± 7 bursts/min, P = 0.74). These findings were also apparent when comparing burst incidence and total activity. Although still within the normotensive range, systolic blood pressure was greater in the obesity group across all time points (P = 0.002). Diastolic blood pressure was lower during pregnancy compared with postpartum (P < 0.001) and not different between groups (P = 0.488). Heart rate increased throughout pregnancy in both groups (P < 0.001). Our findings suggest that maternal obesity is associated with greater increases in sympathetic activity even during uncomplicated pregnancy. Future research is needed to determine if this is linked with an increased risk of adverse outcomes or is required to maintain homeostasis in pregnancy.NEW & NOTEWORTHY The impact of maternal obesity on resting muscle sympathetic nerve activity was examined during (early and late) and after uncomplicated pregnancy. Resting muscle sympathetic nerve activity is not different during early pregnancy or postpartum but is significantly elevated in women with obesity during late pregnancy when compared with normal-weight women. Future research is needed to determine if this is linked with an increased risk of adverse outcomes or is required to maintain homeostasis in pregnancy.
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Obesidade Materna , Humanos , Feminino , Gravidez , Masculino , Pressão Sanguínea/fisiologia , Frequência Cardíaca/fisiologia , Músculo Esquelético/inervação , Obesidade/diagnóstico , Sistema Nervoso SimpáticoRESUMO
N-Heterocyclic carbene (NHC)-derived selenoureas comprise a fundamentally important class of NHC derivatives, with key applications in coordination chemistry and the determination of NHC electronic properties. Considering the broad reactivity of chalcogen-containing compounds, it is surprising to note that the use of NHC-derived selenoureas as organic synthons remains essentially unexplored. The present contribution introduces a novel, straightforward transformation leading to azines bearing a guanidine moiety, through the reaction of a wide range of NHC-derived selenoureas with commercially available diazo compounds, in the presence of triphenylphosphine. This transformation offers a new approach to such products, having biological, materials chemistry, and organic synthesis applications. The guanidine-bearing azines are obtained in excellent yields, with all manipulations taking place in air. A reaction mechanism is proposed, based on both experimental mechanistic findings and density functional theory (DFT) calculations. A one-pot, multicomponent transesterification reaction between selenoureas, α-diazoesters, alcohols, and triphenylphosphine was also developed, providing highly functionalized azines.
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BACKGROUND: Lung cancer is the third most common cancer in the UK and the leading cause of cancer mortality globally. NHS England guidance for optimum lung cancer care recommends management and treatment by a specialist team, with experts concentrated in one place, providing access to specialised diagnostic and treatment facilities. However, the complex and rapidly evolving diagnostic and treatment pathways for lung cancer, together with workforce limitations, make achieving this challenging. This place-based, behavioural science-informed qualitative study aims to explore how person-related characteristics interact with a person's location relative to specialist services to impact their engagement with the optimal lung pathway, and to compare and contrast experiences in rural, coastal, and urban communities. This study also aims to generate translatable evidence to inform the evidence-based design of a patient engagement intervention to improve lung cancer patients' and informal carers' participation in and experience of the lung cancer care pathway. METHODS: A qualitative cross-sectional interview study with people diagnosed with lung cancer < 6 months before recruitment (in receipt of surgery, radical radiotherapy, or living with advanced disease) and their informal carers. Participants will be recruited purposively from Barts Health NHS Trust and United Lincolnshire Hospitals NHS Trusts to ensure a diverse sample across urban and rural settings. Semi-structured interviews will explore factors affecting individuals' capability, opportunity, and motivation to engage with their recommended diagnostic and treatment pathway. A framework approach, informed by the COM-B model, will be used to thematically analyse facilitators and barriers to patient engagement. DISCUSSION: The study aligns with the current policy priority to ensure that people with cancer, no matter where they live, can access the best quality treatments and care. The evidence generated will be used to ensure that lung cancer services are developed to meet the needs of rural, coastal, and urban communities. The findings will inform the development of an intervention to support patient engagement with their recommended lung cancer pathway. PROTOCOL REGISTRATION: The study received NHS Research Ethics Committee (Ref: 23/SC/0255) and NHS Health Research Authority (IRAS ID 328531) approval on 04/08/2023. The study was prospectively registered on Open Science Framework (16/10/2023; https://osf.io/njq48 ).
