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Sunitinib-paracetamol sex-divergent pharmacokinetics and tissue distribution drug-drug interaction in mice

Liew MH, Ng S, Chew CC, Koo TW, Chee YL, Chee EL, et al.

Invest New Drugs, 2017 04;35(2):145-157.
PMID: 28070719 DOI: 10.1007/s10637-016-0415-y

The sex-divergent pharmacokinetics and interaction of tyrosine kinase inhibitor sunitinib with paracetamol was evaluated in male and female mice. Mice (control groups) were administered 60 mg/kg PO sunitinib alone or with 200 mg/kg PO paracetamol (study groups). Sunitinib concentration in plasma, brain, kidney and liver were determined and non-compartmental pharmacokinetic analysis performed. Female control mice showed 36% higher plasma sunitinib AUC0→∞, 31% and 27% lower liver and kidney AUC0→∞ and 2.2-fold higher AUC0→∞ in brain (all p
Diclofenac sex-divergent drug-drug interaction with Sunitinib: pharmacokinetics and tissue distribution in male and female mice

Chew CC, Ng S, Chee YL, Koo TW, Liew MH, Chee EL, et al.

Invest New Drugs, 2017 08;35(4):399-411.
PMID: 28285369 DOI: 10.1007/s10637-017-0447-y

Coadministration of diclofenac and sunitinib, tyrosine kinase inhibitor, led to sex-divergent pharmacokinetic drug-drug interaction outcomes. Male and female mice were administered 60 mg/kg PO sunitinib alone (control groups) or with 30 mg/kg PO diclofenac. Sunitinib concentration in plasma, brain, kidney and liver were determined by HPLC and non-compartmental pharmacokinetic parameters calculated. In male mice, diclofenac decreased AUC0→∞ 38% in plasma (p
Sunitinib DDI with paracetamol, diclofenac, mefenamic acid and ibuprofen shows sex-divergent effects on the tissue uptake and distribution pattern of sunitinib in mice

Tan SY, Wong MM, Tiew AL, Choo YW, Lim SH, Ooi IH, et al.

Cancer Chemother Pharmacol, 2016 10;78(4):709-18.
PMID: 27495788 DOI: 10.1007/s00280-016-3120-9

PURPOSE: Pharmacokinetic interaction of sunitinib with diclofenac, paracetamol, mefenamic acid and ibuprofen was evaluated due to their P450 mediated metabolism and OATP1B1, OATP1B3, ABCB1, ABCG2 transporters overlapping features.
METHODS: Male and female mice were administered 6 sunitinib doses (60 mg/kg) PO every 12 h and 30 min before the last dose were administered vehicle (control groups), 250 mg/kg paracetamol, 30 mg/kg diclofenac, 50 mg/kg mefenamic acid or 30 mg/kg ibuprofen (study groups), euthanized 6 h post last administration and sunitinib plasma, liver, kidney, brain concentrations analyzed.
RESULTS: Ibuprofen halved sunitinib plasma concentration in female mice (p
Fulltext Impact of mediterranean diet promotion on environmental sustainability: a longitudinal analysis

Álvarez-Álvarez L, Vitelli-Storelli F, Rubín-García M, García S, Bouzas C, Ruíz-Canela M, et al.

Public Health, 2024 May;230:12-20.
PMID: 38479163 DOI: 10.1016/j.puhe.2024.02.010

