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This study determines the functional role of the plant ultraviolet-B radiation (UV-B) photoreceptor, UV RESISTANCE LOCUS 8 (UVR8) under natural conditions using a large-scale 'synchronized-genetic-perturbation-field-experiment'. Laboratory experiments have demonstrated a role for UVR8 in UV-B responses but do not reflect the complexity of outdoor conditions where 'genotype × environment' interactions can mask laboratory-observed responses. Arabidopsis thaliana knockout mutant, uvr8-7, and the corresponding Wassilewskija wild type, were sown outdoors on the same date at 21 locations across Europe, ranging from 39°N to 67°N latitude. Growth and climatic data were monitored until bolting. At the onset of bolting, rosette size, dry weight, and phenolics and glucosinolates were quantified. The uvr8-7 mutant developed a larger rosette and contained less kaempferol glycosides, quercetin glycosides and hydroxycinnamic acid derivatives than the wild type across all locations, demonstrating a role for UVR8 under field conditions. UV effects on rosette size and kaempferol glycoside content were UVR8 dependent, but independent of latitude. In contrast, differences between wild type and uvr8-7 in total quercetin glycosides, and the quercetin-to-kaempferol ratio decreased with increasing latitude, that is, a more variable UV response. Thus, the large-scale synchronized approach applied demonstrates a location-dependent functional role of UVR8 under natural conditions.
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Chronic urticaria is an inflammatory skin disorder defined by the presence of evanescent erythematous pruritic wheals, angioedema, or both. While treatment guidelines are continuing to become more clearly defined, there is still a gap in the medical literature surrounding chronic spontaneous urticaria (CSU) treatment in vulnerable populations such as children (aged 0-18 years), pregnant women, and the elderly (aged >65 years). The purpose of this review is to provide an update on CSU in each of these special population categories by defining prevalence, identifying diagnostic considerations, and exploring current and future management options.
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Urticária Crônica , Humanos , Gravidez , Feminino , Criança , Urticária Crônica/diagnóstico , Urticária Crônica/etiologia , Idoso , Pré-Escolar , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/epidemiologia , Complicações na Gravidez/terapia , Adolescente , Prevalência , Recém-Nascido , Gerenciamento Clínico , Lactente , Urticária/diagnóstico , Urticária/etiologia , Urticária/epidemiologiaRESUMO
Introduction: Acute kidney injury (AKI) is one of the most common causes of organ failure in critically ill patients. Following AKI, the canonical pro-inflammatory cytokine interleukin-1ß (IL-1ß) is released predominantly from activated myeloid cells and binds to the interleukin-1 receptor R1 (IL-1R1) on leukocytes and kidney parenchymal cells. IL-1R1 on kidney tubular cells is known to amplify the immune response and exacerbate AKI. However, the specific role of IL-1R1 on myeloid cells during AKI is poorly understood. The objective of the present study was to elucidate the function of myeloid cell IL-1R1 during AKI. As IL-1R1 is known to signal through the pro-inflammatory Toll-like receptor (TLR)/MyD88 pathway, we hypothesized that myeloid cells expressing IL-1R1 would exacerbate AKI. Methods: IL-1R1 was selectively depleted in CD11c+-expressing myeloid cells with CD11cCre + /IL-1R1 fl/fl (Myel KO) mice. Myel KO and littermate controls (CD11cCre - /IL-1R1 fl/fl-Myel WT) were subjected to kidney ischemia/reperfusion (I/R) injury. Kidney injury was assessed by blood urea nitrogen (BUN), serum creatinine and injury marker neutrophil gelatinase-associated lipocalin (NGAL) protein expression. Renal tubular cells (RTC) were co-cultured with CD11c+ bone marrow-derived dendritic cells (BMDC) from Myel KO and Myel WT mice. Results: Surprisingly, compared to Myel WT mice, Myel KO mice displayed exaggerated I/R-induced kidney injury, as measured by elevated levels of serum creatinine and BUN, and kidney NGAL protein expression. In support of these findings, in vitro co-culture studies showed that RTC co-cultured with Myel KO BMDC (in the presence of IL-1ß) exhibited higher mRNA levels of the kidney injury marker NGAL than those co-cultured with Myel WT BMDC. In addition, we observed that IL-1R1 on Myel WT BMDC preferentially augmented the expression of anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1ra/Il1rn), effects that were largely abrogated in Myel KO BMDC. Furthermore, recombinant IL-1Ra could rescue IL-1ß-induced tubular cell injury. Discussion: Our findings suggest a novel function of IL-1R1 is to serve as a critical negative feedback regulator of IL-1 signaling in CD11c+ myeloid cells to dampen inflammation to limit AKI. Our results lend further support for cell-specific, as opposed to global, targeting of immunomodulatory agents.
