Nonalcoholic fatty liver disease (i.e., increased intrahepatic triglyceride IHTG content), predisposes to type 2 diabetes and cardiovascular disease. Adipose tissue lipolysis and hepatic de novo ...lipogenesis (DNL) are the main pathways contributing to IHTG. We hypothesized that dietary macronutrient composition influences the pathways, mediators, and magnitude of weight gain-induced changes in IHTG.
We overfed 38 overweight subjects (age 48 ± 2 years, BMI 31 ± 1 kg/m
, liver fat 4.7 ± 0.9%) 1,000 extra kcal/day of saturated (SAT) or unsaturated (UNSAT) fat or simple sugars (CARB) for 3 weeks. We measured IHTG (
H-MRS), pathways contributing to IHTG (lipolysis (
H
glycerol) and DNL (
H
O) basally and during euglycemic hyperinsulinemia), insulin resistance, endotoxemia, plasma ceramides, and adipose tissue gene expression at 0 and 3 weeks.
Overfeeding SAT increased IHTG more (+55%) than UNSAT (+15%,
< 0.05). CARB increased IHTG (+33%) by stimulating DNL (+98%). SAT significantly increased while UNSAT decreased lipolysis. SAT induced insulin resistance and endotoxemia and significantly increased multiple plasma ceramides. The diets had distinct effects on adipose tissue gene expression.
Macronutrient composition of excess energy influences pathways of IHTG: CARB increases DNL, while SAT increases and UNSAT decreases lipolysis. SAT induced the greatest increase in IHTG, insulin resistance, and harmful ceramides. Decreased intakes of SAT could be beneficial in reducing IHTG and the associated risk of diabetes.
The authors developed a global chronic total occlusion crossing algorithm following 10 steps: 1) dual angiography; 2) careful angiographic review focusing on proximal cap morphology, occlusion ...segment, distal vessel quality, and collateral circulation; 3) approaching proximal cap ambiguity using intravascular ultrasound, retrograde, and move-the-cap techniques; 4) approaching poor distal vessel quality using the retrograde approach and bifurcation at the distal cap by use of a dual-lumen catheter and intravascular ultrasound; 5) feasibility of retrograde crossing through grafts and septal and epicardial collateral vessels; 6) antegrade wiring strategies; 7) retrograde approach; 8) changing strategy when failing to achieve progress; 9) considering performing an investment procedure if crossing attempts fail; and 10) stopping when reaching high radiation or contrast dose or in case of long procedural time, occurrence of a serious complication, operator and patient fatigue, or lack of expertise or equipment. This algorithm can improve outcomes and expand discussion, research, and collaboration.
Declines in European bird populations are reported for decades but the direct effect of major anthropogenic pressures on such declines remains unquantified. Causal relationships between pressures and ...bird population responses are difficult to identify as pressures interact at different spatial scales and responses vary among species. Here, we uncover direct relationships between population time-series of 170 common bird species, monitored at more than 20,000 sites in 28 European countries, over 37 y, and four widespread anthropogenic pressures: agricultural intensification, change in forest cover, urbanisation and temperature change over the last decades. We quantify the influence of each pressure on population time-series and its importance relative to other pressures, and we identify traits of most affected species. We find that agricultural intensification, in particular pesticides and fertiliser use, is the main pressure for most bird population declines, especially for invertebrate feeders. Responses to changes in forest cover, urbanisation and temperature are more species-specific. Specifically, forest cover is associated with a positive effect and growing urbanisation with a negative effect on population dynamics, while temperature change has an effect on the dynamics of a large number of bird populations, the magnitude and direction of which depend on species' thermal preferences. Our results not only confirm the pervasive and strong effects of anthropogenic pressures on common breeding birds, but quantify the relative strength of these effects stressing the urgent need for transformative changes in the way of inhabiting the world in European countries, if bird populations shall have a chance of recovering.
