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Objectives: This study was designed to assess the prognostic value of pericoronary adipose tissue computed tomography attenuation (PCATa) beyond quantitative coronary computed tomography angiography (CCTA)–derived plaque volume and positron emission tomography (PET) determined ischemia. Background: Inflammation plays a crucial role in atherosclerosis. PCATa has been shown to assess coronary-specific inflammation and is of prognostic value in patients with suspected coronary artery disease (CAD). Methods: A total of 539 patients who underwent CCTA and [ 15O]H 2O PET perfusion imaging because of suspected CAD were included. Imaging assessment included coronary artery calcium score (CACS), presence of obstructive CAD (≥50% stenosis) and high-risk plaques (HRPs), total plaque volume (TPV), calcified/noncalcified plaque volume (CPV/NCPV), PCATa, and myocardial ischemia. The endpoint was a composite of death and nonfatal myocardial infarction. Prognostic thresholds were determined for quantitative CCTA variables. Results: During a median follow-up of 5.0 (interquartile range: 4.7 to 5.0) years, 33 events occurred. CACS >59 Agatston units, obstructive CAD, HRPs, TPV >220 mm 3, CPV >110 mm 3, NCPV >85 mm 3, and myocardial ischemia were associated with shorter time to the endpoint with unadjusted hazard ratios (HRs) of 4.17 (95% confidence interval [CI]: 1.80 to 9.64), 4.88 (95% CI: 1.88 to 12.65), 3.41 (95% CI: 1.72 to 6.75), 7.91 (95% CI: 3.05 to 20.49), 5.82 (95% CI: 2.40 to 14.10), 8.07 (95% CI: 3.33 to 19.55), and 4.25 (95% CI: 1.84 to 9.78), respectively (p < 0.05 for all). Right coronary artery (RCA) PCATa above scanner specific thresholds was associated with worse prognosis (unadjusted HR: 2.84; 95% CI: 1.44 to 5.63; p = 0.003), whereas left anterior descending artery and circumflex artery PCATa were not related to outcome. RCA PCATa above scanner specific thresholds retained is prognostic value adjusted for imaging variables and clinical characteristics associated with the endpoint (adjusted HR: 2.45; 95% CI: 1.23 to 4.93; p = 0.011). Conclusions: Parameters associated with atherosclerotic burden and ischemia were more strongly associated with outcome than RCA PCATa. Nonetheless, RCA PCATa was of prognostic value beyond clinical characteristics, CACS, obstructive CAD, HRPs, TPV, CPV, NCPV, and ischemia.