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The European ammonia industry emits 36 million tons of carbon dioxide annually, primarily from steam methane reforming (SMR) hydrogen production. These emissions can be mitigated by producing hydrogen via water electrolysis using dedicated renewables with grid backup. This study investigates the impact of decarbonization targets for hydrogen synthesis on the economic viability and technical feasibility of retrofitting existing European ammonia plants for on-site, semi-islanded electrolytic hydrogen production. Results show that electrolytic hydrogen cuts emissions, on average, by 85% (36%-100% based on grid price and carbon intensity), even without enforcing emission limits. However, an optimal lifespan average well-to-gate emission cap of 1 kg carbon dioxide equivalent (CO2e)/kg H2 leads to a 95% reduction (92%-100%) while maintaining cost-competitiveness with SMR in renewable-rich regions (mean levelized cost of hydrogen (LCOH) of 4.1 euro/kg H2). Conversely, a 100% emissions reduction target dramatically increases costs (mean LCOH: 6.3 euro/kg H2) and land area for renewables installations, likely hindering the transition to electrolytic hydrogen in regions with poor renewables and limited land. Increasing plant flexibility effectively reduces costs, particularly in off-grid plants (mean reduction: 32%). This work guides policymakers in defining cost-effective decarbonization targets and identifying region-based strategies to support an electrolytic hydrogen-fed ammonia industry.
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Mild traumatic brain injury (mTBI) is a leading cause of disability in the United States, with neuropsychiatric disturbances such as depression, anxiety, PTSD, and social disturbances being common comorbidities following injury. The molecular mechanisms driving neuropsychiatric complications following neurotrauma are not well understood and current FDA-approved pharmacotherapies employed to ameliorate these comorbidities lack desired efficacy. Concerted efforts to understand the molecular mechanisms of and identify novel drug candidates for treating neurotrauma-elicited neuropsychiatric sequelae are clearly needed. Serotonin (5-HT) is linked to the etiology of neuropsychiatric disorders, however our understanding of how various forms of TBI directly affect 5-HT neurotransmission is limited. 5-HT neurons originate in the raphe nucleus (RN) of the midbrain and project throughout the brain to regulate diverse behavioral phenotypes. We hypothesize that the characterization of the dynamics governing 5-HT neurotransmission after injury will drive the discovery of novel drug targets and lead to a greater understanding of the mechanisms associated with neuropsychiatric disturbances following mild TBI (mTBI). Herein, we provide evidence that closed-head mTBI alters total DRN 5-HT levels, with RNA sequencing of the DRN revealing injury-derived alterations in transcripts required for the development, identity, and functional stability of 5-HT neurons. Further, using gene ontology analyses combined with immunohistological analyses, we have identified a novel mechanism of transcriptomic control within 5-HT neurons that may directly influence 5-HT neuron identity/function post-injury. These studies provide molecular evidence of injury-elicited 5-HT neuron dysregulation, data which may expedite the identification of novel therapeutic targets to attenuate TBI-elicited neuropsychiatric sequelae.