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Acessibilidade aos Serviços de Saúde , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/terapia , Pesquisa Qualitativa , Estudos Transversais , População Rural , Feminino , MasculinoRESUMO
Genetics has become a critical component of medicine over the past five to six decades. Alongside genetics, a relatively new discipline, dysmorphology, has also begun to play an important role in providing critically important diagnoses to individuals and families. Both have become indispensable to unraveling rare diseases. Almost every medical specialty relies on individuals experienced in these specialties to provide diagnoses for patients who present themselves to other doctors. Additionally, both specialties have become reliant on molecular geneticists to identify genes associated with human disorders. Many of the medical geneticists, dysmorphologists, and molecular geneticists traveled a circuitous route before arriving at the position they occupied. The purpose of collecting the memoirs contained in this article was to convey to the reader that many of the individuals who contributed to the advancement of genetics and dysmorphology since the late 1960s/early 1970s traveled along a journey based on many chances taken, replying to the necessities they faced along the way before finding full enjoyment in the practice of medical and human genetics or dysmorphology. Additionally, and of equal importance, all exhibited an ability to evolve with their field of expertise as human genetics became human genomics with the development of novel technologies.
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Genética Médica , Humanos , História do Século XX , História do Século XXI , Genética HumanaRESUMO
BACKGROUND: Although cesarean delivery is the most common surgery performed in the United States, prescribing practices for analgesia vary. Strategies to manage postpartum pain have mostly focused on the immediate postpartum period when patients are still admitted to the hospital. At discharge, most providers prescribe a fixed number of opioid tablets. Most patients do not use all the opioids that they are prescribed at hospital discharge. This leads to an excess of opioids in the community, which can ultimately lead to misuse and diversion. OBJECTIVE: This study aimed to determine whether a transition from universal opioid prescribing to a personalized, patient-specific protocol decreases morphine milligram equivalents prescribed at hospital discharge after cesarean delivery while adequately controlling pain. STUDY DESIGN: This was a prospective cohort study of patients undergoing cesarean delivery before and after the implementation of a personalized opioid-prescribing practice at the time of hospital discharge. Each patient was prescribed scheduled ibuprofen and acetaminophen, with a prescription for oxycodone tablets equal to 5 times the morphine milligram equivalents used in the 24 hours before discharge, calculated via an electronic order set. The previous traditional cohorts were routinely prescribed 30 tablets of acetaminophen-codeine 300/30 mg. The primary outcome was morphine milligram equivalents prescribed at discharge. A hotline to address pain control issues after discharge was established, and calls, emergency department visits, and readmissions were examined. Statistical analyses was performed using chi-square and Wilcoxon rank-sum test, with a P value of <.05 considered statistically significant. RESULTS: Overall, 412 patients underwent cesarean delivery in the 6 weeks after initiation of the personalized prescribing protocol and were compared with 367 patients before the change. The median morphine milligram equivalents prescribed at discharge was lower with personalized prescribing (37.5 [interquartile range, 0-75] vs 135 [interquartile range, 135-135]; P<.001). Moreover, 176 patients (43%) were not prescribed opioids at discharge, which was a substantial change as all 367 patients in the traditional cohort received opioids at discharge (P<.001). Of note, 9 hotline phone calls were received; none required additional opioids after a 24-hour trial of scheduled ibuprofen, which none had taken before the call. In addition, 11 patients (2.7%) presented to the emergency department for pain evaluation, of which none required readmission or an outpatient prescription of opioids. CONCLUSION: A personalized protocol for opioid prescriptions after cesarean delivery decreased the total morphine milligram equivalents and the number of opioid tablets at discharge, without hospital readmissions or need for rescue opioid prescriptions after discharge. Opioids released into our community will be reduced by more than 90,000 tablets per year, without demonstrable adverse effect.