Background: The coronavirus disease 2019 (COVID-19) pandemic is having significant impact on oncological care (Joode et al, Eur J Cancer 2020;136:132-139) and patients with cancer might have an increased risk for severe outcome of COVID-19 In order to identify risk factors associated with a worse outcome of COVID-19, a nationwide registry was developed for patients with cancer and COVID-19 Methods: This ongoing multicentre nationwide observational cohort study was designed as a quality of care registry and is executed by the Dutch Oncology COVID-19 Consortium (DOCC), a collaboration of oncology physicians in the Netherlands A questionnaire was developed to collect pseudonymised patient data on patients’ characteristics, cancer diagnosis, cancer treatment, and outcome of COVID-19 All patients with COVID-19 and a cancer diagnosis or cancer treatment in the past 5 years were eligible for inclusion Results: To date, > 600 cancer patients diagnosed with COVID-19 have been registered by 45 Dutch hospitals Data of 442 registered patients with at least 4 weeks follow-up were cleaned and 351 patients could be included for the first analyses The main cancer diagnoses were non-small cell lung cancer (13 4%), breast cancer (13 4%), and chronic lymphocytic leukaemia (8 8%) Overall, 114 (32 3%) out of 351 patients with cancer died from COVID-19 In multivariate analyses, age ≥ 65 years (p < 0 001), male gender (p = 0 035), prior or other malignancy (p = 0 045), and active diagnosis of haematological malignancy (p = 0 046) or lung cancer (p = 0 003) were independent risk factors for a fatal outcome of COVID-19 In a subgroup analysis of patients with active malignancy, the risk for a fatal outcome was mainly determined by tumour type (haematological malignancy or lung cancer) and age (≥ 65 years) Conclusions: The findings in this registry indicate that patients with a haematological malignancy or lung cancer have an increased risk of a worse outcome of COVID-19 During the ongoing COVID-19 pandemic, these vulnerable patients should avoid exposure to SARS-CoV-2, whereas treatment adjustments and prioritizing vaccination, when available, should also be considered Legal entity responsible for the study: Erasmus Medical Center Funding: Dutch Cancer Society Disclosure: D W Dumoulin: Honoraria (self), Speakers fee: MSD;Honoraria (self), Speakers fee : Roche;Honoraria (self), Speakers fee: Astazeneca;Honoraria (self), Speakers fee: BMS;Honoraria (self), Speakers fee: Novartis;Honoraria (self), Speakers fee: Pfizer H M Westgeest: Honoraria (self): Astellas;Honoraria (self): Roche;Travel/Accommodation/Expenses: Ipsen L E L Hendriks: Advisory/Consultancy, Mentorship program with key opinion leaders: funded by AstraZeneca: AstraZeneca;Honoraria (self), Educational webinars: Quadia;Research grant/Funding (institution): AstraZeneca;Advisory/Consultancy, Paid to institution: Eli Lilly;Advisory/Consultancy, Paid to institution: Roche Genentech;Advisory/Consultancy, Paid to institution: Pfizer;Advisory/Consultancy, Advisory board and speakers fee all paid to institution: MSD;Advisory/Consultancy, Paid to institution: Takeda;Leadership role, Local PI of pharma initiated research: AstraZeneca;Leadership role, Local PI of pharma initiated research: Novartis;Leadership role, Local PI of pharma initiated research: BMS;Leadership role, Local PI of pharma initiated research: MSD / Merck;Leadership role, Local PI of pharma initiated research: GSK;Leadership role, Local PI of pharma initiated research: Takeda;Leadership role, Local PI of pharma initiated research: Blueprint Medicines;Leadership role, Local PI of pharma initiated research: Roche Genentech;Advisory/Consultancy, Paid to institution: Amgen;Advisory/Consultancy, Paid to institution: Boehringer Ingelheim;Advisory/Consultancy, Paid to institution: BMS;Advisory/Consultancy, Travel/Accommodation/Expenses, Advisory board paid to institution: Roche Genentech;Travel/Accommodation/Expenses: BMS;Research grant/Funding (institution): Roche Genentech;R search grant/Funding (institution): Boehringer Ingelheim A-M C Dingemans: Honoraria (self): Roche;Honoraria (self): Eli Lilly;Honoraria (self): Boehringer Ingelheim;Honoraria (self): Pfizer;Honoraria (self): BMS;Honoraria (self): Novartis;Honoraria (self): Takeda;Honoraria (self): PharmaMar;Advisory/Consultancy, non financial support: AbbVie;Research grant/Funding (institution): BMS;Research grant/Funding (institution): Amgen A A M Van der Veldt: Honoraria (institution), Advisory/Consultancy: BMS;Honoraria (institution), Advisory/Consultancy: MSD;Honoraria (institution), Advisory/Consultancy: Pfizer;Honoraria (institution), Advisory/Consultancy: Sanofi;Honoraria (institution), Advisory/Consultancy: Eisai;Honoraria (institution), Advisory/Consultancy: Ipsen;Honoraria (institution), Advisory/Consultancy: Roche;Honoraria (institution), Advisory/Consultancy: Novartis;Honoraria (institution), Advisory/Consultancy: Merck;Honoraria (institution), Advisory/Consultancy: Pierre Fabre All other authors have declared no conflicts of interest