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Concussão Encefálica , Núcleo Dorsal da Rafe , Humanos , Serotonina , Concussão Encefálica/complicações , Neurônios , Perfilação da Expressão Gênica , Neurônios SerotoninérgicosRESUMO
We design a novel experiment to identify aversion to pure (univariate) health inequality separately from aversion to income-related and income-caused health inequality. Participants allocate resources to determine health of individuals. Identification comes from random variation in resource productivity and information on income and its causal effect. We gather data (26,286 observations) from a sample of UK adults (n = 337) and estimate pooled and participant-specific social preferences while accounting for noise. The median person has strong aversion to pure health inequality, challenging the health maximisation objective of economic evaluation. Aversion to health inequality is even stronger when it is related to income. However, the median person prioritises health of poorer individuals less than is assumed in the standard measure of income-related health inequality. On average, aversion to that inequality does not become stronger when low income is known to cause ill-health. There is substantial heterogeneity in all three types of inequality aversion.
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Disparidades nos Níveis de Saúde , Renda , Adulto , Humanos , Pobreza , Seguridade Social , Fatores SocioeconômicosRESUMO
Traumatic brain injury (TBI) is a pervasive public health crisis that severely impacts the quality of life of affected individuals. Like peripheral forms of trauma, TBI results from extraordinarily heterogeneous environmental forces being imparted on the cranial space, resulting in heterogeneous disease pathologies. This has made therapies for TBI notoriously difficult to develop, and currently, there are no FDA-approved pharmacotherapies specifically for the acute or chronic treatment of TBI. TBI is associated with changes in cognition and can precipitate the onset of debilitating psychiatric disorders like major depressive disorder (MDD), generalized anxiety disorder (GAD), and post-traumatic stress disorder (PTSD). Complicating these effects of TBI, FDA-approved pharmacotherapies utilized to treat these disorders often fail to reach the desired level of efficacy in the context of neurotrauma. Although a complicated association, decades of work have linked central serotonin (5-HT) neurotransmission as being involved in the etiology of a myriad of neuropsychiatric disorders, including MDD and GAD. 5-HT is a biogenic monoamine neurotransmitter that is highly conserved across scales of biology. Though the majority of 5-HT is isolated to peripheral sites such as the gastrointestinal (GI) tract, 5-HT neurotransmission within the CNS exerts exquisite control over diverse biological functions, including sleep, appetite and respiration, while simultaneously establishing normal mood, perception, and attention. Although several key studies have begun to elucidate how various forms of neurotrauma impact central 5-HT neurotransmission, a full determination of precisely how TBI disrupts the highly regulated dynamics of 5-HT neuron function and/or 5-HT neurotransmission has yet to be conceptually or experimentally resolved. The purpose of the current review is, therefore, to integrate the disparate bodies of 5-HT and TBI research and synthesize insight into how new combinatorial research regarding 5-HT neurotransmission and TBI may offer an informed perspective into the nature of TBI-induced neuropsychiatric complications.
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PURPOSE: To show that B 0 $$ {\mathrm{B}}_0 $$ variations through slice and slice profile effects are two major confounders affecting 2D dual angle B 1 + $$ {\mathrm{B}}_1^{+} $$ maps using gradient-echo signals and thus need to be corrected to obtain accurate B 1 + $$ {\mathrm{B}}_1^{+} $$ maps. METHODS: The 2D gradient-echo transverse complex signal was Bloch-simulated and integrated across the slice dimension including nonlinear variations in B 0 $$ {\mathrm{B}}_0 $$ inhomogeneities through slice. A nonlinear least squares fit was used to find the B 1 + $$ {\mathrm{B}}_1^{+} $$ factor corresponding to the best match between the two gradient-echo signals experimental ratio and the Bloch-simulated ratio. The correction was validated in phantom and in vivo at 3T. RESULTS: For our RF excitation pulse, the error in the B 1 + $$ {\mathrm{B}}_1^{+} $$ factor scales by approximately 3.8% for every 10 Hz/cm variation in B 0 $$ {\mathrm{B}}_0 $$ along the slice direction. Higher accuracy phantom B 1 + $$ {\mathrm{B}}_1^{+} $$ maps were obtained after applying the proposed correction; the root mean square B 1 + $$ {\mathrm{B}}_1^{+} $$ error relative to the gold standard B 1 + $$ {\mathrm{B}}_1^{+} $$ decreased from 6.4% to 2.6%. In vivo whole-liver T 1 $$ {\mathrm{T}}_1 $$ maps using the corrected B 1 + $$ {\mathrm{B}}_1^{+} $$ map registered a significant decrease in T 1 $$ {\mathrm{T}}_1 $$ gradient through slice. CONCLUSION: B 0 $$ {\mathrm{B}}_0 $$ inhomogeneities varying through slice were seen to have an impact on the accuracy of 2D double angle B 1 + $$ {\mathrm{B}}_1^{+} $$ maps using gradient-echo sequences. Consideration of this confounder is crucial for research relying on accurate knowledge of the true excitation flip angles, as is the case of T 1 $$ {\mathrm{T}}_1 $$ mapping using a spoiled gradient recalled echo sequence.