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Acetaminofen , Analgésicos Opioides , Gravidez , Feminino , Humanos , Estados Unidos , Analgésicos Opioides/uso terapêutico , Ibuprofeno/uso terapêutico , Estudos Prospectivos , Pacientes Ambulatoriais , Registros Eletrônicos de Saúde , Dor Pós-Operatória/tratamento farmacológico , Padrões de Prática Médica , Oxicodona , PrescriçõesRESUMO
Bird populations are declining globally. Wind and solar energy can reduce emissions of fossil fuels that drive anthropogenic climate change, yet renewable-energy production represents a potential threat to bird species. Surveys to assess potential effects at renewable-energy facilities are exclusively local, and the geographic extent encompassed by birds killed at these facilities is largely unknown, which creates challenges for minimizing and mitigating the population-level and cumulative effects of these fatalities. We performed geospatial analyses of stable hydrogen isotope data obtained from feathers of 871 individuals of 24 bird species found dead at solar- and wind-energy facilities in California (USA). Most species had individuals with a mix of origins, ranging from 23% to 98% nonlocal. Mean minimum distances to areas of likely origin for nonlocal individuals were as close as 97 to >1250 km, and these minimum distances were larger for species found at solar-energy facilities in deserts than at wind-energy facilities in grasslands (Cohen's d = 6.5). Fatalities were drawn from an estimated 30-100% of species' desingated ranges, and this percentage was significantly smaller for species with large ranges found at wind facilities (Pearson's r = -0.67). Temporal patterns in the geographic origin of fatalities suggested that migratory movements and nonmigratory movements, such as dispersal and nomadism, influence exposure to fatality risk for these birds. Our results illustrate the power of using stable isotope data to assess the geographic extent of renewable-energy fatalities on birds. As the buildout of renewable-energy facilities continues, accurate assessment of the geographic footprint of wildlife fatalities can be used to inform compensatory mitigation for their population-level and cumulative effects.
Extensión geográfica de las poblaciones de aves afectadas por desarrollos de energía renovable Resumen Las poblaciones mundiales de aves están en declive. Las energías solar y eólica pueden reducir las emisiones de combustibles fósiles que causan el cambio climático, aunque la producción de energías renovables representa una amenaza potencial para las aves. Los censos para evaluar los efectos potenciales en los centros de energía renovable son exclusivamente locales y se sabe poco sobre la extensión geográfica representada por las aves que mueren en estas instalaciones, lo que plantea obstáculos para mitigar los efectos acumulativos y de nivel poblacional de estas muertes. Realizamos análisis geoespaciales con datos del isótopo de hidrógeno estable obtenido de las plumas de 871 ejemplares de 24 especies de aves que fueron hallados muertos en los centros de energía solar y eólica en California, EE.UU. La mayoría de las especies contó con ejemplares de orígenes mixtos, con un rango del 23% al 98% no local. La media de la distancia mínima a las áreas de probable origen de los ejemplares no locales varía entre los 97 hasta > 1,250 km. Estas distancias mínimas fueron mayores para las especies encontradas en los centros de energía solar situadas en desiertos que para las especies encontradas en los centros de energía eólica localizadas en pastizales (d de Cohen = 6.5). Las muertes representan un 30100% de la extensión de las especies. Este porcentaje fue significativamente menor para las especies con extensiones amplias encontradas en instalaciones eólicas (r de Pearson = 0.67). Los patrones temporales en el origen geográfico de las muertes sugieren que los movimientos migratorios y no migratorios, como la dispersión y el nomadismo, influyen en la exposición de estas aves al riesgo de muerte. Nuestros resultados demuestran la utilidad de los isótopos estables para evaluar el alcance geográfico de las muertes de aves asociadas a energías renovables. Con el progresivo aumento de instalaciones de energía renovable, una evaluación precisa de la huella geográfica de la mortandad de fauna salvaje podrá guiar la mitigación compensatoria de sus efectos acumulativos y de nivel poblacional.
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Conservação dos Recursos Naturais , Energia Renovável , Animais , Aves , Isótopos , VentoRESUMO
In plants, G proteins modulate signaling by the stress hormone, abscisic acid (ABA). We identify and characterize two novel Arabidopsis proteins that show homology to an orphan vertebrate GPCR (GPR89) and interact with the sole Arabidopsis G protein alpha subunit, GPA1, but also have intrinsic GTP-binding and GTPase activity. We have named these proteins GPCR-type G proteins (GTG1 and GTG2). Arabidopsis mutants lacking both GTG1 and GTG2 exhibit ABA hyposensitivity. GTG1 and GTG2 bind ABA specifically. The GDP-bound form of the GTGs exhibits greater ABA binding than the GTP-bound form, the GTPase activity of the GTGs is inhibited by GPA1, and gpa1 null mutants exhibit ABA-hypersensitive phenotypes. These results predict that, unusually, it is the GDP-bound, not the GTP-bound, form of the GTGs that actively relays the signal. We propose that GTG proteins function both as a new type of G protein and as a class of membrane-localized ABA receptors.
