REASONS FOR PERFORMING THE STUDY: Although gentamicin is highly active against Rhodococcus equi in vitro, its clinical efficacy has been limited presumably due to poor cellular uptake. Encapsulation ...of drugs in liposomes enhances their cellular uptake. OBJECTIVES: To compare the disposition of liposomal gentamicin (LG) and free gentamicin (FG) in the plasma, pulmonary epithelial lining fluid and bronchoalveolar cells of healthy foals after i.v. administration or by nebulisation, and to assess the tolerability of the drug after repeated i.v. dosing. STUDY DESIGN: Experimental study. METHODS: Eight healthy foals received a single i.v. or nebulised dose (6.6 mg/kg bwt) of LG or FG in a balanced Latin square design, with a 14‐day washout period between treatments. Subsequently, 12 healthy foals were given either LG or FG at 6.6 mg/kg bwt i.v. q. 24 h for 7 doses and urinary protein, creatinine, γ‐glutamyltransferase and electrolytes were measured on Days 0, 3 and 7 to quantify renal injury. Concentrations of gentamicin were measured using liquid chromatography‐tandem mass spectrometry. RESULTS: After i.v. administration, LG had a significantly higher mean (± s.d.) half‐life (16.3 ± 3.5 vs. 6.2 ± 1.8 h) and volume of distribution (2.00 ± 1.03 vs. 0.72 ± 0.32 l/kg bwt) compared with FG. Peak gentamicin concentrations in bronchoalveolar cells were significantly higher for LG compared with FG after administration by both the i.v. (5.27 ± 2.67 vs. 2.98 ± 1.67 mg/l) and the nebulised (4.47 ± 2.66 vs. 1.49 ± 0.57 mg/l) routes. Liposomal gentamicin was well tolerated by all foals and indices of renal injury were not significantly different from those of foals administered FG. CONCLUSIONS: Administration of LG is well tolerated and results in higher intracellular drug concentrations than FG. Liposomal gentamicin warrants further investigation for the treatment of infections caused by intracellular pathogens such as Rhodococcus equi.
Climate impacts increasingly unfold in interlinked systems of people, nature, and infrastructure. The cascading consequences are revealing sometimes surprising connections across sectors and regions, ...and prospects for climate responses also depend on complex, difficult‐to‐understand interactions. In this commentary, we build on the innovations of the United States Fifth National Climate Assessment to suggest a framework for understanding and responding to complex climate challenges. This approach involves: (a) integration of disciplines and expertise to understand how intersectionality shapes complex climate impacts and the wide‐ranging effects of climate responses, (b) collaborations among diverse knowledge holders to improve responses and better encompass intersectionality, and (c) sustained experimentation with and learning about governance approaches capable of handling the complexity of climate change. Together, these three pillars underscore that usability of climate‐relevant knowledge requires transdisciplinary coordination of research and practice. We outline actionable steps for climate research to incorporate intersectionality, integration, and innovative governance, as is increasingly necessary for confronting climate complexity and sustaining equitable, ideally vibrant climate futures.
Plain Language Summary
Climate impacts are complex, and prospects for climate responses depend on difficult‐to‐understand interactions. Lived experiences are increasingly revealing limits to what we in the scientific community have successfully modeled and ongoing challenges in how we help others understand the complexity of climate impacts and support decision‐making. Here, we chart a path for confronting the complexity of climate change with actionable advances in equity and governance research.