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Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Imagens de Fantasmas , Análise dos Mínimos Quadrados , Frequência CardíacaRESUMO
Hematopoietic stem cells (HSCs) residing in specialized niches in the bone marrow are responsible for the balanced output of multiple short-lived blood cell lineages in steady-state and in response to different challenges. However, feedback mechanisms by which HSCs, through their niches, sense acute losses of specific blood cell lineages remain to be established. While all HSCs replenish platelets, previous studies have shown that a large fraction of HSCs are molecularly primed for the megakaryocyte-platelet lineage and are rapidly recruited into proliferation upon platelet depletion. Platelets normally turnover in an activation-dependent manner, herein mimicked by antibodies inducing platelet activation and depletion. Antibody-mediated platelet activation upregulates expression of Interleukin-1 (IL-1) in platelets, and in bone marrow extracellular fluid in vivo. Genetic experiments demonstrate that rather than IL-1 directly activating HSCs, activation of bone marrow Lepr+ perivascular niche cells expressing IL-1 receptor is critical for the optimal activation of quiescent HSCs upon platelet activation and depletion. These findings identify a feedback mechanism by which activation-induced depletion of a mature blood cell lineage leads to a niche-dependent activation of HSCs to reinstate its homeostasis.
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Interleucina-1 , Trombocitopenia , Humanos , Interleucina-1/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Medula Óssea/metabolismo , Megacariócitos , Trombocitopenia/metabolismoRESUMO
BACKGROUND: Accurate assessment of plaque accumulation near the carotid bifurcation is important for the effective prevention and treatment of stroke. However, vessel and plaque delineation using MRI can be limited by low contrast-to-noise ratio (CNR) and long acquisition times. In this work, a 10-channel phased-array receive coil design for bilateral imaging of the carotid bifurcation using 3T MRI is proposed. METHODS: The proposed 10-channel receive coil was compared to a commercial 4-channel receive coil configuration using data acquired from phantoms and healthy volunteers (N = 9). The relative performance of the coils was assessed, by comparing signal-to-noise ratio (SNR), noise correlation, g-factor noise amplification, and the CNR between vessel wall and lumen using black-blood sequences. Patient data were acquired from 12 atherosclerotic carotid artery disease patients. RESULTS: The 10-channel coil consistently provided substantially increased SNR in phantoms (+77 ± 27%) and improved CNR in healthy carotid arteries (+62 ± 11%), or reduced g-factor noise amplification. Patient data showed excellent delineation of atherosclerotic plaque along the length of the carotid bifurcation using the 10-channel coil. CONCLUSIONS: The proposed 10-channel coil design allows for improved visualization of the carotid arteries and the carotid bifurcation and increased parallel imaging acceleration factors relative to a commercial 4-channel coil design.