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Ácido Abscísico/metabolismo , Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Reguladores de Crescimento de Plantas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Sequência de Aminoácidos , Arabidopsis/química , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/genética , GTP Fosfo-Hidrolases , Regulação da Expressão Gênica de Plantas , Dados de Sequência Molecular , Mutagênese Insercional , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Alinhamento de Sequência , Transdução de SinaisRESUMO
BACKGROUND: Moderate-to-severe traumatic brain injury (TBI) has a global mortality rate of about 30%, resulting in acquired life-long disabilities in many survivors. To potentially improve outcomes in this TBI population, the management of secondary injuries, particularly the failure of cerebrovascular reactivity (assessed via the pressure reactivity index; PRx, a correlation between intracranial pressure (ICP) and mean arterial blood pressure (MAP)), has gained interest in the field. However, derivation of PRx requires high-resolution data and expensive technological solutions, as calculations use a short time-window, which has resulted in it being used in only a handful of centers worldwide. As a solution to this, low resolution (longer time-windows) PRx has been suggested, known as Long-PRx or LPRx. Though LPRx has been proposed little is known about the best methodology to derive this measure, with different thresholds and time-windows proposed. Furthermore, the impact of ICP monitoring on cerebrovascular reactivity measures is poorly understood. Hence, this observational study establishes critical thresholds of LPRx associated with long-term functional outcome, comparing different time-windows for calculating LPRx as well as evaluating LPRx determined through external ventricular drains (EVD) vs intraparenchymal pressure device (IPD) ICP monitoring. METHODS: The study included a total of n = 435 TBI patients from the Karolinska University Hospital. Patients were dichotomized into alive vs. dead and favorable vs. unfavorable outcomes based on 1-year Glasgow Outcome Scale (GOS). Pearson's chi-square values were computed for incrementally increasing LPRx or ICP thresholds against outcome. The thresholds that generated the greatest chi-squared value for each LPRx or ICP parameter had the highest outcome discriminatory capacity. This methodology was also completed for the segmentation of the population based on EVD, IPD, and time of data recorded in hospital stay. RESULTS: LPRx calculated with 10-120-min windows behaved similarly, with maximal chi-square values ranging at around a LPRx of 0.25-0.35, for both survival and favorable outcome. When investigating the temporal relations of LPRx derived thresholds, the first 4 days appeared to be the most associated with outcomes. The segmentation of the data based on intracranial monitoring found limited differences between EVD and IPD, with similar LPRx values around 0.3. CONCLUSION: Our work suggests that the underlying prognostic factors causing impairment in cerebrovascular reactivity can, to some degree, be detected using lower resolution PRx metrics (similar found thresholding values) with LPRx found clinically using as low as 10 min-by-minute samples of MAP and ICP. Furthermore, EVD derived LPRx with intermittent cerebrospinal fluid draining, seems to present similar outcome capacity as IPD. This low-resolution low sample LPRx method appears to be an adequate substitute for the clinical prognostic value of PRx and may be implemented independent of ICP monitoring method when PRx is not feasible, though further research is warranted.
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Lesões Encefálicas Traumáticas , Pressão Intracraniana , Humanos , Lesões Encefálicas Traumáticas/fisiopatologia , Pressão Intracraniana/fisiologia , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Monitorização Fisiológica/métodos , Monitorização Fisiológica/instrumentação , Idoso , Pressão Arterial/fisiologiaRESUMO
BACKGROUND: The proportion of heart failure patients with preserved ejection fraction has been rising over the past decades and has coincided with increases in the prevalence of obesity and metabolic syndrome. The relationship between these interconnected comorbidities and heart failure with preserved ejection fraction (HFpEF) is still poorly understood. This study characterized obesity and metabolic syndrome among real-world patients with HFpEF. METHODS: We identified adults with heart failure in the Veradigm Cardiology Registry, previously the PINNACLE Registry, with a left ventricular ejection fraction measurement ≥ 50% between 01/01/2016 and 12/31/2019. Patients were stratified by obesity diagnosis and presence of metabolic syndrome (≥ 3 of the following: diabetes, hypertension, hyperlipidemia, and obesity). We captured baseline demographic and clinical characteristics and used multivariable logistic regression to examine the odds of having cardiac (atrial fibrillation, coronary artery disease, coronary artery bypass surgery, myocardial infarction, and stroke/transient ischemic attack) and non-cardiac (chronic kidney disease, chronic liver disease, and peripheral artery disease) comorbidities of interest. The models adjusted for age and sex, and the main covariates of interest were obesity and metabolic burden score (0-3 based on the presence of diabetes, hypertension, and hyperlipidemia). The models were run with and without an obesity*metabolic burden score interaction term. RESULTS: This study included 264,571 patients with HFpEF, of whom 55.7% had obesity, 52.5% had metabolic syndrome, 42.5% had both, and 34.3% had neither. After adjusting for age, sex, and burden of other metabolic syndrome-associated diagnoses, patients with HFpEF with obesity had lower odds of a diagnosis of other evaluated comorbidities relative to patients without obesity. The presence of metabolic syndrome in HFpEF appears to increase comorbidity burden as each additional metabolic syndrome-associated diagnosis was associated with higher odds of assessed comorbidities except atrial fibrillation. CONCLUSION: Obesity was common among patients with HFpEF and not always co-occurring with metabolic syndrome. Multivariable analysis suggested that patients with obesity may develop HFpEF in the absence of other driving factors such as cardiovascular disease or metabolic syndrome.