OBJECTIVE: This article aims to estimate the differences in environmental impact (greenhouse gas [GHG] emissions, land use, energy used, acidification and potential eutrophication) after one year of promoting a Mediterranean diet (MD).
METHODS: Baseline and 1-year follow-up data from 5800 participants in the PREDIMED-Plus study were used. Each participant's food intake was estimated using validated semi-quantitative food frequency questionnaires, and the adherence to MD using the Dietary Score. The influence of diet on environmental impact was assessed through the EAT-Lancet Commission tables. The influence of diet on environmental impact was assessed through the EAT-Lancet Commission tables. The association between MD adherence and its environmental impact was calculated using adjusted multivariate linear regression models.
RESULTS: After one year of intervention, the kcal/day consumed was significantly reduced (-125,1 kcal/day), adherence to a MD pattern was improved (+0,9) and the environmental impact due to the diet was significantly reduced (GHG: -361 g/CO2-eq; Acidification:-11,5 g SO2-eq; Eutrophication:-4,7 g PO4-eq; Energy use:-842,7 kJ; and Land use:-2,2 m2). Higher adherence to MD (high vs. low) was significantly associated with lower environmental impact both at baseline and one year follow-up. Meat products had the greatest environmental impact in all the factors analysed, both at baseline and at one-year follow-up, in spite of the reduction observed in their consumption.
CONCLUSIONS: A program promoting a MD, after one year of intervention, significantly reduced the environmental impact in all the factors analysed. Meat products had the greatest environmental impact in all the dimensions analysed.
Fulltext Late-spring frost risk between 1959 and 2017 decreased in North America but increased in Europe and Asia

Zohner CM, Mo L, Renner SS, Svenning JC, Vitasse Y, Benito BM, et al.

Proc Natl Acad Sci U S A, 2020 06 02;117(22):12192-12200.
PMID: 32393624 DOI: 10.1073/pnas.1920816117

Late-spring frosts (LSFs) affect the performance of plants and animals across the world's temperate and boreal zones, but despite their ecological and economic impact on agriculture and forestry, the geographic distribution and evolutionary impact of these frost events are poorly understood. Here, we analyze LSFs between 1959 and 2017 and the resistance strategies of Northern Hemisphere woody species to infer trees' adaptations for minimizing frost damage to their leaves and to forecast forest vulnerability under the ongoing changes in frost frequencies. Trait values on leaf-out and leaf-freezing resistance come from up to 1,500 temperate and boreal woody species cultivated in common gardens. We find that areas in which LSFs are common, such as eastern North America, harbor tree species with cautious (late-leafing) leaf-out strategies. Areas in which LSFs used to be unlikely, such as broad-leaved forests and shrublands in Europe and Asia, instead harbor opportunistic tree species (quickly reacting to warming air temperatures). LSFs in the latter regions are currently increasing, and given species' innate resistance strategies, we estimate that ∼35% of the European and ∼26% of the Asian temperate forest area, but only ∼10% of the North American, will experience increasing late-frost damage in the future. Our findings reveal region-specific changes in the spring-frost risk that can inform decision-making in land management, forestry, agriculture, and insurance policy.
One-year outcomes after discharge from noncardiac surgery and association between pre-discharge complications and death after discharge: analysis of the VISION prospective cohort study

Roshanov PS, Chan MTV, Borges FK, Conen D, Wang CY, Xavier D, et al.

Anesthesiology, 2023 Sep 15.
PMID: 37713506 DOI: 10.1097/ALN.0000000000004763

BACKGROUND: In prior analyses, myocardial injury after noncardiac surgery, major bleeding, and sepsis were independently associated with most deaths in the 30 days after noncardiac surgery, but most of these deaths occurred during the index hospitalization for surgery. We set out to describe outcomes after discharge from hospital up to one year after inpatient noncardiac surgery and associations between pre-discharge complications and post-discharge death up to one year after surgery.
METHODS: Analysis of patients discharged after inpatient noncardiac surgery in a large international prospective cohort study across 28 centers from 2007-2013 of patients aged ≥45 years followed to one year after surgery. We estimated 1) the cumulative post-discharge incidence of death and other outcomes up to a year after surgery and 2) the adjusted time-varying associations between post-discharge death and pre-discharge complications including myocardial injury after noncardiac surgery, major bleeding, sepsis, infection without sepsis, stroke, congestive heart failure, clinically important atrial fibrillation or flutter, amputation, venous thromboembolism, and acute kidney injury managed with dialysis.
RESULTS: Among 38,898 patients discharged after surgery, the cumulative one-year incidence was 5.8% (95% CI, 5.5-6.0%) for all-cause death and 24.7% (24.2-25.1%) for all-cause hospital readmission. Pre-discharge complications were associated with 33.7% (27.2-40.2%) of deaths up to 30 days after discharge and 15.0% (12.0-17.9%) up to one year. Most of the association with death was due to myocardial injury after noncardiac surgery (15.6% [9.3-21.9%) of deaths within 30 days, 6.4% [4.1-8.7%] within one year), major bleeding (15.0% [8.3-21.7%] within 30 days, 4.7% [2.2-7.2%] within one year), and sepsis (5.4% [2.2-8.6%] within 30 days, 2.1% [1.0-3.1%] within one year).
CONCLUSIONS: One in 18 patients ≥45 years old discharged after inpatient noncardiac surgery died within one year and one quarter were readmitted to hospital. The risk of death associated with pre-discharge perioperative complications persists for weeks to months after discharge.
Fulltext Native diversity buffers against severity of non-native tree invasions