Background: Multi-resistant organisms (MROs) pose a critical threat to public health. Recently, population-based systems for surveillance and control of MROs such as Carbapenemase-producing Enterobacterales (CPE) have emerged globally and evaluation is needed. In this study, we assess the feasibility and impact of a state-wide CPE surveillance and response program deployed in December 2015 across Victoria, Australia (population 6·5 million). Methods: A prospective population-based multi-modal intervention, including active screening, carrier isolation, centralised case investigation and comparative pathogen genomics was implemented. We assess impact by analysing trend in CPE incidence and clinical presentation, risk factors for acquisition and local transmission, using data from the first three years of implementation (January 2016 to December 2018). Findings: CPE case ascertainment increased over the study period to 1·42 cases/100,000 population, linked to increased screening without a concomitant rise in active clinical infections (0·45-0·60 infections/100,000 population, p=0·640). Occurrence of KPC-2 infection decreased from 0·29 infections/100,000 population prior to intervention to 0·03 infections/100,000 population in 2018 (p=0·003). Comprehensive case investigation enabled identification of novel risk factors, including non-healthcare-related overseas acquisition. Median time between isolate referral and initial centralised genomic and epidemiological assessment for local transmission was 11 days (IQR 9-14). Prospective surveillance identified numerous small transmission networks (median 2, range 1-19 cases), predominantly IMP- and KPC-producing organisms. Genomic and epidemiologically defined clusters had a median pairwise distance of 8 (IQR 4-13) single nucleotide polymorphisms, however low diversity between clusters of the same sequence type suggested genomic cluster definitions alone are insufficient for targeted control measures. Interpretation: Our results demonstrate the value of centralised CPE surveillance and control programs to increase case ascertainment, resolve risk factors and identify putative local transmission through combined genomic and epidemiological surveillance; methodologies are transferable to other low-prevalence settings and MROs globally. Funding Statement: National Health and Medical Research Council (NHMRC) partnership grant (GNT1149991) and the Victorian Government. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All data were collected in accordance with the Victorian Public Health and Wellbeing Act 2008. Ethical approval was obtained from the Human Ethics Advisory Group of the School of Biomedical Sciences, University of Melbourne (Ethics ID 1954615.2).

This paper compares recent global energy scenarios developed by governments, international bodies, businesses and the scientific community. We divide the scenarios into three broad classes: outlooks which extrapolate current trends and anticipate policy developments; exploratory scenarios which may consider disruptions; and normative scenarios which derive energy system pathways consistent with a long-term goal. Many organisations are starting to blend outlooks, exploratory and normative approaches. The paper covers trends in primary energy demand to 2040, snapshots of the energy mix in 2040, drivers of demand, and the evolution of scenarios projections developed in recent years. We find sharp divergences between outlooks and normative scenarios compatible with the Paris Agreement on climate change. All published outlooks imply that the world is not on an energy pathway compatible with the Paris Agreement. We conclude with an assessment of emerging themes including: scenario benchmarking and group think; adaptation of scenarios to real world developments; and the plausibility of different types of scenarios. We propose that more dialogue between scenario developers from the scientific community and those working in governments and commercial organisations could be beneficial. Research focusing on the organisational processes through which scenarios are developed could usefully extend this work.