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Insuficiência Cardíaca , Síndrome Metabólica , Obesidade , Sistema de Registros , Volume Sistólico , Humanos , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/complicações , Masculino , Feminino , Obesidade/complicações , Obesidade/epidemiologia , Obesidade/fisiopatologia , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/etiologia , Idoso , Estudos Transversais , Volume Sistólico/fisiologia , Pessoa de Meia-Idade , Comorbidade , Idoso de 80 Anos ou mais , Prevalência , PrognósticoRESUMO
PURPOSE: Urban cancer survivors have been shown to have better opportunities for recovery of health and wellbeing than their rural counterparts. Whilst there is a considerable body of evidence that explores urban people with cancers' experiences and outcomes, there is a dearth of research that explicitly explores 'urban cancer survivorship' in its own right. This study aimed to explore cancer survivorship in urban people living with cancer who have completed primary treatment. METHODS: Secondary analysis of in-depth interview data (n = 18) with adults living with cancer who resided in urban parts of the UK. Data were drawn from a broader study on self-management of people living with cancer. An adapted version of Foster and Fenlon's recovery of health and wellbeing in cancer survivorship framework was used to inform the analysis of the data. RESULTS: Recovery of health and wellbeing was impacted by a variety of contributory factors, which had a largely positive impact. Access to amenities, social support, travel, and healthcare factors were opportunities for urban cancer survivors, whilst pollution, traffic and a lack of green spaces acted as challenges for health management. CONCLUSION: This study demonstrated how urban residency acted as both a barrier and a facilitator to recovery of health and wellbeing in urban cancer survivors following the completion of primary treatment. Area of residence should be taken into account by health providers and policymakers supporting cancer survivorship and the views of those with lived experiences should be included in informing future practice.
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Sobreviventes de Câncer , Neoplasias , Adulto , Humanos , Neoplasias/terapia , Atenção à Saúde , População Rural , Pesquisa QualitativaRESUMO
PURPOSE: To synthesize the qualitative literature exploring the experiences of people living with lung cancer in rural areas. METHODS: Searches were performed in MEDLINE, CINAHL, and PsycINFO. Articles were screened independently by two reviewers against pre-determined eligibility criteria. Data were synthesized using Thomas and Harden's framework for the thematic synthesis of qualitative research. The CASP qualitative checklist was used for quality assessment and the review was reported in accordance with the ENTREQ and PRISMA checklists. RESULTS: Nine articles were included, from which five themes were identified: (1) diagnosis and treatment pathways, (2) travel and financial burden, (3) communication and information, (4) experiences of interacting with healthcare professionals, (5) symptoms and health-seeking behaviors. Lung cancer diagnosis was unexpected for some with several reporting treatment delays and long wait times regarding diagnosis and treatment. Accessing treatment was perceived as challenging and time-consuming due to distance and financial stress. Inadequate communication of information from healthcare professionals was a common concern expressed by rural people living with lung cancer who also conveyed dissatisfaction with their healthcare professionals. Some were reluctant to seek help due to geographical distance and sociocultural factors whilst others found it challenging to identify symptoms due to comorbidities. CONCLUSIONS: This review provides a deeper understanding of the challenges faced by people with lung cancer in rural settings, through which future researchers can begin to develop tailored support to address the existing disparities that affect this population.