Delavaux CS, Crowther TW, Zohner CM, Robmann NM, Lauber T, van den Hoogen J, et al.

Nature, 2023 Sep;621(7980):773-781.
PMID: 37612513 DOI: 10.1038/s41586-023-06440-7

Determining the drivers of non-native plant invasions is critical for managing native ecosystems and limiting the spread of invasive species1,2. Tree invasions in particular have been relatively overlooked, even though they have the potential to transform ecosystems and economies3,4. Here, leveraging global tree databases5-7, we explore how the phylogenetic and functional diversity of native tree communities, human pressure and the environment influence the establishment of non-native tree species and the subsequent invasion severity. We find that anthropogenic factors are key to predicting whether a location is invaded, but that invasion severity is underpinned by native diversity, with higher diversity predicting lower invasion severity. Temperature and precipitation emerge as strong predictors of invasion strategy, with non-native species invading successfully when they are similar to the native community in cold or dry extremes. Yet, despite the influence of these ecological forces in determining invasion strategy, we find evidence that these patterns can be obscured by human activity, with lower ecological signal in areas with higher proximity to shipping ports. Our global perspective of non-native tree invasion highlights that human drivers influence non-native tree presence, and that native phylogenetic and functional diversity have a critical role in the establishment and spread of subsequent invasions.
Fulltext Author Correction: Native diversity buffers against severity of non-native tree invasions

Delavaux CS, Crowther TW, Zohner CM, Robmann NM, Lauber T, van den Hoogen J, et al.

Nature, 2023 Oct;622(7982):E2.
PMID: 37752352 DOI: 10.1038/s41586-023-06654-9
Fulltext Integrated global assessment of the natural forest carbon potential

Mo L, Zohner CM, Reich PB, Liang J, de Miguel S, Nabuurs GJ, et al.

Nature, 2023 Dec;624(7990):92-101.
PMID: 37957399 DOI: 10.1038/s41586-023-06723-z

Forests are a substantial terrestrial carbon sink, but anthropogenic changes in land use and climate have considerably reduced the scale of this system1. Remote-sensing estimates to quantify carbon losses from global forests2-5 are characterized by considerable uncertainty and we lack a comprehensive ground-sourced evaluation to benchmark these estimates. Here we combine several ground-sourced6 and satellite-derived approaches2,7,8 to evaluate the scale of the global forest carbon potential outside agricultural and urban lands. Despite regional variation, the predictions demonstrated remarkable consistency at a global scale, with only a 12% difference between the ground-sourced and satellite-derived estimates. At present, global forest carbon storage is markedly under the natural potential, with a total deficit of 226 Gt (model range = 151-363 Gt) in areas with low human footprint. Most (61%, 139 Gt C) of this potential is in areas with existing forests, in which ecosystem protection can allow forests to recover to maturity. The remaining 39% (87 Gt C) of potential lies in regions in which forests have been removed or fragmented. Although forests cannot be a substitute for emissions reductions, our results support the idea2,3,9 that the conservation, restoration and sustainable management of diverse forests offer valuable contributions to meeting global climate and biodiversity targets.
Fulltext The global biogeography of tree leaf form and habit

Ma H, Crowther TW, Mo L, Maynard DS, Renner SS, van den Hoogen J, et al.