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Doenças das Artérias Carótidas , Placa Aterosclerótica , Humanos , Artérias Carótidas/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Doenças das Artérias Carótidas/diagnóstico por imagem , Razão Sinal-Ruído , Imagens de FantasmasRESUMO
SIGNIFICANCE STATEMENT: Activation of the type 1 IL-1 receptor (IL-1R1) triggers a critical innate immune signaling cascade that contributes to the pathogenesis of AKI. However, blockade of IL-1 signaling in AKI has not consistently demonstrated kidney protection. The current murine experiments show that IL-1R1 activation in the proximal tubule exacerbates toxin-induced AKI and cell death through local suppression of apolipoprotein M. By contrast, IL-1R1 activation in endothelial cells ameliorates AKI by restoring VEGFA-dependent endothelial cell viability. Using this information, future delivery strategies can maximize the protective effects of blocking IL-1R1 while mitigating unwanted actions of IL-1R1 manipulation. BACKGROUND: Activation of the type 1 IL-1 receptor (IL-1R1) triggers a critical innate immune signaling cascade that contributes to the pathogenesis of AKI. IL-1R1 is expressed on some myeloid cell populations and on multiple kidney cell lineages, including tubular and endothelial cells. Pharmacological inhibition of the IL-1R1 does not consistently protect the kidney from injury, suggesting there may be complex, cell-specific effects of IL-1R1 stimulation in AKI. METHODS: To examine expression of IL-1 and IL-1R1 in intrinsic renal versus infiltrating immune cell populations during AKI, we analyzed single-cell RNA sequencing (scRNA-seq) data from kidney tissues of humans with AKI and mice with acute aristolochic acid exposure. We then investigated cell-specific contributions of renal IL-1R1 signaling to AKI using scRNA-seq, RNA microarray, and pharmacological interventions in mice with IL-1R1 deletion restricted to the proximal tubule or endothelium. RESULTS: scRNA-seq analyses demonstrated robust IL-1 expression in myeloid cell populations and low-level IL-1R1 expression in kidney parenchymal cells during toxin-induced AKI. Our genetic studies showed that IL-1R1 activation in the proximal tubule exacerbated toxin-induced AKI and cell death through local suppression of apolipoprotein M. By contrast, IL-1R1 activation in endothelial cells ameliorated aristolochic acid-induced AKI by restoring VEGFA-dependent endothelial cell viability and density. CONCLUSIONS: These data highlight opposing cell-specific effects of IL-1 receptor signaling on AKI after toxin exposure. Disrupting pathways activated by IL-1R1 in the tubule, while preserving those triggered by IL-1R1 activation on endothelial cells, may afford renoprotection exceeding that of global IL-1R1 inhibition while mitigating unwanted actions of IL-1R1 blockade.
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Injúria Renal Aguda , Receptores de Interleucina-1 , Humanos , Camundongos , Animais , Receptores de Interleucina-1/genética , Apolipoproteínas M , Células Endoteliais/metabolismo , Injúria Renal Aguda/patologia , Camundongos Knockout , Interleucina-1 , Endotélio/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Adoptive T-cell therapy aims to achieve lasting tumor clearance, requiring enhanced engraftment and survival of the immune cells. Cytokines are paramount modulators of T-cell survival and proliferation. Cytokine receptors signal via ligand-induced dimerization, and this principle has been hijacked utilizing nonnative dimerization domains. A major limitation of current technologies resides in the absence of a module that recapitulates the natural cytokine receptor heterodimeric pairing. To circumvent this, we created a new engineered cytokine receptor able to constitutively recreate receptor-heterodimer utilizing the heterodimerization domain derived from the IgG1 antibody (dFab_CCR). We found that the signal delivered by the dFab_CCR-IL2 proficiently mimicked the cytokine receptor heterodimerization, with transcriptomic signatures like those obtained by activation of the native IL2 receptor. Moreover, we found that this dimerization structure was agnostic, efficiently activating signaling through four cytokine receptor families. Using a combination of in vivo and in vitro screening approaches, we characterized a library of 18 dFab_CCRs coexpressed with a clinically relevant solid tumor-specific GD2-specific chimeric antigen receptor (CAR). Based on this characterization, we suggest that the coexpression of either the common ß-chain GMCSF or the IL18 dFab_CCRs is optimal to improve CAR T-cell expansion, engraftment, and efficacy. Our results demonstrate how Fab dimerization is efficient and versatile in recapitulating a cytokine receptor heterodimerization signal. This module could be applied for the enhancement of adoptive T-cell therapies, as well as therapies based on other immune cell types. Furthermore, these results provide a choice of cytokine signal to incorporate with adoptive T-cell therapies.