Survival of patients after resection of colorectal cancer liver metastasis (CRCLM) is 36%-58%. Positron emission tomography (PET) tracers, imaging the expression of prognostic biomarkers, may contribute to assign appropriate management to individual patients. Aurora kinase A (AURKA) expression is associated with survival of patients after CRCLM resection.We synthesized [(3)H]alisertib and [(11)C]alisertib, starting from [(3)H]methyl nosylate and [(11)C]methyl iodide, respectively. We measured in vitro uptake of [(3)H]alisertib in cancer cells with high (Caco2), moderate (A431, HCT116, SW480) and low (MKN45) AURKA expression, before and after siRNA-mediated AURKA downmodulation, as well as after inhibition of P-glycoprotein (P-gp) activity. We measured in vivo uptake and biodistribution of [(11)C]alisertib in nude mice, xenografted with A431, HCT116 or MKN45 cells, or P-gp knockout mice.[(3)H]Alisertib was synthesized with an overall yield of 42% and [(11)C]alisertib with an overall yield of 23%±9% (radiochemical purity ≥99%). Uptake of [(3)H]alisertib in Caco2 cells was higher than in A431 cells (P=.02) and higher than in SW480, HCT116 and MKN45 cells (P.01). Uptake in A431 cells was higher than in SW480, HCT116 and MKN45 cells (P.01). Downmodulation of AURKA expression reduced [(3)H]alisertib uptake in Caco2 cells (P.01). P-gp inhibition increased [(3)H]alisertib uptake in Caco2 (P.01) and MKN45 (P.01) cells. In vivo stability of [(11)C]alisertib 90min post-injection was 94.7%±1.3% and tumor-to-background ratios were 2.3±0.8 (A431), 1.6±0.5 (HCT116) and 1.9±0.5 (MKN45). In brains of P-gp knockout mice [(11)C]alisertib uptake was increased compared to uptake in wild-type mice (P.01) CONCLUSIONS: Radiolabeled alisertib can be synthesized and may have potential for the imaging of AURKA, particularly when AURKA expression is high. However, the exact mechanisms underlying alisertib accumulation need further investigation.Radiolabeled alisertib may be used for non-invasively measuring AURKA protein expression and to stratify patients for treatment accordingly.

Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder characterized by low levels of cortisol despite high adrenocorticotropin (ACTH) levels, due to the reduced ability of the adrenal cortex to produce cortisol in response to stimulation by ACTH. FGD is a heterogeneous disorder for which causal mutations have been identified in MC2R, MRAP, MCM4 and TXNRD2. Also mutations in STAR and CYP11A1 can sometimes present with a phenotype resembling FGD. Recently, it has been indicated that FGD can also be caused by mutations in NNT (nicotinamide nucleotide transhydrogenase).We identified a 6.67 Mb homozygous region harboring the NNT gene by SNP haplotyping in a 1-year old Dutch boy presenting with FGD, but without mutations in MC2R and MRAP. Exome-sequencing revealed a novel homozygous mutation (NM_012343.3: c.1259dupG) in NNT that was predicted to be disease-causing. The mutation is located in exon 9 and creates a frameshift leading to a premature stopcodon (p.His421Serfs*4) that is known to result in FGD. Both parents were shown to be heterozygous carriers. We reviewed the literature for all the reported NNT mutations and their clinical presentation. The median age of disease onset in 23 reported patients, including the present patient, was 12 months (range 3 dayse39 months). There was no difference in age of disease onset between truncating and nontruncating NNT mutations. Based on recent literature, we advise to monitor patients with FGD due to NNT mutations for possible combined mineralocorticoid insufficiency and extra-adrenal manifestations. (C) 2015 Elsevier Masson SAS. All rights reserved.

Current guidelines advocate viability assessment before revascularization of chronic coronary total occlusions (CTO). The present study evaluated associations between coronary collaterals and myocardial viability assessed by cardiac magnetic resonance (CMR) imaging in patients with a CTO. Patients

A myocardial ischemic burden (IB) of 10% or more denotes high risk patients who benefit from revascularization. This threshold has been assessed by SPECT, the higher resolution of PET presumably results in a better detection of the extent and severity of ischemia. As such, a PET-derived IB might

Quantitative flow ratio (QFR) has emerged as a promising tool assessing the significance of coronary artery disease (CAD) using solely cine coronary contrast images acquired during invasive coronary angiography (ICA) to obtain QFR values equivalent to fractional flow reserve (FFR). Our objective was

Many companies have introduced self-service technologies (SSTs) although not every customer wants to use or is able to use new technologies. This study aims to explain the actual use of SSTs by analysing a framework based on antecedents derived from the social cognitive theory, such as role clarity, perceived crowdedness, and need for interaction, and technology readiness dimensions. Survey data were collected from 525 passengers (40% response rate) at a European airport. The passengers choose between a self-service check-in and an interpersonal check-in counter. Perceived crowdedness appears to have the strongest impact on the customers' decision to use SSTs. In addition, need for interaction and role clarity seem to have a significant impact on the actual use of SSTs. The results indicate that technology readiness does not have a significant impact on the use of SSTs. These findings contribute to the domain of knowledge concerning the implementation of SSTs and consumer behaviour, providing important implications for academia and practice.

