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.

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.

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.

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.

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.

Fisp12/mouse connective tissue growth factor mediates endothelial cell adhesion and migration through integrin alphavbeta3, promotes endothelial cell survival, and induces angiogenesis in vivo.

Fisp12 was first identified as a secreted protein encoded by a growth factor-inducible immediate-early gene in mouse fibroblasts, whereas its human ortholog, CTGF (connective tissue growth factor), was identified as a mitogenic activity in conditioned media of human umbilical vein endothelial cells. Fisp12/CTGF is a member of a family of secreted proteins that includes CYR61, Nov, Elm-1, Cop-1/WISP-2, and WISP-3. Fisp12/CTGF has been shown to promote cell adhesion and mitogenesis in both fibroblasts and endothelial cells and to stimulate cell migration in fibroblasts. These findings, together with the localization of Fisp12/CTGF in angiogenic tissues, as well as in atherosclerotic plaques, suggest a possible role for Fisp12/CTGF in the regulation of vessel growth during development, wound healing, and vascular disease. In this study, we show that purified Fisp12 (mCTGF) protein promotes the adhesion of microvascular endothelial cells through the integrin receptor alphavbeta3. Furthermore, Fisp12 stimulates the migration of microvascular endothelial cells in culture, also through an integrin-alphavbeta3-dependent mechanism. In addition, the presence of Fisp12 promotes endothelial cell survival when cells are plated on laminin and deprived of growth factors, a condition that otherwise induces apoptosis. In vivo, Fisp12 induces neovascularization in rat corneal micropocket implants. These results demonstrate that Fisp12 is a novel angiogenic inducer and suggest a direct role for Fisp12 in the adhesion, migration, and survival of endothelial cells during blood vessel growth. Taken together with the recent finding that the related protein CYR61 also induces angiogenesis, we suggest that Fisp12/mCTGF and CYR61 comprise prototypes of a new family of angiogenic regulators that function, at least in part, through integrin-alphavbeta3-dependent pathways.

Hemopump treatment in patients with postcardiotomy heart failure.

BACKGROUND: This study examined the use of the Hemopump to treat low cardiac output syndrome after cardiopulmonary bypass. METHODS: We used the Hemopump temporary cardiac assist system in 29 patients with severe left ventricular dysfunction after open heart operations from September 1991 to November 1994. RESULTS: Five patients were excluded from the study due to initial patient/device-related problems. Ten patients died in the operating room or early during the stay in the intensive care unit due to progressive biventricular failure. Fourteen patients (58.3%) were weaned from the device, and all of them were later discharged. In a subgroup of patients (54%) in whom we had a more aggressive approach for early insertion of the pump, the survival rate was 85%. Preoperative Higging risk score was significantly related to survival. CONCLUSIONS: The Hemopump can effectively unload a failing left ventricle with preservation of multiorgan perfusion. A minor decrease in kidney function was observed in most patients, but none of the surviving patients needed hemodialysis. One patient required a short period of peritoneal dialysis to get rid of fluid overload. Hemolysis or platelet dysfunction was not a clinical problem.

Postoperative management of patients with Hemopump support after coronary artery bypass grafting.

BACKGROUND: In this study, we describe postoperative monitoring, pharmacologic therapy, and hemodynamic responses in patients receiving Hemopump support after postcardiotomy heart failure. METHODS: The Hemopump was used in 24 patients with severe left ventricular dysfunction after coronary artery bypass grafting. RESULTS: Fourteen patients (58%) were weaned from the Hemopump. Low to moderate doses of a combination of catecholamines, phosphodiesterase inhibitors, vasodilators, and vasoconstrictors were required to optimize Hemopump function and left ventricular unloading. Mean arterial blood pressure, mixed venous oxygen saturation, and urinary output were the most important therapy guidelines. CONCLUSIONS: Together with our clinical protocol, the Hemopump effectively unloaded the failing ventricle while maintaining vital-organ perfusion. Doses of vasoactive drugs could be kept low. This approach to treatment provides good conditions for recovery of the stunned myocardium.

Knowledge discovery for advanced clinical data management and analysis.