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Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Imunoterapia Adotiva/métodos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Citocinas , Neoplasias/patologia , CitocinasRESUMO
PURPOSE: The spoiled gradient recalled echo (SPGR) sequence with variable flip angles (FAs) enables whole liver T 1 $$ {T}_1 $$ mapping at high spatial resolutions but is strongly affected by B 1 + $$ {B}_1^{+} $$ inhomogeneities. The aim of this work was to study how the precision of acquired T 1 $$ {T}_1 $$ maps is affected by the T 1 $$ {T}_1 $$ and B 1 + $$ {B}_1^{+} $$ ranges observed in the liver at 3T, as well as how noise propagates from the acquired signals into the resulting T 1 $$ {T}_1 $$ map. THEORY: The T 1 $$ {T}_1 $$ variance was estimated through the Fisher information matrix with a total noise variance including, for the first time, the B 1 + $$ {B}_1^{+} $$ map noise as well as contributions from the SPGR noise. METHODS: Simulations were used to find the optimal FAs for both the B 1 + $$ {B}_1^{+} $$ mapping and T 1 $$ {T}_1 $$ mapping. The simulations results were validated in 10 volunteers. RESULTS: Four optimized SPGR FAs of 2°, 2°, 15°, and 15° (TR = 4.1 ms) and B 1 + $$ {B}_1^{+} $$ map FAs of 65° and 130° achieved a T 1 $$ {T}_1 $$ coefficient of variation of 6.2 ± 1.7% across 10 volunteers and validated our theoretical model. Four optimal FAs outperformed five uniformly spaced FAs, saving the patient one breath-hold. For the liver B 1 + $$ {B}_1^{+} $$ and T 1 $$ {T}_1 $$ parameter space at 3T, a higher return in T 1 $$ {T}_1 $$ precision was obtained by investing FAs in the SPGR acquisition rather than in the B 1 + $$ {B}_1^{+} $$ map. CONCLUSION: A novel framework was developed and validated to calculate the SPGR T 1 $$ {T}_1 $$ variance. This framework efficiently identifies optimal FA values and determines the total number of SPGR and B 1 + $$ {B}_1^{+} $$ measurements needed to achieve a desired T 1 $$ {T}_1 $$ precision.
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Aumento da Imagem , Imageamento por Ressonância Magnética , Humanos , Aumento da Imagem/métodos , Imageamento por Ressonância Magnética/métodos , Algoritmos , Imagens de Fantasmas , Reprodutibilidade dos Testes , Fígado/diagnóstico por imagemRESUMO
BACKGROUND: Long COVID is associated with multiple symptoms and impairment in multiple organs. Cross-sectional studies have reported cardiac impairment to varying degrees by varying methodologies. Using cardiac MR (CMR), we investigated a 12-month trajectory of abnormalities in Long COVID. OBJECTIVES: To investigate cardiac abnormalities 1-year post-SARS-CoV-2 infection. METHODS: 534 individuals with Long COVID underwent CMR (T1/T2 mapping, cardiac mass, volumes, function and strain) and multiorgan MRI at 6 months (IQR 4.3-7.3) since first post-COVID-19 symptoms. 330 were rescanned at 12.6 (IQR 11.4-14.2) months if abnormal baseline findings were reported. Symptoms, questionnaires and blood samples were collected at both time points. CMR abnormalities were defined as ≥1 of low left or right ventricular ejection fraction (LVEF), high left or right ventricular end diastolic volume, low 3D left ventricular global longitudinal strain (GLS), or elevated native T1 in ≥3 cardiac segments. Significant change over time was reported by comparison with 92 healthy controls. RESULTS: Technical success of multiorgan and CMR assessment in non-acute settings was 99.1% and 99.6% at baseline, and 98.3% and 98.8% at follow-up. Of individuals with Long COVID, 102/534 (19%) had CMR abnormalities at baseline; 71/102 had complete paired data at 12 months. Of those, 58% presented with ongoing CMR abnormalities at 12 months. High sensitivity cardiac troponin I and B-type natriuretic peptide were not predictive of CMR findings, symptoms or clinical outcomes. At baseline, low LVEF was associated with persistent CMR abnormality, abnormal GLS associated with low quality of life and abnormal T1 in at least three segments was associated with better clinical outcomes at 12 months. CONCLUSION: CMR abnormalities (left entricular or right ventricular dysfunction/dilatation and/or abnormal T1mapping), occurred in one in five individuals with Long COVID at 6 months, persisting in over half of those at 12 months. Cardiac-related blood biomarkers could not identify CMR abnormalities in Long COVID. TRIAL REGISTRATION NUMBER: NCT04369807.
