Search for Gamma-Ray Spectral Lines from Dark Matter Annihilation up to 100 TeV toward the Galactic Center with MAGIC.

Linelike features in TeV γ rays constitute a "smoking gun" for TeV-scale particle dark matter and new physics. Probing the Galactic Center region with ground-based Cherenkov telescopes enables the search for TeV spectral features in immediate association with a dense dark matter reservoir at a sensitivity out of reach for satellite γ-ray detectors, and direct detection and collider experiments. We report on 223 hours of observations of the Galactic Center region with the MAGIC stereoscopic telescope system reaching γ-ray energies up to 100 TeV. We improved the sensitivity to spectral lines at high energies using large-zenith-angle observations and a novel background modeling method within a maximum-likelihood analysis in the energy domain. No linelike spectral feature is found in our analysis. Therefore, we constrain the cross section for dark matter annihilation into two photons to ⟨σv⟩≲5×10^{-28} cm^{3} s^{-1} at 1 TeV and ⟨σv⟩≲1×10^{-25} cm^{3} s^{-1} at 100 TeV, achieving the best limits to date for a dark matter mass above 20 TeV and a cuspy dark matter profile at the Galactic Center. Finally, we use the derived limits for both cuspy and cored dark matter profiles to constrain supersymmetric wino models.

The age-dependent association of risk factors with pancreatic cancer.

BACKGROUND: Pancreatic cancer presents as advanced disease in >80% of patients; yet, appropriate ages to consider prevention and early detection strategies are poorly defined. We investigated age-specific associations and attributable risks of pancreatic cancer for established modifiable and non-modifiable risk factors. PATIENTS AND METHODS: We included 167 483 participants from two prospective US cohort studies with 1190 incident cases of pancreatic cancer during >30 years of follow-up; 5107 pancreatic cancer cases and 8845 control participants of European ancestry from a completed multicenter genome-wide association study (GWAS); and 248 893 pancreatic cancer cases documented in the US Surveillance, Epidemiology, and End Results (SEER) Program. Across different age categories, we investigated cigarette smoking, obesity, diabetes, height, and non-O blood group in the prospective cohorts; weighted polygenic risk score of 22 previously identified single nucleotide polymorphisms in the GWAS; and male sex and black race in the SEER Program. RESULTS: In the prospective cohorts, all five risk factors were more strongly associated with pancreatic cancer risk among younger participants, with associations attenuated among those aged >70 years. The hazard ratios comparing participants with three to five risk factors with those with no risk factors were 9.24 [95% confidence interval (CI) 4.11-20.77] among those aged ≤60 years, 3.00 (95% CI 1.85-4.86) among those aged 61-70 years, and 1.46 (95% CI 1.10-1.94) among those aged >70 years (Pheterogeneity = 3×10-5). These factors together were related to 65.6%, 49.7%, and 17.2% of incident pancreatic cancers in these age groups, respectively. In the GWAS and the SEER Program, the associations with the polygenic risk score, male sex, and black race were all stronger among younger individuals (Pheterogeneity ≤0.01). CONCLUSIONS: Established risk factors are more strongly associated with earlier-onset pancreatic cancer, emphasizing the importance of age at initiation for cancer prevention and control programs targeting this highly lethal malignancy.

Strain wave pathway to semiconductor-to-metal transition revealed by time-resolved X-ray powder diffraction.

One of the main challenges in ultrafast material science is to trigger phase transitions with short pulses of light. Here we show how strain waves, launched by electronic and structural precursor phenomena, determine a coherent macroscopic transformation pathway for the semiconducting-to-metal transition in bistable Ti3O5 nanocrystals. Employing femtosecond powder X-ray diffraction, we measure the lattice deformation in the phase transition as a function of time. We monitor the early intra-cell distortion around the light absorbing metal dimer and the long range deformations governed by acoustic waves propagating from the laser-exposed Ti3O5 surface. We developed a simplified elastic model demonstrating that picosecond switching in nanocrystals happens concomitantly with the propagating acoustic wavefront, several decades faster than thermal processes governed by heat diffusion.