Summary Background We designed the EURAMOS-1 trial to investigate whether intensified postoperative chemotherapy for patients whose tumour showed a poor response to preoperative chemotherapy (≥10% ...viable tumour) improved event-free survival in patients with high-grade osteosarcoma. Methods EURAMOS-1 was an open-label, international, phase 3 randomised, controlled trial. Consenting patients with newly diagnosed, resectable, high-grade osteosarcoma aged 40 years or younger were eligible for randomisation. Patients were randomly assigned (1:1) to receive either postoperative cisplatin, doxorubicin, and methotrexate (MAP) or MAP plus ifosfamide and etoposide (MAPIE) using concealed permuted blocks with three stratification factors: trial group; location of tumour (proximal femur or proximal humerus vs other limb vs axial skeleton); and presence of metastases (no vs yes or possible). The MAP regimen consisted of cisplatin 120 mg/m2 , doxorubicin 37·5 mg/m2 per day on days 1 and 2 (on weeks 1 and 6) followed 3 weeks later by high-dose methotrexate 12 g/m2 over 4 h. The MAPIE regimen consisted of MAP as a base regimen, with the addition of high-dose ifosfamide (14 g/m2 ) at 2·8 g/m2 per day with equidose mesna uroprotection, followed by etoposide 100 mg/m2 per day over 1 h on days 1–5. The primary outcome measure was event-free survival measured in the intention-to-treat population. This trial is registered with ClinicalTrials.gov , number NCT00134030. Findings Between April 14, 2005, and June 30, 2011, 2260 patients were registered from 325 sites in 17 countries. 618 patients with poor response were randomly assigned; 310 to receive MAP and 308 to receive MAPIE. Median follow-up was 62·1 months (IQR 46·6–76·6); 62·3 months (IQR 46·9–77·1) for the MAP group and 61·1 months (IQR 46·5–75·3) for the MAPIE group. 307 event-free survival events were reported (153 in the MAP group vs 154 in the MAPIE group). 193 deaths were reported (101 in the MAP group vs 92 in the MAPIE group). Event-free survival did not differ between treatment groups (hazard ratio HR 0·98 95% CI 0·78–1·23); hazards were non-proportional (p=0·0003). The most common grade 3–4 adverse events were neutropenia (268 89% patients in MAP vs 268 90% in MAPIE), thrombocytopenia (231 78% in MAP vs 248 83% in MAPIE), and febrile neutropenia without documented infection (149 50% in MAP vs 217 73% in MAPIE). MAPIE was associated with more frequent grade 4 non-haematological toxicity than MAP (35 12% of 301 in the MAP group vs 71 24% of 298 in the MAPIE group). Two patients died during postoperative therapy, one from infection (although their absolute neutrophil count was normal), which was definitely related to their MAP treatment (specifically doxorubicin and cisplatin), and one from left ventricular systolic dysfunction, which was probably related to MAPIE treatment (specifically doxorubicin). One suspected unexpected serious adverse reaction was reported in the MAP group: bone marrow infarction due to methotrexate. Interpretation EURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival. The results define standard of care for this population. New strategies are required to improve outcomes in this setting. Funding UK Medical Research Council, National Cancer Institute, European Science Foundation, St Anna Kinderkrebsforschung, Fonds National de la Recherche Scientifique, Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, Parents Organization, Danish Medical Research Council, Academy of Finland, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Federal Ministry of Education and Research, Semmelweis Foundation, ZonMw (Council for Medical Research), Research Council of Norway, Scandinavian Sarcoma Group, Swiss Paediatric Oncology Group, Cancer Research UK, National Institute for Health Research, University College London Hospitals, and Biomedical Research Centre.
Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from ...27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P<5 × 10
), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.
The CHEOPS space mission dedicated to exoplanet follow-up was launched in December 2019, equipped with the capacity to perform photometric measurements at the 20 ppm level. As CHEOPS carries out its ...observations in a broad optical passband, it can provide insights into the reflected light from exoplanets and constrain the short-wavelength thermal emission for the hottest of planets by observing occultations and phase curves. Here, we report the first CHEOPS observation of an occultation, namely, that of the hot Jupiter WASP-189 b, a
M
P
≈ 2
M
J
planet orbiting an A-type star. We detected the occultation of WASP-189 b at high significance in individual measurements and derived an occultation depth of dF = 87.9 ± 4.3 ppm based on four occultations. We compared these measurements to model predictions and we find that they are consistent with an unreflective atmosphere heated to a temperature of 3435 ± 27 K, when assuming inefficient heat redistribution. Furthermore, we present two transits of WASP-189 b observed by CHEOPS. These transits have an asymmetric shape that we attribute to gravity darkening of the host star caused by its high rotation rate. We used these measurements to refine the planetary parameters, finding a ~25% deeper transit compared to the discovery paper and updating the radius of WASP-189 b to 1.619 ± 0.021
R
J
. We further measured the projected orbital obliquity to be
λ
= 86.4
−4.4
+2.9°
, a value that is in good agreement with a previous measurement from spectroscopic observations, and derived a true obliquity of Ψ = 85.4 ± 4.3°. Finally, we provide reference values for the photometric precision attained by the CHEOPS satellite: for the
V
= 6.6 mag star, and using a 1-h binning, we obtain a residual RMS between 10 and 17 ppm on the individual light curves, and 5.7 ppm when combining the four visits.