Nat Plants, 2023 Nov;9(11):1795-1809.
PMID: 37872262 DOI: 10.1038/s41477-023-01543-5

Understanding what controls global leaf type variation in trees is crucial for comprehending their role in terrestrial ecosystems, including carbon, water and nutrient dynamics. Yet our understanding of the factors influencing forest leaf types remains incomplete, leaving us uncertain about the global proportions of needle-leaved, broadleaved, evergreen and deciduous trees. To address these gaps, we conducted a global, ground-sourced assessment of forest leaf-type variation by integrating forest inventory data with comprehensive leaf form (broadleaf vs needle-leaf) and habit (evergreen vs deciduous) records. We found that global variation in leaf habit is primarily driven by isothermality and soil characteristics, while leaf form is predominantly driven by temperature. Given these relationships, we estimate that 38% of global tree individuals are needle-leaved evergreen, 29% are broadleaved evergreen, 27% are broadleaved deciduous and 5% are needle-leaved deciduous. The aboveground biomass distribution among these tree types is approximately 21% (126.4 Gt), 54% (335.7 Gt), 22% (136.2 Gt) and 3% (18.7 Gt), respectively. We further project that, depending on future emissions pathways, 17-34% of forested areas will experience climate conditions by the end of the century that currently support a different forest type, highlighting the intensification of climatic stress on existing forests. By quantifying the distribution of tree leaf types and their corresponding biomass, and identifying regions where climate change will exert greatest pressure on current leaf types, our results can help improve predictions of future terrestrial ecosystem functioning and carbon cycling.
Fulltext The global distribution and drivers of wood density and their impact on forest carbon stocks

Mo L, Crowther TW, Maynard DS, van den Hoogen J, Ma H, Bialic-Murphy L, et al.

Nat Ecol Evol, 2024 Dec;8(12):2195-2212.
PMID: 39406932 DOI: 10.1038/s41559-024-02564-9

The density of wood is a key indicator of the carbon investment strategies of trees, impacting productivity and carbon storage. Despite its importance, the global variation in wood density and its environmental controls remain poorly understood, preventing accurate predictions of global forest carbon stocks. Here we analyse information from 1.1 million forest inventory plots alongside wood density data from 10,703 tree species to create a spatially explicit understanding of the global wood density distribution and its drivers. Our findings reveal a pronounced latitudinal gradient, with wood in tropical forests being up to 30% denser than that in boreal forests. In both angiosperms and gymnosperms, hydrothermal conditions represented by annual mean temperature and soil moisture emerged as the primary factors influencing the variation in wood density globally. This indicates similar environmental filters and evolutionary adaptations among distinct plant groups, underscoring the essential role of abiotic factors in determining wood density in forest ecosystems. Additionally, our study highlights the prominent role of disturbance, such as human modification and fire risk, in influencing wood density at more local scales. Factoring in the spatial variation of wood density notably changes the estimates of forest carbon stocks, leading to differences of up to 21% within biomes. Therefore, our research contributes to a deeper understanding of terrestrial biomass distribution and how environmental changes and disturbances impact forest ecosystems.
Fulltext Myocardial injury after noncardiac surgery: a large, international, prospective cohort study establishing diagnostic criteria, characteristics, predictors, and 30-day outcomes

Botto F, Alonso-Coello P, Chan MT, Villar JC, Xavier D, Srinathan S, et al.

Anesthesiology, 2014 Mar;120(3):564-78.
PMID: 24534856 DOI: 10.1097/ALN.0000000000000113