Bounds on Lorentz Invariance Violation from MAGIC Observation of GRB 190114C.

On January 14, 2019, the Major Atmospheric Gamma Imaging Cherenkov telescopes detected GRB 190114C above 0.2 TeV, recording the most energetic photons ever observed from a gamma-ray burst. We use this unique observation to probe an energy dependence of the speed of light in vacuo for photons as predicted by several quantum gravity models. Based on a set of assumptions on the possible intrinsic spectral and temporal evolution, we obtain competitive lower limits on the quadratic leading order of speed of light modification.

Pharmacokinetics and biodistribution study of self-assembled Gd-micelles demonstrating blood-pool contrast enhancement for MRI.

Magnetic resonance angiography (MRA) requires the use of contrast agents (CAs) to enable accurate diagnosis. There are currently no CAs on the market with appropriate pharmacokinetic (PK) parameters, namely long persistence in the blood, that can be easily used for MRA. We have recently synthesized amphiphilic building blocks loaded with gadolinium (Gd), which self-assemble into Gd-micelles in aqueous media, and have evaluated their potential as a blood-pool contrast agent (BPCA) in vivo. To assess the short and long term PK of Gd-micelles, the blood and organs of the mice were analyzed at t = 30 min, 1, 2, 3 h, 7, 14 and 21 days. Gd-DOTA was used as a control because it is the gold-standard CA for MRA despite its rapid clearance from the blood compartment. Gd-micelles circulated in the blood for more than 3 h postinjection whereas Gd-DOTA was eliminated less than half an hour postinjection. No side effects were observed in the mice up to the end of the study at 21 days and no accumulation of Gd was observed in the brain or bones. The Magnetic Resonance Imaging (MRI) parameters and the results of this in vivo study indicate the true BCPA properties of Gd-micelles and warrant further development.

Plasma inflammatory cytokines and survival of pancreatic cancer patients.

OBJECTIVES: Inflammation and inflammatory conditions have been associated with pancreatic cancer risk and progression in a number of clinical, epidemiological, and animal model studies. The goal of the present study is to identify plasma markers of inflammation associated with survival of pancreatic cancer patients, and assess their joint contribution to patient outcome. METHODS: We measured circulating levels of four established markers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), soluble tumor necrosis factor receptor type II (sTNF-RII), and macrophage inhibitory cytokine-1 (MIC-1)) in 446 patients enrolled in an ongoing prospective clinic-based study. Hazard ratios (HRs) and 95% confidence intervals (CI) for death were estimated using multivariate Cox proportional hazards models. RESULTS: Overall mortality was significantly increased in patients in the top quartile of CRP (HR = 2.52, 95% CI: 1.82-3.49), IL-6 (HR = 2.78, 95% CI: 2.03-3.81), sTNF-RII (HR = 2.00, 95% CI: 1.46-2.72), and MIC-1 (HR = 2.53, 95% CI: 1.83-3.50), compared to those in the bottom quartile (P-trend <0.0001 for all four comparisons). Furthermore, patients with higher circulating concentrations of all four cytokines had a median survival of 3.7 months; whereas, those with lower levels had a median survival of 19.2 months (HR = 4.55, 95% CI: 2.87-7.20, P-trend <0.0001). CONCLUSION: Individual elevated plasma inflammatory cytokines are associated with significant and dramatic reductions in pancreatic cancer patient survival. Furthermore, we observed an independent combined effect of those cytokines on patient survival, suggesting that multiple inflammatory pathways are likely involved in PDAC progression. Future research efforts to target the inflammatory state using combination strategies in pancreatic cancer patients are warranted.

Design, synthesis and in vitro evaluation of ß-glucuronidase-sensitive prodrug of 5-aminolevulinic acid for photodiagnosis of breast cancer cells.