Key Points
Climate impacts increasingly unfold in interlinked systems of people, nature, and infrastructure
The cascading consequences are revealing sometimes surprising connections and complex, difficult‐to‐understand interactions
We suggest a research framework for climate complexity prioritizing intersectionality, integration, and innovative governance
BRD4 is a bromodomain extraterminal domain family member and functions primarily as a chromatin reader regulating genes involved in cell-fate decisions. Here, we bred Brd4fl/fl Ox40-Cre mice in which ...Brd4 was conditionally deleted in OX40-expressing cells to examine the role of BRD4 in regulating immune responses. We found that the Brd4fl/fl Ox40-Cre mice developed profound alopecia and dermatitis, while other organs and tissues were not affected. Surprisingly, lineage-tracing experiments using the Rosa26fl/fl-Yfp mice identified a subset of hair follicle stem cells (HFSCs) that constitutively express OX40, and deletion of Brd4 specifically in such HFSCs resulted in cell death and a complete loss of skin hair growth. We also found that death of HFSCs triggered massive activation of the intradermal γδ T cells, which induced epidermal hyperplasia and dermatitis by producing the inflammatory cytokine IL-17. Interestingly, deletion of Brd4 in Foxp3+ Tregs, which also constitutively express OX40, compromised their suppressive functions, and this, in turn, contributed to the enhanced activation of γδ T cells, as well as the severity of dermatitis and hair follicle destruction. Thus, our data demonstrate an unexpected role of BRD4 in regulating skin follicle stem cells and skin inflammation.
The development and diversity of neuronal subtypes in the human hypothalamus has been insufficiently characterized. To address this, we integrated transcriptomic data from 241,096 cells (126,840 ...newly generated) in the prenatal and adult human hypothalamus to reveal a temporal trajectory from proliferative stem cell populations to mature hypothalamic cell types. Iterative clustering of the adult neurons identified 108 robust transcriptionally distinct neuronal subtypes representing 10 hypothalamic nuclei. Pseudotime trajectories provided insights into the genes driving formation of these nuclei. Comparisons to single-cell transcriptomic data from the mouse hypothalamus suggested extensive conservation of neuronal subtypes despite certain differences in species-enriched gene expression. The uniqueness of hypothalamic neuronal lineages was examined developmentally by comparing excitatory lineages present in cortex and inhibitory lineages in ganglionic eminence, revealing both distinct and shared drivers of neuronal maturation across the human forebrain. These results provide a comprehensive transcriptomic view of human hypothalamus development through gestation and adulthood at cellular resolution.
The Australian 2019/2020 bushfires were unprecedented in their extent and intensity, causing a catastrophic loss of habitat, human and animal life across eastern‐Australia. We use a regional air ...quality model to assess the impact of the bushfires on particulate matter with a diameter less than 2.5 μm (PM2.5) concentrations and the associated health impact from short‐term population exposure to bushfire PM2.5. The mean population Air Quality Index (AQI) exposure between September and February in the fires and no fires simulations indicates an additional ∼437,000 people were exposed to “Poor” or worse AQI levels due to the fires. The AQ impact was concentrated in the cities of Sydney, Newcastle‐Maitland, Canberra‐Queanbeyan and Melbourne. Between October and February 171 (95% CI: 66–291) deaths were brought forward due to short‐term exposure to bushfire PM2.5. The health burden was largest in New South Wales (NSW) (109 (95% CI: 41–176) deaths brought forward), Queensland (15 (95% CI: 5–24)), and Victoria (35 (95% CI: 13–56)). This represents 38%, 13% and 30% of the total deaths brought forward by short‐term exposure to all PM2.5. At a city‐level 65 (95% CI: 24–105), 23 (95% CI: 9–38) and 9 (95% CI: 4–14) deaths were brought forward from short‐term exposure to bushfire PM2.5, accounting for 36%, 20%, and 64% of the total deaths brought forward from all PM2.5. Thus, the bushfires caused substantial AQ and health impacts across eastern‐Australia. Climate change is projected to increase bushfire risk, therefore future fire management policies should consider this.
Plain Language Summary
The Australian 2019/2020 bushfires were unprecedented in their size and intensity, resulting in a catastrophic loss of habitat and human and animal life across eastern‐Australia. We use an air pollution model (WRF‐Chem) to quantify the impact of the bushfires on particulate matter with a diameter less than 2.5 μm (PM2.5) concentrations. We run the model with and without emissions from the fires so their impact on PM2.5 can be isolated. We find that between September and February an additional ∼437,000 people were exposed to “Poor” or worse air quality index levels due to the fires across eastern‐Australia. Short‐term exposure to high PM2.5 concentrations has been linked to negative health impacts. Therefore, we estimate the health impact of population exposure to bushfire PM2.5 across eastern‐Australia, regionally and at city level. Our estimate indicates that between October and February 171 deaths were brought forward due to exposure to PM2.5 from the fires. Regionally, most deaths were brought forward in New South Wales (109 deaths brought forward), Queensland (15), and Victoria (35). Within these regions, the most deaths were brought forward in Sydney (65), Melbourne (23), and Canberra‐Queanbeyan (9) as large populations were exposed to high PM2.5 concentrations due to the bushfires.
