Limits to Gauge Coupling in the Dark Sector Set by the Nonobservation of Instanton-Induced Decay of Super-Heavy Dark Matter in the Pierre Auger Observatory Data.

Instantons, which are nonperturbative solutions to Yang-Mills equations, provide a signal for the occurrence of quantum tunneling between distinct classes of vacua. They can give rise to decays of particles otherwise forbidden. Using data collected at the Pierre Auger Observatory, we search for signatures of such instanton-induced processes that would be suggestive of super-heavy particles decaying in the Galactic halo. These particles could have been produced during the post-inflationary epoch and match the relic abundance of dark matter inferred today. The nonobservation of the signatures searched for allows us to derive a bound on the reduced coupling constant of gauge interactions in the dark sector: α_{X}≲0.09, for 10^{9}≲M_{X}/GeV<10^{19}. Conversely, we obtain that, for instance, a reduced coupling constant α_{X}=0.09 excludes masses M_{X}≳3×10^{13} GeV. In the context of dark matter production from gravitational interactions alone, we illustrate how these bounds are complementary to those obtained on the Hubble rate at the end of inflation from the nonobservation of tensor modes in the cosmological microwave background.

Measurement of the Fluctuations in the Number of Muons in Extensive Air Showers with the Pierre Auger Observatory.

We present the first measurement of the fluctuations in the number of muons in extensive air showers produced by ultrahigh energy cosmic rays. We find that the measured fluctuations are in good agreement with predictions from air shower simulations. This observation provides new insights into the origin of the previously reported deficit of muons in air shower simulations and constrains models of hadronic interactions at ultrahigh energies. Our measurement is compatible with the muon deficit originating from small deviations in the predictions from hadronic interaction models of particle production that accumulate as the showers develop.

Features of the Energy Spectrum of Cosmic Rays above 2.5×10

We report a measurement of the energy spectrum of cosmic rays above 2.5×10^{18} eV based on 215 030 events. New results are presented: at about 1.3×10^{19} eV, the spectral index changes from 2.51±0.03(stat)±0.05(syst) to 3.05±0.05(stat)±0.10(syst), evolving to 5.1±0.3(stat)±0.1(syst) beyond 5×10^{19} eV, while no significant dependence of spectral features on the declination is seen in the accessible range. These features of the spectrum can be reproduced in models with energy-dependent mass composition. The energy density in cosmic rays above 5×10^{18} eV is [5.66±0.03(stat)±1.40(syst)]×10^{53} erg Mpc^{-3}.

Incompatibilities in paediatric intensive care - pitfalls in drug information.

Drug incompatibilities can lead to loss of effectiveness of drugs or to increased risk for undesirable effects that can even be life-threatening. Especially children are at high risk. Databases are an important source of information in routine care to avoid incompatibilities. However, they were supposedly developed considering drugs for use in adults. Thus, we analysed to what extent databases are appropriate for the identification of incompatibilities in intravenous (i.v.) drug therapy in paediatric intensive care. We analysed the information provided by two databases (Database A and B) on all pairs of two drugs prescribed to be administered via the same i.v. access line in a university paediatric intensive care unit during the study period of 50 days. A total of 50 different i.v. drugs was prescribed in 318 different combinations (drug pairs). We found information on (in)compatibilities in 23.0 % (73/318) in Database A and in 31.1 % (99/318) in Database B. Only in 11.0 % (35/318) of the drug pairs, both databases provided information. Considering those drug pairs, in 17.1 % (6/35) Database B indicated compatibility whereas Database A indicated incompatibility. Compatibility information delivered by databases on drugs used in paediatric intensive care is incomplete, heterogeneous, and partly contradictory. Thus, an increased awareness on the strengths and limitations of different databases is necessary to avoid patient harm.

Kneelike structure in the spectrum of the heavy component of cosmic rays observed with KASCADE-Grande.

We report the observation of a steepening in the cosmic ray energy spectrum of heavy primary particles at about 8×10(16) eV. This structure is also seen in the all-particle energy spectrum, but is less significant. Whereas the "knee" of the cosmic ray spectrum at 3-5×10(15) eV was assigned to light primary masses by the KASCADE experiment, the new structure found by the KASCADE-Grande experiment is caused by heavy primaries. The result is obtained by independent measurements of the charged particle and muon components of the secondary particles of extensive air showers in the primary energy range of 10(16) to 10(18) eV. The data are analyzed on a single-event basis taking into account also the correlation of the two observables.

Detection and imaging of atmospheric radio flashes from cosmic ray air showers.