Knowledge discovery is a broad research field in which methods are developed to support discovery of novel and potentially useful knowledge from clinical databases and registers in systems for patient care. However, the techniques available are not readily applicable in medical domains, due to, among other reasons, low user friendliness and lack of proper methodological background. Data mining approaches to be explored and improved are predictive modelling, segmentation, dependency modelling, summarization, and change and deviation detection/modelling (in data or knowledge). Another and original contribution of the research is to build up efficient feedback loops. Human experts and available domain expert systems could provide suggestions as how to improve all major steps in the knowledge discovery process such as evaluation of knowledge, choice of data mining methods and data input. A long tradition of collecting and maintaining clinical and administrative data could be found in fields of oncology, cardiology, coronary surgery, social and primary health care medicine. All these areas, that gather data over long periods of time, could benefit from knowledge discovery.

Quantitative collagen as a golden standard in differential diagnosing of fibrotic changes in liver tissue.

Determining a presence and degree of liver fibrosis provides means for diagnosing disease related processes. We have used two data mining methods, discriminant and regression analyses, to acquire knowledge from the data of 211 patients. We have shown and discussed that quantitative collagen has a distinguished discriminating power and can serve as a golden standard. We have additionally succeeded to obtain a formula consisting of standardised blood tests that can replace quantitative collagen. Practical implications of this is a non-invasive and cost efficient patient examination. All the results are now left for clinical evaluation and so is the current way of histopathological classifications.

Diagnostic systems for assessing alveolar bone loss.

Radiological diagnostics serves as a basic monitoring technique for alveolar bone loss which is a severe consequence of periodontal disease. To evaluate efficacy of Conventional Visual Radiography (CVR), and to assess a complete clinical status, we had used two more diagnostic systems. These are Digital Subtraction Radiography (DSR) and Probing Pocket Depth (PPD). Experimental Periodontitis was studied in 20 beagle dogs based on the measurements taken in the beginning (baseline), and before (11th month) and after the medical treatment (12th month). Data analyses pointed out the same clinical trend, i.e. a significant bone loss prior to medical treatment and its recovery to the initial state. Differences in metrics and measurement errors could be identified as causes for discrepancies between the systems, but a relationship between the CVR and PPD is worth of further research, as these systems do not appear to be entirely compatible, but rather complementary to each other.

Studies of responsiveness in the R-EGFR and Rcerb-B2 oncogenes spaces: a customized application for thyroid lesions.

Among variety of diagnostic approaches suitable for clinical analysis of thyroid lesions, the two oncogenes (R-EGFR and Rcerb-B2) are believed to be of discriminative power. In a retrospectively collected patient material we have defined different lesion types (normal tissue, benign and malignant tumours). Those were taken as class definitions in analysis performed to assign discriminating performance. Standard multivariate statistics has not performed satisfactory partly due to the data distribution and partly due to presence of the noise. Therefore we have developed a method for the classification purpose, which was based on principle of minimising generalised classification error. Results of the separation between carcinoma and normal tissue reached accuracy 70%, other classification attempts ended up in poor results. In general, misclassifications could be explained with the data quality (noise) and, when it came to benign lesions, with responsiveness of the oncogenes to tumour tissues.

Take care: guidelines for patients with chronic hepatitis C.

Alcohol consumption has significant impact on the condition of the liver, by itself, and even more in conjunction with other liver diseases such as chronic hepatitis C. Drinking habits might be delicate issues to address and could harm otherwise satisfying communication. Therefore, we intended to outline guidelines for advising hepatitis C patients concerning alcohol consumption. Analysis of a relatively limited knowledge base revealed the complexity of the disease rather than statistically significant findings regarding consumption. Thus, we instead chose to suggest a set of patient educational guidelines, which could be implemented on the Internet, hypothesizing that a better informed patient will be more able to comply with restrictions concerning alcohol consumption. A brief ad hoc evaluation pointed out Internet as a favourable media to present the information. We also suggest a tentative algorithm for further development of clinical decision support systems addressing monitoring of chronic hepatitis C patients.