The recognition of low molecular weight proteins by sera obtained during a single oral (primary) infection with 100 000 3rd-stage Cooperia oncophora larvae was studied in calves. Three groups of 6 or 7 calves were selected based on different egg excretion patterns. SDS-gel electrophoresis of adult Cooperia antigen under reducing conditions, followed by Western blotting, revealed that resistance of individual calves to C. oncophora might be related with antibody responses (42 days post infection) against at least 2 protein fragments (14–16 kDa and 27 kDa). The 14–16-kDa protein complex was bound, to some extent, by individual sera from all calves. The intensity of staining was negatively correlated with egg excretion on Day 42 p.i. Calves with high egg counts on Day 21 p.i. either did not or only weakly recognized the 27-kDa band. It has to be established whether the 14–16 kDa (or recombinant 14.2 kDa) provides a tool for immunodiagnostics and whether the 27-kDa fragment can help further unravel immune-mediated resistance to Cooperia .

Frequencies of spontaneously occurring and X-ray induced, stable and unstable types of chromosome aberrations in peripheral blood lymphocytes from two groups of radiosensitive patients, i.e., aplastic anemia (AA) and Diamond-Blackfan anemia (DBA), were determined. Two types of staining methods, i.e., chromosome painting with two cocktails of chromosome-specific DNA libraries (Nos. 1, 3, X and Nos. 2, 4 and 8), as well as conventional Giemsa staining, were employed. Chromosome painting was done with single and multicolor fluorescence in situ hybridization (FISH). The frequencies of spontaneously occurring chromosome aberrations in AA and DBA patients were not significantly different from healthy individuals. Hypersensitivity to X-rays was seen both in G0 as well as in G2 phase of the cell cycle in lymphocytes from AA and DBA patients, confirming our earlier findings using micronucleus (DBA) and G2 radiosensitivity (AA) assays.

Effects of subclinical atrophic rhinitis and exposure to adverse climatic conditions on partitioning of energy (metabolism) and performance in pigs under field-like conditions were determined. Eight groups of 30 5-week-old pigs each, were assigned to a 2 × 2 factorial arrangement of treatments: to 0 or 13 μg/ml of Pm-T challenge-exposure, and to a thermoneutral or adverse (below thermoneutrality with draught periods) climatic environment. Climatic treatment lasted 5 weeks. Subsequently, pigs were fattened till 100 kg live weight. All Pm-T exposed piglets had moderate nasal damage, which was not affected by climatic treatment. The adverse climatic environment resulted in a lower amount of energy available for production due to an increased maintenance requirement (57 kJ kg−0.75) and to a lower food intake (76 g/d). This resulted in growth retardation (86 g/d). The Pm-T administration did not change metabolizability and maintenance requirements of energy. The slight growth retardation with Pm-T (17 g/d) was thought to be the outcome of a lower food intake (34 g/d). Both treatments and their interaction affected D100 kg (days to reach 100 kg body weight). Pm-T treated and control pigs from the good environment differed 3 days in D100 kg, while for those groups from the adverse environment this difference was 8 days.