Treatment of cancer cells by clinically approved hexyl ester of 5-aminolevulinic acid (ALA-Hex) induces accumulation of fluorescent porphyrins in tumors. This allows fluorescence photodiagnosis (PD) of bladder cancer by blue light illumination. However, PD of other cancers is hampered by acute toxicity of the compound limiting its use to local applications. We have designed and synthesized a new prodrug of ALA-Hex that tackles the stability-activity paradox of amino-modified 5-ALA prodrugs. The glucuronide prodrug Glu-ALA-Hex demonstrates excellent stability under physiological conditions and activation in the presence of the target enzyme. ß-glucuronidase-triggered release of 5-ALA is programmed to yield fluorescence in tumor environment with elevated ß-glucuronidase activity, a characteristic of many solid tumors. Glu-ALA-Hex produces similar levels of fluorescence as ALA-Hex in breast cancer MCF7 cells in vitro but with much lower non-specific cell toxicity.

A forward modelling approach for the estimation of oxygen extraction fraction by calibrated fMRI.

The measurement of the absolute rate of cerebral metabolic oxygen consumption (CMRO2) is likely to offer a valuable biomarker in many brain diseases and could prove to be important in our understanding of neural function. As such there is significant interest in developing robust MRI techniques that can quantify CMRO2 non-invasively. One potential MRI method for the measurement of CMRO2 is via the combination of fMRI and cerebral blood flow (CBF) data acquired during periods of hypercapnic and hyperoxic challenges. This method is based on the combination of two, previously independent, signal calibration techniques. As such analysis of the data has been approached in a stepwise manner, feeding the results of one calibration experiment into the next. Analysing the data in this manner can result in unstable estimates of the output parameter (CMRO2), due to the propagation of errors along the analysis pipeline. Here we present a forward modelling approach that estimates all the model parameters in a one-step solution. The method is implemented using a regularized non-linear least squares approach to provide a robust and computationally efficient solution. The proposed framework is compared with previous analytical approaches using modelling studies and in vivo acquisitions in healthy volunteers (n=10). The stability of parameter estimates is demonstrated to be superior to previous methods (both in vivo and in simulation). In vivo estimates made with the proposed framework also show better agreement with expected physiological variation, demonstrating a strong negative correlation between baseline CBF and oxygen extraction fraction. It is anticipated that the proposed analysis framework will increase the reliability of absolute CMRO2 measurements made with calibrated BOLD.

Current practices used for the prevention of central venous catheter-associated infection in hematopoietic stem cell transplantation recipients: a survey from the Infectious Diseases Working Party and Nurses' Group of EBMT.

BACKGROUND: Central line-associated bloodstream infection (CLABSI) is one of the most common infectious complications after hematopoietic stem cell transplantation. To prevent this complication, international guidelines recommend the implementation of the CLABSI 'prevention bundle' consisting of hand hygiene, full barrier precautions, cleaning the insertion site with chlorhexidine, avoiding femoral sites for insertion, and removing unnecessary catheters. The aim of this survey was to analyze to what extent European Group for Blood and Marrow Transplantation (EBMT) centers have included the CLABSI prevention bundle in practice. METHODS: A questionnaire used for data collection was sent to the 545 EBMT centers worldwide, 103 of which responded. RESULTS: All 5 components of the CLABSI prevention bundle were recorded in 28% of the centers' standard operating procedures (SOP), and 21% of the centers answered that they used all of the bundle components in clinical practice. The most common recommendation absent from the SOP was specification of all the components of full barrier precautions (43% of the centers did not include at least 1 component). Skin disinfection with chlorhexidine before catheter insertion was reported by 66% centers. CLABSI rates were monitored in 21% of centers. CONCLUSIONS: Although most of the centers lacked 1 or more of the CLABSI prevention bundle components in their SOP, improvements could easily be made by updating the centers' SOP. The first important step is introduction of CLABSI rate monitoring in this high-risk patient population.

Organizational Justice and Perceived Organizational Support: Impact on Negative Work-Home Interference and Well-being Outcomes.