The nature of ultrahigh-energy cosmic rays (UHECRs) at energies >10(20) eV remains a mystery. They are likely to be of extragalactic origin, but should be absorbed within approximately 50 Mpc through interactions with the cosmic microwave background. As there are no sufficiently powerful accelerators within this distance from the Galaxy, explanations for UHECRs range from unusual astrophysical sources to exotic string physics. Also unclear is whether UHECRs consist of protons, heavy nuclei, neutrinos or gamma-rays. To resolve these questions, larger detectors with higher duty cycles and which combine multiple detection techniques are needed. Radio emission from UHECRs, on the other hand, is unaffected by attenuation, has a high duty cycle, gives calorimetric measurements and provides high directional accuracy. Here we report the detection of radio flashes from cosmic-ray air showers using low-cost digital radio receivers. We show that the radiation can be understood in terms of the geosynchrotron effect. Our results show that it should be possible to determine the nature and composition of UHECRs with combined radio and particle detectors, and to detect the ultrahigh-energy neutrinos expected from flavour mixing.

Microvascular retinal changes in patients presenting with acute coronary syndromes.

BACKGROUND: Retinal microvascular changes predict cardiovascular morbidity and mortality independent of classical risk factors. However, it is unclear which retinal changes characterize patients with established coronary artery disease (CAD), and in particular, with acute coronary syndromes (ACS). The aim of the present preliminary study was to assess retinopathy in these patients. METHODS: 43 consecutive patients with ACS and 19 consecutive patients with stable CAD were investigated. Among the patient group with ACS, 20 patients presented with ST-Elevation Myocardial Infarction (STEMI) and 23 patients presented with Non-STEMI (NSTEMI). Standardized protocols were used and retinal fundus photography was taken within 48 h post-coronary angiography to assess retinopathy and general arteriolar narrowing as arterio-venous ratio (AVR). Clinical and laboratory cardiovascular risk factors were recorded. RESULTS: Despite comparable age and comparable frequency of diabetes and hypertension, patients with ACS had a much higher likelihood for retinal microaneurysms and dot bleedings than patients with stable CAD (17 (40%) vs. 1 (5%) patients, OR 11.77; 95%CI 1.43-96.59; p=0.006). Performing multivariate analysis, this association remains significant (OR 20.5, 95%CI 1.6-255, p=0.019). CAD patients presented more often with focal signs of arteriovenous nicking / focal vasoconstriction (10 (53%) vs. 9 (21%) patients, OR 4.2; 95%CI 1.31-13.4; p=0.018), however after multivariate analysis this association lost significance. The AVR was comparably low in both groups. CONCLUSION: Patients with ACS present more often with dot bleedings and microaneurysms. These findings provide preliminary evidence that retinal fundus examination may be useful to contribute to the risk profile of patients, enabling a more intensive survey and care.

The costs of treating glaucoma with combinations of topical drugs in Spain.

PURPOSE: This study describes the treatment in ordinary clinical practice in Spain of patients with glaucoma with a two-drug combination therapy. The authors present the treatment outcome as endof-period intraocular pressure (IOP) and the calculated direct medical costs over a 2-year period. METHODS: Data were extracted retrospectively from patient charts recording the use of all medical resources related to glaucoma. Costs were estimated using unit costs from public sources (2005). Descriptive cost analysis according to combination treatment at baseline was performed. RESULTS: The study included 216 patients from 21 centers. Around half of the patients were started on a beta-blocker/prostaglandin analogue combination, while the rest received various other combinations containing either an alpha2-agonist or a carbonic anhydrase inhibitor. Across the seven groups considered, there was a statistically significant difference in the costs of the least and the two most costly groups, while the confidence intervals were overlapping in all other pairwise comparisons. The least costly drug combination was brimonidine/timolol. Assessing IOP at the end of follow-up, all the groups were equally effective (overlapping confidence intervals). In a multivariate regression analysis, the drug combination did not have an independent, significant impact on total direct medical costs, drug costs, or end-of-period IOP. Significant determinants of these variables were surgical interventions and one or more changes of drug combination during the follow-up. CONCLUSIONS: Costs are determined by the response to treatment. Inadequate response triggers treatment changes and sometimes eventually surgical interventions, thereby increasing costs significantly.

A European perspective on costs and cost effectiveness of ophthalmic combinations in the treatment of open-angle glaucoma.