Experimental atrophic rhinitis (AR), serum antibody titres and in vitro lymphoproliferation to Pasteurella multocida derived toxin (Pm-T) were studied in piglets. Specific immune responses to Pm-T and Pm-T induced conchae atrophy were compared with AR immunity. This immunity was initiated by the Nobi-VAC AR-T vaccine administered at various times with respect to Pm-T challenge. Animals challenged with Pm-T developed conchae atrophy, but no antibodies nor cellular immune responses to Pm-T were detected. Vaccination 3 weeks before Pm-T challenge protected pigs against breakdown of nasal bony tissues. This protection was accompanied by an increase of serum antibodies and in vitro lymphoproliferation to Pm-T. Animals vaccinated 10 days before or after Pm-T challenge also had antibodies and cellular immune responses. However, these animals developed AR. In vitro, Pm-T appeared mitogenic for quiescent (non-immune) peripheral lymphocytes and Concanavalin A stimulated lymphocytes from some pigs. These in vitro lymphoproliferative responses could be partly abrogated by the addition of monomorphic anti-swine major histocompatibility complex class II DQ and DR specific monoclonal antibodies. We conclude that Pm-T is poorly immunogenic in vivo and does not initiate a protective Pm-T specific immune response. Pigs were protected from AR by vaccination, but protection was dependent on the timing of vaccine administration. We speculate that Pm-T modifies the immune response such that the response is not directed towards the toxin but to an unidentified component in the nose of piglets.

This study reports on the neurophysiological measurements that were performed in the context of a randomized, double-blind, placebo-controlled, cross-over study with intravenously administered 4-aminopyridine (4-AP) in 70 patients with definite multiple sclerosis (MS). A beneficial effect of 4-AP was found for both visual evoked response and eye movement registration parameters. This study extends the experimental data obtained on animal nerve fibers, showing that 4-AP can improve impulse conduction in demyelinated nerve, to clinical data which indicate that 4-AP induces an objective improvement in the central nervous system function in MS-patients. It thereby also provides a theoretical basis for clinical efficacy of 4-AP in MS.

A new orthometalated iridium(III) complex [Ir(ppy)2(4mptr)](PF6) with ppy= 2-(2′-phenylato)pyridine and 4mptr=4-methyl-3-(pyridin-2-yl)-l,2,4-triazole has been synthesised and characterised by X-ray structure analysis, NMR spectroscopy, electrochemical measurements, UV-Vis absorption, and emission spectroscopy. The compound crystallises in the orthorhombic space group Pbca, with a = 10.906(4), b = 16.139(6), c =32.876(12) A and Z= 8. The cation has a distorted octahedral IrN4C2 chromophore, with two chelating (C,N) ppy ligands ((IrC)=2.01 A, (IrN)=2.05 A). The two carbon atoms are cis and the two nitrogen atoms trans to each other. The 4mptr ligand chelates via the pyridine nitrogen (IrN13=2.18 A) and N2 of the triazole ring (IrN2=2.14 A), both trans to a carbon atom. The complex is reversibly reduced in CH3CN at −1.57 V (SCE) and irreversibly oxidised at + 1.20 V (SCE). The lowest UV-Vis absorption band at 380 nm (ϵ=5400) has been assigned to a d →-π* (ppy) MLCT transition. A highly-structured emission band (471/505 nm) is observed at 77 K, while at room temperature, only a broad emission (582 nm) is present.

The FeII ion in [Fe(NCS)2(4,4′-bis-1,2,4-triazole)2](H2O) has distorted tetragonal symmetry with two trans-oriented NCS− ligands. It shows a very abrupt high-spin α low-spin transition at 123.5 K on cooling and 144.5 K on warming. The compound is rather stable in vacuo at room temperature; however, samples which have passed the spin transition once lose their water of hydration above 240 K in vacuo. The dehydrated substance does not show a spin transition; it is high spin in the whole temperature range. Mossbauer ligand-field spectra and magnetic behaviour of both the hydrated and non-hydrated compounds are discussed. The spin transition has been followed by EPR measurements with the aid of traces of Cu2+ ions which could be substituted for Fe2+ in the tetragonal structure. In the high-spin phase the EPR signal is very broad and featureless; in the diamagnetic low-spin phase it is very sharp and resolved in hyperfine and superhyperfine structures. This unusual method to follow the spin transition was shown to be quite generally applicable. In the crystal structure of Fe(NCS)2(C4H4N6)2(H2O) the distances FENCS are 2.125(3) A, and FeN(ligand) 2.180(3) and 2.188(2) A. The water molecule is connected to the non-coordinating ligand N-atom by hydrogen bonding.