It is well established that negative work-home interference (NegWHI) impacts upon several work attitudes and behaviors. In the interests of both organizational effectiveness and employee well-being, it is important to identify concepts related to NegWHI and investigate their effects on well-being outcomes. This study examines the mediating role of (1) perceived organizational support (POS) in the relationship between organizational justice (OJ) and NegWHI; and (2) NegWHI in the relationships between POS and four well-being outcomes. A total of 509 employees of a Belgian hospital were surveyed. Data were analyzed using structural equation modeling and the bootstrapping method. Results showed that POS partially mediates the relationships between distributive and passive procedural justice and NegWHI, and fully mediates the relationship between the other justice dimensions and NegWHI. NegWHI partially mediates the relationships between POS and both job satisfaction and intention to quit, and fully mediates the relationship between POS and job strain. Furthermore, POS is positively related to job engagement. This study showed that organizations can help employees to better manage their work and family lives and reduce the impact of NegWHI by enhancing employees' feeling that they are supported by their organization. In order to increase POS, organizations need to promote justice in the workplace.

Black hole physics. Black hole lightning due to particle acceleration at subhorizon scales.

Supermassive black holes with masses of millions to billions of solar masses are commonly found in the centers of galaxies. Astronomers seek to image jet formation using radio interferometry but still suffer from insufficient angular resolution. An alternative method to resolve small structures is to measure the time variability of their emission. Here we report on gamma-ray observations of the radio galaxy IC 310 obtained with the MAGIC (Major Atmospheric Gamma-ray Imaging Cherenkov) telescopes, revealing variability with doubling time scales faster than 4.8 min. Causality constrains the size of the emission region to be smaller than 20% of the gravitational radius of its central black hole. We suggest that the emission is associated with pulsar-like particle acceleration by the electric field across a magnetospheric gap at the base of the radio jet.

Filgrastim XM02 (Tevagrastim®) after autologous stem cell transplantation compared to lenograstim: favourable cost-efficacy analysis.

PURPOSE: Granulocyte colony-stimulating factors (G-CSFs), filgrastim and lenograstim, are recognised to be useful in accelerating engraftment after autologous stem cell transplantation. Several forms of biosimilar non-glycosylated G-CSF have been approved by the European Medicines Agency, with limited published data supporting the clinical equivalence in peripheral blood stem cell mobilisation and recovery after autologous stem cell transplantation. METHOD: With the aim of comparing cost-effective strategies in the use of G-CSF after autologous stem cell transplantation, we retrospectively evaluated 32 patients consecutively treated with biosimilar filgrastim XM02 (Tevagrastim) and 26 with lenograstim. All patients received G-CSF (biosimilar or lenograstim) at a dosage of 5 mcg/kg/day subcutaneously from day 5 to absolute neutrophil count of 1500/mmc for three days. RESULTS: The median time to absolute neutrophil count engraftment was 11 days for the filgrastim XM02 group and 12 days for the lenograstim group. As for platelets recovery, the median time was 12 days in both groups. The median number of G-CSF vials used for patients was 9.5 for Tevagrastim and 10.5 for lenograstim, reflecting a mean estimated cost of about 556.1 euros for Tevagrastim versus 932.2 euros for lenograstim (p< 0.001). The median days of febrile neutropenia were 1.5 and 1 for filgrastim XM02 and lenograstim, respectively. No adverse event related to the use of XM02 filgrastim was recorded. CONCLUSION: In our experience, filgrastim XM02 and lenograstim showed comparable efficacy in shortening the period of neutropenia after cytoreduction and autologous stem cell transplantation, with a favourable cost effect for filgrastim XM02.

Synergy between medical informatics and bioinformatics: facilitating genomic medicine for future health care.

In this paper, we review the results of BIOINFOMED, a study funded by the European Commission (EC) with the purpose to analyse the different issues and challenges in the area where Medical Informatics and Bioinformatics meet. Traditionally, Medical Informatics has been focused on the intersection between computer science and clinical medicine, whereas Bioinformatics have been predominantly centered on the intersection between computer science and biological research. Although researchers from both areas have occasionally collaborated, their training, objectives and interests have been quite different. The results of the Human Genome and related projects have attracted the interest of many professionals, and introduced new challenges that will transform biomedical research and health care. A characteristic of the 'post genomic' era will be to correlate essential genotypic information with expressed phenotypic information. In this context, Biomedical Informatics (BMI) has emerged to describe the technology that brings both disciplines (BI and MI) together to support genomic medicine. In recognition of the dynamic nature of BMI, institutions such as the EC have launched several initiatives in support of a research agenda, including the BIOINFOMED study.