Key Points
The fires led to widespread exposure to “Poor” or worse Air Quality Index levels across eastern‐Australia
The highest all‐cause, all‐age mortality from short‐term exposure to bushfire particulate matter with a diameter less than 2.5 μm (PM2.5) was seen in the states of New South Wales, Queensland, and Victoria
All‐cause, all‐age mortality from short‐term exposure to bushfire PM2.5 was highest in the cities of Sydney, Melbourne, and Canberra
Incidence estimates of hospitalizations for community-acquired pneumonia among children in the United States that are based on prospective data collection are limited. Updated estimates of pneumonia ...that has been confirmed radiographically and with the use of current laboratory diagnostic tests are needed.
We conducted active population-based surveillance for community-acquired pneumonia requiring hospitalization among children younger than 18 years of age in three hospitals in Memphis, Nashville, and Salt Lake City. We excluded children with recent hospitalization or severe immunosuppression. Blood and respiratory specimens were systematically collected for pathogen detection with the use of multiple methods. Chest radiographs were reviewed independently by study radiologists.
From January 2010 through June 2012, we enrolled 2638 of 3803 eligible children (69%), 2358 of whom (89%) had radiographic evidence of pneumonia. The median age of the children was 2 years (interquartile range, 1 to 6); 497 of 2358 children (21%) required intensive care, and 3 (<1%) died. Among 2222 children with radiographic evidence of pneumonia and with specimens available for bacterial and viral testing, a viral or bacterial pathogen was detected in 1802 (81%), one or more viruses in 1472 (66%), bacteria in 175 (8%), and both bacterial and viral pathogens in 155 (7%). The annual incidence of pneumonia was 15.7 cases per 10,000 children (95% confidence interval CI, 14.9 to 16.5), with the highest rate among children younger than 2 years of age (62.2 cases per 10,000 children; 95% CI, 57.6 to 67.1). Respiratory syncytial virus was more common among children younger than 5 years of age than among older children (37% vs. 8%), as were adenovirus (15% vs. 3%) and human metapneumovirus (15% vs. 8%). Mycoplasma pneumoniae was more common among children 5 years of age or older than among younger children (19% vs. 3%).
The burden of hospitalization for children with community-acquired pneumonia was highest among the very young, with respiratory viruses the most commonly detected causes of pneumonia. (Funded by the Influenza Division of the National Center for Immunization and Respiratory Diseases.).
Aims
The aim of the study was to assess the association of P‐selectin with outcomes in heart failure with preserved ejection fraction (HFpEF).
Methods and results
This is a prospective, observational ...study of 130 HFpEF patients who underwent clinical profiling, blood sampling, 6 min walk testing, Minnesota Living with Heart Failure Questionnaire evaluation, echocardiography, cardiovascular magnetic resonance imaging, calculation of the Meta‐Analysis Global Group in Chronic Heart Failure (MAGGIC) risk scores, and blinded plasma P‐selectin measurement. Patients were followed up for the endpoint of all‐cause mortality. The HFpEF subgroup with higher P‐selectin levels overall median 26 372, inter‐quartile range (19 360–34 889) pg/mL was associated with lower age, higher heart rate, less prevalent atrial fibrillation, more frequent current smoking status, and lower right ventricular end‐diastolic volumes. During follow‐up (median 1428 days), there were 38 deaths. Following maximal sensitivity and specificity receiver operating characteristic curve analysis, P‐selectin levels above 35 506 pg/mL were associated with greater risk of all‐cause mortality hazard ratio (HR) 2.700; 95% confidence interval (CI) 1.416–5.146; log‐rank P = 0.002. Following multivariable Cox proportional hazards regression analysis and when added to MAGGIC scores, only P‐selectin (adjusted HR 1.707; 95% CI 1.099–2.650; P < 0.017) and myocardial infarction detected by cardiovascular magnetic resonance imaging (HR 2.377; 95% CI 1.114–5.075; P < 0.025) remained significant predictors. In a final model comprising all three parameters, only P‐selectin (HR 1.447; 95% CI 1.130–1.853; P < 0.003) and MAGGIC scores (HR 1.555; 95% CI 1.136–2.129; P < 0.006) remained independent predictors of death. Adding P‐selectin (0.618, P = 0.035) improved the area under the receiver operating characteristic curve for mortality prediction for MAGGIC scores (0.647, P = 0.009) to 0.710, P < 0.0001.