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COVID-19 , Humanos , Volume Sistólico , Síndrome de COVID-19 Pós-Aguda , Estudos Transversais , Qualidade de Vida , Valor Preditivo dos Testes , SARS-CoV-2 , Função Ventricular DireitaRESUMO
OBJECTIVES: To determine the prevalence of organ impairment in long COVID patients at 6 and 12 months after initial symptoms and to explore links to clinical presentation. DESIGN: Prospective cohort study. PARTICIPANTS: Individuals. METHODS: In individuals recovered from acute COVID-19, we assessed symptoms, health status, and multi-organ tissue characterisation and function. SETTING: Two non-acute healthcare settings (Oxford and London). Physiological and biochemical investigations were performed at baseline on all individuals, and those with organ impairment were reassessed. MAIN OUTCOME MEASURES: Primary outcome was prevalence of single- and multi-organ impairment at 6 and 12 months post COVID-19. RESULTS: A total of 536 individuals (mean age 45 years, 73% female, 89% white, 32% healthcare workers, 13% acute COVID-19 hospitalisation) completed baseline assessment (median: 6 months post COVID-19); 331 (62%) with organ impairment or incidental findings had follow-up, with reduced symptom burden from baseline (median number of symptoms 10 and 3, at 6 and 12 months, respectively). Extreme breathlessness (38% and 30%), cognitive dysfunction (48% and 38%) and poor health-related quality of life (EQ-5D-5L < 0.7; 57% and 45%) were common at 6 and 12 months, and associated with female gender, younger age and single-organ impairment. Single- and multi-organ impairment were present in 69% and 23% at baseline, persisting in 59% and 27% at follow-up, respectively. CONCLUSIONS: Organ impairment persisted in 59% of 331 individuals followed up at 1 year post COVID-19, with implications for symptoms, quality of life and longer-term health, signalling the need for prevention and integrated care of long COVID.Trial Registration: ClinicalTrials.gov Identifier: NCT04369807.
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COVID-19 , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , COVID-19/epidemiologia , SARS-CoV-2 , Síndrome de COVID-19 Pós-Aguda , Estudos Prospectivos , Qualidade de Vida , Estudos LongitudinaisRESUMO
Perovskites have shown tremendous promise as functional materials for several energy conversion and storage technologies, including rechargeable batteries, (electro)catalysts, fuel cells, and solar cells. Due to their excellent operational stability and performance, high-entropy perovskites (HEPs) have emerged as a new type of perovskite framework. Herein, this work reviews the recent progress in the development of HEPs, including synthesis methods and applications. Effective strategies for the design of HEPs through atomistic computations are also surveyed. Finally, an outlook of this field provides guidance for the development of new and improved HEPs.
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Magnitude-based PDFF (Proton Density Fat Fraction) and R2∗ mapping with resolved water-fat ambiguity is extended to calculate field inhomogeneity (field map) using the phase images. The estimation is formulated in matrix form, resolving the field map in a least-squares sense. PDFF and R2∗ from magnitude fitting may be updated using the estimated field maps. The limits of quantification of our voxel-independent implementation were assessed. Bland-Altman was used to compare PDFF and field maps from our method against a reference complex-based method on 152 UK Biobank subjects (1.5 T Siemens). A separate acquisition (3 T Siemens) presenting field inhomogeneities was also used. The proposed field mapping was accurate beyond double the complex-based limit range. High agreement was obtained between the proposed method and the reference in UK. Robust field mapping was observed at 3 T, for inhomogeneities over 400 Hz including rapid variation across edges. Field mapping following unambiguous magnitude-based water-fat separation was demonstrated in-vivo and showed potential at 3 T.