Cytological grading of breast cancer in Giemsa-stained fine needle aspiration smears.

A potential cytological nuclear grading based on a semi-quantitative evaluation of three basic nuclear features, size of cell nuclei, anisonucleosis and the proportion of nucleoli-containing-nuclei, was tested on 74 Giemsa-stained fine needle aspiration of breast smears for its reliability in establishing the malignant potential of breast cancer. The prognostic impact of DNA-ploidy and S-phase fraction was also assessed. A good correlation between the three basic nuclear features, DNA-ploidy, S-phase fraction, cytological nuclear grade and histological grade, was shown. Using the cytological nuclear grade proposed, correct classification of cases between low histological grade (HG I) and high histological grade (HG II + HG III) was achieved in 79.73%. A statistically significant difference in 5-year survival rate was also observed between low malignancy grade and high malignancy grade breast cancer patients, regardless of the grading method used. DNA-ploidy and S-phase fraction were not statistically significant in establishing the malignant potential of breast cancer.

Medical students exchange program organized by Croatian Medical Students International Committee, 1996-2000.

AIM: To assess the interest of Croatian medical students in going to foreign countries and foreign medical students' interest in coming to Croatia for one-month professional and research clerkship in the period from 1996 to 2000. METHOD: Data were obtained from contracts between Croatian Medical Students' International Committee and other National Member Organizations of the International Federation of Medical Students' Associations; from student Application forms; reports of the Local Committees of Croatian Medical Students' International Committee summed up in a Statistical form and used for statistical analysis in the International Federation of Medical Students' Associations; and from Cards of acceptance and Cards of confirmation. RESULTS: The number of available bilateral exchange places increased from 28 in 1996 to 66 in 1999. Croatian students going for clerkship abroad used 65.8% of available places and foreign students realized 59.3% of all places available in Croatia. Most of the exchange students chose clinical, whereas only a small number chose preclinical clerkship. The most visited were the departments of medicine and general surgery. All the students preferred doing their clerkships in August. Most foreign students came from Italy, Spain, Slovakia, and Hungary. Croatian students preferred to go to Italy, Spain, Egypt, and Finland. CONCLUSION: Political problems strongly affected students' interest in doing clerkship in a certain country. Croatia needs to attract more students from different countries and to increase the interest of Croatian students in doing clerkship in Eastern European countries.

Liver guide for monitoring of chronic hepatitis C.

The severity of chronic hepatitis C infection in the individual patient is monitored using blood laboratory findings and liver biopsy. If blood test results could be shown to provide sufficient information concerning the disease, the invasive procedure of liver biopsy could perhaps be avoided in some instances. This study assessed the clinical relevance of blood laboratory tests for detecting disease-related changes in the liver. Histopathological classification was used to assign class membership of the patients and data mining operations were performed in an elaborate way on 19 different data sets. Disease activity could be detected by a small set of blood tests. Extended sets could identify more severe changes, but failed to distinguish them. The extracted rules are implemented as a part of the knowledge base of a corresponding decision support system aimed at specialists and general practitioners.

Knowledge representation forms for data mining methodologies as applied in thoracic surgery.

Typical ways of disseminating and using results of clinical research are scientific journals and reports. Presentation forms are condensed and comprehensible mainly to the experts following the specific topics. A vast amount of information remains unutilized due to the complex form of presenting the knowledge. Subject of this research is to explore possibilities of representation and also visualization of the results obtained using data mining methodologies. The intention is to formulate more than scientific ways to communicate facts that are of interest for the clinicians, medical students and even patients. Internet technologies as already widely established media support knowledge representation forms such as hypertext documents and structured knowledge components. The "Assist Me" decision support system for surgical treatment of cardiac patients integrates several forms of data mining and representation methodologies. We are showing a feasibility study in which scientific outcomes were forwarded to a broad group of potential users.