Conclusions
Plasma P‐selectin is an independent predictor of mortality and provides incremental prognostic information beyond MAGGIC scores in HFpEF.
Air pollution exposure is a leading public health problem in China. The majority of the total air pollution disease burden is from fine particulate matter (PM2.5) exposure, with smaller contributions ...from ozone (O3) exposure. Recent emission reductions have reduced PM2.5 exposure. However, levels of exposure and the associated risk remain high, some pollutant emissions have increased, and some sectors lack effective emission control measures. We quantified the potential impacts of relevant policy scenarios on ambient air quality and public health across China. We show that PM2.5 exposure inside the Greater Bay Area (GBA) is strongly controlled by emissions outside the GBA. We find that reductions in residential solid fuel use and agricultural fertilizer emissions result in the greatest reductions in PM2.5 exposure and the largest health benefits. A 50% transition from residential solid fuel use to liquefied petroleum gas outside the GBA reduced PM2.5 exposure by 15% in China and 3% within the GBA, and avoided 191,400 premature deaths each year across China. Reducing agricultural fertilizer emissions of ammonia by 30% outside the GBA reduced PM2.5 exposure by 4% in China and 3% in the GBA, avoiding 56,500 annual premature deaths across China. Our simulations suggest that reducing residential solid fuel or industrial emissions will reduce both PM2.5 and O3 exposure, whereas other policies may increase O3 exposure. Improving particulate air quality inside the GBA will require consideration of residential solid fuel and agricultural sectors, which currently lack targeted policies, and regional cooperation both inside and outside the GBA.
Key Points
Ambient fine particulate matter exposure inside the Greater Bay Area is strongly controlled by emissions outside the Greater Bay Area
Residential solid fuel and agricultural emissions lack effective controls that could improve air quality and public health across China
Improving particulate air quality inside the Greater Bay Area will require regional cooperation inside and outside the Greater Bay Area
Non-neurogenic cell types, such as cortical astroglia and fibroblasts, can be directly converted into neurons by the overexpression of defined transcription factors. Normally, the cellular phenotype ...of such differentiated cells is remarkably stable and resists direct cell transdifferentiation. Here we show that the Ink4a/Arf (also known as Cdkn2a) locus is a developmental barrier to direct neuronal transdifferentiation induced by transcription factor overexpression. With serial passage in vitro, wild-type postnatal cortical astroglia become progressively resistant to Dlx2-induced neuronal transdifferentiation. In contrast, the neurogenic competence of Ink4a/Arf-deficient astroglia is both greatly increased and does not diminish through serial cell culture passage. Electrophysiological analysis further demonstrates the neuronal identity of cells induced from Ink4a/Arf-null astroglia, and short hairpin RNA-mediated acute knockdown of p16Ink4a and p19Arf p16(Ink4a) and p19(Arf) indicates that these gene products function postnatally as a barrier to cellular transdifferentiation. Finally, we found that mouse fibroblasts deficient for Ink4a/Arf also exhibit greatly enhanced transcription factor-induced neuronal induction. These data indicate that Ink4a/Arf is a potent barrier to direct neuronal transdifferentiation and further suggest that this locus functions normally in the progressive developmental restriction of postnatal astrocytes.
PDF