Assuntos
Acessibilidade aos Serviços de Saúde , Neoplasias Pulmonares , Pesquisa Qualitativa , População Rural , Humanos , Neoplasias Pulmonares/psicologia , Neoplasias Pulmonares/terapia , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , ComunicaçãoRESUMO
Mounting empirical research suggests that the stroma, or interface between healthy and cancerous tissue, is a critical determinate of cancer invasion. At the same time, a cancer cell's location and potential to proliferate can influence its sensitivity to cancer treatments. In this paper, we use ordinary differential equations to develop spatially structured models for solid tumors wherein the growth of tumor components is coordinated. The model tumors feature two components, a proliferating peripheral growth region, which potentially includes a mix of cancerous and noncancerous stroma cells, and a solid tumor core. Mathematical and numerical analysis are used to investigate how coordinated expansion of the tumor growth region and core can influence overall growth dynamics in a variety of tumor types. Model assumptions, which are motivated by empirical and in silico solid tumor research, are evaluated through comparison to tumor volume data and existing models of tumor growth.
Assuntos
Conceitos Matemáticos , Neoplasias , Humanos , Modelos BiológicosRESUMO
Millions of individuals require anesthesia services each year. Although anesthesia-associated mortality rates have declined, anesthetic-related morbidity remains high, particularly among vulnerable populations. Disparities in perioperative screening, optimization, surveillance, and follow-up contribute to worse outcomes in these populations. Community-engaged collaborations may be the essential ingredient needed for anesthesiologists to improve disparities in anesthetic outcomes and prioritize the needs of patients and communities. This scoping review seeks to examine the available literature on community engagement among anesthesiologists to identify gaps and seek opportunities for future work. This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). OVID MEDLINE, Scopus, and Web of Science Core Collection were searched to identify sources that used or recognized community-engaged strategies and involved the work of anesthesiologists. Sources were selected based on inclusion criteria and consistent data were extracted from each paper for compilation in a data chart. The initial search generated 1230 articles of which 16 met criteria for inclusion in the review. An updated search of the literature and reference scan of included sources resulted in 7 additional articles being included. The sources were grouped according to overarching themes and methods used and ultimately categorized according to the spectrum of public participation developed by the International Association for Public Participation (IAP2). This spectrum includes 5 levels: inform, consult, involve, collaborate, and empower. This review identified 5 sources at the inform level, 8 studies in consult, 0 in involve, 7 in collaborate, and 3 in empower. Results indicate that most initiatives representing deeper levels of community engagement, at the collaborate or empower level, occur internationally. Efforts that occur in the United States tend to emphasize engagement of individual patients rather than communities. There is a need to pursue deeper, more meaningful community-engaged efforts within the field of anesthesiology at a local and national level.
Assuntos
Anestesia , Anestesiologia , Anestésicos , Humanos , Anestesiologistas , Encaminhamento e ConsultaRESUMO
BACKGROUND: Physical activity (PA) among Hispanic and other minority adolescents in the U.S. lag behind White, non-Hispanic adolescents. Previous studies have examined the beneficial impact of culturally informed, community-based health programs within the Hispanic community on PA levels. There is a need for longer term follow up to determine the impact on family and individual habits over time. Our study aims to explore the aspects of a two-year PA and nutrition program, Families Inspired Together 4 Youth Empowered to Succeed (FIT4YES), that continue to influence family health habits and child development. METHODS: Community-based focus groups were held in Milwaukee, WI with Hispanic parent participants of the FIT4YES program three years after program conclusion. A semi-structured guide of open-ended questions was used to facilitate the discussion of the lasting impact of FIT4YES. Each group was audio recorded, transcribed, and translated from Spanish when necessary. Four student researchers utilized a grounded theory qualitative approach to identify overarching themes. RESULTS: Three focus groups with 16 total parents (N = 16) spoke about the program. Three overarching themes emerged from the transcripts indicating that cultural exposure, relationships, and self-growth were necessary for families to sustain the healthy behaviors promoted in FIT4YES. Specifically, parents discussed increased comfort levels with their children participating in school sports, the impact of shared experiences with community members, and continued skills initially taught and practiced during active programming. CONCLUSIONS: Our group adapted our previously published model to a "post-program" state that incorporated the major themes and sub-themes with levels of the social-ecological model. Although the FIT4YES program ended, multiple ideals instilled by the program continued, we believe, due to the common themes illustrated by our model. This study utilized a community check-in approach to gain insight into the long-term impacts of the FIT4YES program. We propose three recommendations for consideration in the creation of community-based health programs: utilize dynamic, culturally appropriate components based on the intended community; understand the strength of the program as a whole is dependent on the strength of each individual component; and incorporate an anchor institution for consistency and trust within the community.