In the last few decades the effect of lead contamination on human health has received significant attention. Based on such concerns elimination of lead from ceramic glaze, paint, plumbing etc. has ...been legislated and implemented. However, till recently, solders used in electronics, remained lead-based. The worldwide multi-facetted research efforts to arrive at suitable solutions, especially as the deadline for implementation of lead-free electronic solders approaches, have resulted in an exhaustive number of research papers in several reviewed scientific journals. Similarly there have been presentations in several national and international meetings of various technical societies. It is impossible for any researcher or student to be aware of all the materials that have been, and are being, published in these many different sources, so it becomes essential to have most of the relevant and currently available information presented in a single publication. With this goal in mind the important issues encountered in the lead-free electronic solder area were identified, and researchers recognized for their significant scientific contributions in those areas were invited to write articles on those topics. They were asked to address the importance of a given issue, the current status of understanding and available solutions, the problems that still need to be tackled and suggestions for potential approaches to do so. The chapters are organized around the following subject areas: themodynamics and phase diagrams, solder developments, processing issues, mechanical property considerations, effects of thermal excursions (TMF), electromigraion, whisker growth, tin pest, and industrial perspectives (consumer electronics, and high-end high reliability applications). This material orig
Background
Among sarcomas, which are rare cancers, many types are exceedingly rare; however, a definition of ultra‐rare cancers has not been established. The problem of ultra‐rare sarcomas is ...particularly relevant because they represent unique diseases, and their rarity poses major challenges for diagnosis, understanding disease biology, generating clinical evidence to support new drug development, and achieving formal authorization for novel therapies.
Methods
The Connective Tissue Oncology Society promoted a consensus effort in November 2019 to establish how to define ultra‐rare sarcomas through expert consensus and epidemiologic data and to work out a comprehensive list of these diseases. The list of ultra‐rare sarcomas was based on the 2020 World Health Organization classification, The incidence rates were estimated using the Information Network on Rare Cancers (RARECARENet) database and NETSARC (the French Sarcoma Network's clinical‐pathologic registry). Incidence rates were further validated in collaboration with the Asian cancer registries of Japan, Korea, and Taiwan.
Results
It was agreed that the best criterion for a definition of ultra‐rare sarcomas would be incidence. Ultra‐rare sarcomas were defined as those with an incidence of approximately ≤1 per 1,000,000, to include those entities whose rarity renders them extremely difficult to conduct well powered, prospective clinical studies. On the basis of this threshold, a list of ultra‐rare sarcomas was defined, which comprised 56 soft tissue sarcoma types and 21 bone sarcoma types.
conclusions
Altogether, the incidence of ultra‐rare sarcomas accounts for roughly 20% of all soft tissue and bone sarcomas. This confirms that the challenges inherent in ultra‐rare sarcomas affect large numbers of patients.
The list of ultra‐rare sarcomas, defined as those sarcomas with an incidence ≤1 per 1,000,000, comprises 56 soft tissue sarcoma and 21 bone sarcoma types. The incidence of ultra‐rare sarcomas accounts for roughly 20% of all soft tissue and bone sarcomas, confirming that challenges inherent to ultra‐rare sarcomas affect large numbers of patients.
The developments of the open-source OpenMolcas chemistry software environment since spring 2020 are described, with a focus on novel functionalities accessible in the stable branch of the package or ...via interfaces with other packages. These developments span a wide range of topics in computational chemistry and are presented in thematic sections: electronic structure theory, electronic spectroscopy simulations, analytic gradients and molecular structure optimizations, ab initio molecular dynamics, and other new features. This report offers an overview of the chemical phenomena and processes OpenMolcas can address, while showing that OpenMolcas is an attractive platform for state-of-the-art atomistic computer simulations.
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