BACKGROUND: Myocardial injury after noncardiac surgery (MINS) was defined as prognostically relevant myocardial injury due to ischemia that occurs during or within 30 days after noncardiac surgery. The study's four objectives were to determine the diagnostic criteria, characteristics, predictors, and 30-day outcomes of MINS.
METHODS: In this international, prospective cohort study of 15,065 patients aged 45 yr or older who underwent in-patient noncardiac surgery, troponin T was measured during the first 3 postoperative days. Patients with a troponin T level of 0.04 ng/ml or greater (elevated "abnormal" laboratory threshold) were assessed for ischemic features (i.e., ischemic symptoms and electrocardiography findings). Patients adjudicated as having a nonischemic troponin elevation (e.g., sepsis) were excluded. To establish diagnostic criteria for MINS, the authors used Cox regression analyses in which the dependent variable was 30-day mortality (260 deaths) and independent variables included preoperative variables, perioperative complications, and potential MINS diagnostic criteria.
RESULTS: An elevated troponin after noncardiac surgery, irrespective of the presence of an ischemic feature, independently predicted 30-day mortality. Therefore, the authors' diagnostic criterion for MINS was a peak troponin T level of 0.03 ng/ml or greater judged due to myocardial ischemia. MINS was an independent predictor of 30-day mortality (adjusted hazard ratio, 3.87; 95% CI, 2.96-5.08) and had the highest population-attributable risk (34.0%, 95% CI, 26.6-41.5) of the perioperative complications. Twelve hundred patients (8.0%) suffered MINS, and 58.2% of these patients would not have fulfilled the universal definition of myocardial infarction. Only 15.8% of patients with MINS experienced an ischemic symptom.
CONCLUSION: Among adults undergoing noncardiac surgery, MINS is common and associated with substantial mortality.
Fulltext Global Impact of the COVID-19 Pandemic on Cerebral Venous Thrombosis and Mortality

Nguyen TN, Qureshi MM, Klein P, Yamagami H, Abdalkader M, Mikulik R, et al.

J Stroke, 2022 May;24(2):256-265.
PMID: 35677980 DOI: 10.5853/jos.2022.00752

BACKGROUND AND PURPOSE: Recent studies suggested an increased incidence of cerebral venous thrombosis (CVT) during the coronavirus disease 2019 (COVID-19) pandemic. We evaluated the volume of CVT hospitalization and in-hospital mortality during the 1st year of the COVID-19 pandemic compared to the preceding year.
METHODS: We conducted a cross-sectional retrospective study of 171 stroke centers from 49 countries. We recorded COVID-19 admission volumes, CVT hospitalization, and CVT in-hospital mortality from January 1, 2019, to May 31, 2021. CVT diagnoses were identified by International Classification of Disease-10 (ICD-10) codes or stroke databases. We additionally sought to compare the same metrics in the first 5 months of 2021 compared to the corresponding months in 2019 and 2020 (ClinicalTrials.gov Identifier: NCT04934020).
RESULTS: There were 2,313 CVT admissions across the 1-year pre-pandemic (2019) and pandemic year (2020); no differences in CVT volume or CVT mortality were observed. During the first 5 months of 2021, there was an increase in CVT volumes compared to 2019 (27.5%; 95% confidence interval [CI], 24.2 to 32.0; P<0.0001) and 2020 (41.4%; 95% CI, 37.0 to 46.0; P<0.0001). A COVID-19 diagnosis was present in 7.6% (132/1,738) of CVT hospitalizations. CVT was present in 0.04% (103/292,080) of COVID-19 hospitalizations. During the first pandemic year, CVT mortality was higher in patients who were COVID positive compared to COVID negative patients (8/53 [15.0%] vs. 41/910 [4.5%], P=0.004). There was an increase in CVT mortality during the first 5 months of pandemic years 2020 and 2021 compared to the first 5 months of the pre-pandemic year 2019 (2019 vs. 2020: 2.26% vs. 4.74%, P=0.05; 2019 vs. 2021: 2.26% vs. 4.99%, P=0.03). In the first 5 months of 2021, there were 26 cases of vaccine-induced immune thrombotic thrombocytopenia (VITT), resulting in six deaths.
CONCLUSIONS: During the 1st year of the COVID-19 pandemic, CVT hospitalization volume and CVT in-hospital mortality did not change compared to the prior year. COVID-19 diagnosis was associated with higher CVT in-hospital mortality. During the first 5 months of 2021, there was an increase in CVT hospitalization volume and increase in CVT-related mortality, partially attributable to VITT.

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