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Imageamento por Ressonância Magnética , Água , Humanos , Imageamento por Ressonância Magnética/métodos , Prótons , Fígado , Reprodutibilidade dos TestesRESUMO
INTRODUCTION: Traumatic brain injury (TBI) can lead to neurocognitive decline, in part due to phosphorylated tau (p-tau). Whether p-tau accumulation worsens in the setting of polytrauma remains unknown. Propranolol has shown clinical benefit in head injuries; however, the underlying mechanism is also unknown. We hypothesize that hemorrhagic shock would worsen p-tau accumulation but that propranolol would improve functional outcomes on behavioral studies. METHODS: A murine polytrauma model was developed to examine the accumulation of p-tau and whether it can be mitigated by early administration of propranolol. TBI was induced using a weight-drop model and hemorrhagic shock was achieved via controlled hemorrhage for 1 h. Mice were given intraperitoneal propranolol 4 mg/kg or saline control. The animals underwent behavioral testing at 30 d postinjury and were sacrificed for cerebral histological analysis. These studies were completed in male and female mice. RESULTS: TBI alone led to increased p-tau generation compared to sham on both immunohistochemistry and immunofluorescence (P < 0.05). The addition of hemorrhage led to greater accumulation of p-tau in the hippocampus (P < 0.007). In male mice, p-tau accumulation decreased with propranolol administration for both polytrauma and TBI alone (P < 0.0001). Male mice treated with propranolol also outperformed saline-control mice on the hippocampal-dependent behavioral assessment (P = 0.0013). These results were not replicated in female mice; the addition of hemorrhage did not increase p-tau accumulation and propranolol did not demonstrate a therapeutic effect. CONCLUSIONS: Polytrauma including TBI generates high levels of hippocampal p-tau, but propranolol may help prevent this accumulation to improve both neuropathological and functional outcomes in males.
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Lesões Encefálicas Traumáticas , Traumatismo Múltiplo , Choque Hemorrágico , Animais , Camundongos , Masculino , Feminino , Propranolol/farmacologia , Propranolol/uso terapêutico , Choque Hemorrágico/complicações , Choque Hemorrágico/tratamento farmacológico , Modelos Animais de DoençasRESUMO
Acceleration/deceleration forces are a common component of various causes of mild traumatic brain injury (mTBI) and result in strain and shear forces on brain tissue. A small quantifiable volume dubbed the compensatory reserve volume (CRV) permits energy transmission to brain tissue during acceleration/deceleration events. The CRV is principally regulated by cerebral blood flow (CBF) and CBF is primarily determined by the concentration of inspired carbon dioxide (CO2). We hypothesized that experimental hypercapnia (i.e. increased inspired concentration of CO2) may act to prevent and mitigate the actions of acceleration/deceleration-induced TBI. To determine these effects C57Bl/6 mice underwent experimental hypercapnia whereby they were exposed to medical-grade atmospheric air or 5% CO2 immediately prior to an acceleration/deceleration-induced mTBI paradigm. mTBI results in significant increases in righting reflex time (RRT), reductions in core body temperature, and reductions in general locomotor activity-three hours post injury (hpi). Experimental hypercapnia immediately preceding mTBI was found to prevent mTBI-induced increases in RRT and reductions in core body temperature and general locomotor activity. Ribonucleic acid (RNA) sequencing conducted four hpi revealed that CO2 exposure prevented mTBI-induced transcriptional alterations of several targets related to oxidative stress, immune, and inflammatory signaling. Quantitative real-time PCR analysis confirmed the prevention of mTBI-induced increases in mitogen-activated protein kinase kinase kinase 6 and metallothionein-2. These initial proof of concept studies reveal that increases in inspired CO2 mitigate the detrimental contributions of acceleration/deceleration events in mTBI and may feasibly be translated in the future to humans using a medical device seeking to prevent mTBI among high-risk groups.