PURPOSE: Efficacy, safety, and cost implications are important considerations when choosing an ophthalmic treatment. Fixed-combination glaucoma medications containing brimonidine 0.2% and timolol 0.5%, or dorzolamide 2% and timolol 0.5%, were compared with brimonidine 0.2% and dorzolamide 2% that were used as adjunctive therapy to timolol 0.5%. METHODS: A literature review was conducted to determine the outcome parameters of intraocular pressure reduction and tolerability after 3 months of use of brimonidine or dorzolamide, each together with timolol as a fixed-combination or in concomitant therapy. Modelled cost-minimization and cost-effectiveness analyses were performed to investigate the economic consequences of ophthalmic therapy with brimonidine, dorzolamide, and timolol from a societal perspective. RESULTS: The literature review found that brimonidine and dorzolamide used as fixed combinations with timolol as well as in adjunctive therapy to timolol were equally effective and safe. Furthermore, in the European countries studied, the fixed combination of brimonidine/timolol represented a less costly option when compared to the fixed combination of dorzolamide/timolol evaluated over both a 3-month and a 12-month horizon. CONCLUSIONS: Brimonidine used as a fixed-combination therapy with timolol provided better cost value than dorzolamide/timolol in all the countries studied. For most countries, the fixed combination of brimonidine and timolol also provided better cost value than adjunctive therapy with brimonidine, which was more cost effective than adjunctive therapy with dorzolamide.

Quality of life and relative importance: a comparison of time trade-off and conjoint analysis methods in patients with age-related macular degeneration.

AIM: To investigate the relative priorities in quality of life (QoL) in patients with age-related macular degeneration (AMD). METHODS: Measures of visual function, QoL and utility associated with visual loss were obtained from 122 patients with AMD classified according to macular morphology. The two methods of utility assessment were time trade-off (TTO) and conjoint analysis (CA), which have been recommended by the UK's National Institute of Clinical Excellence as techniques for the assessment of healthcare priorities. RESULTS: Results show that the two methods for assessing utility are poorly related: TTO relates moderately to visual function and disease severity but CA does not. CA identified two different subgroups of patients: one with outdoor mobility and the other with reading as their main priority. CONCLUSION: Further work is needed and caution required in interpreting data obtained using these methodologies for determining their relative importance in vision-related QoL studies.

Direct costs of glaucoma and severity of the disease: a multinational long term study of resource utilisation in Europe.

BACKGROUND: Resource utilisation and direct costs associated with glaucoma progression in Europe are unknown. As population progressively ages, the economic impact of the disease will increase. METHODS: From a total of 1655 consecutive cases, the records of 194 patients were selected and stratified by disease severity. Record selection was based on diagnoses of primary open angle glaucoma, glaucoma suspect, ocular hypertension, or normal tension glaucoma; 5 years minimum follow up were required. Glaucoma severity was assessed using a six stage glaucoma staging system based on static threshold visual field parameters. Resource utilisation data were abstracted from the charts and unit costs were applied to estimate direct costs to the payer. Resource utilisation and estimated direct cost of treatment, per person year, were calculated. RESULTS: A statistically significant increasing linear trend (p = 0.018) in direct cost as disease severity worsened was demonstrated. The direct cost of treatment increased by an estimated 86 for each incremental step ranging from 455 euro per person year for stage 0 to 969 euro per person year for stage 4 disease. Medication costs ranged from 42% to 56% of total direct cost for all stages of disease. CONCLUSIONS: These results demonstrate for the first time in Europe that resource utilisation and direct medical costs of glaucoma management increase with worsening disease severity. Based on these findings, managing glaucoma and effectively delaying disease progression would be expected to significantly reduce the economic burden of this disease. These data are relevant to general practitioners and healthcare administrators who have a direct influence on the distribution of resources.

Pathogenicity of Salmonella pullorum in northern bobwhite quail and mallard ducks.

Ten-day-old northern bobwhite quail and mallard ducks were inoculated orally and intravenously with Salmonella pullorum at selected concentrations (10(3) to 10(10) colony-forming units). Mortality in bobwhites ranged from 65% to 100%, whereas no mallards died or exhibited any signs of morbidity. Significantly (P less than 0.05) increased values for serum calcium, uric acid, and lactate dehydrogenase were observed in mallards inoculated with live S. pullorum, and antibody titers were detected as early as 1 week postinoculation. Viable bacteria were cultured from feces, liver, lungs, heart, kidneys, pancreas, and spleen of bobwhites and from livers of four mallards. Bacterial colonies were frequently found in the capillaries of various organs of the quail, particularly in the heart and kidneys, with slight-to-moderate diffuse or multifocal necrotizing inflammation present in all organs examined. Bobwhites are susceptible to infection from S. pullorum, with morbidity and mortality rates similar to those of chicks and poults, whereas mallards undergo a short, subclinical infection that is resolved without lasting tissue damage.

Antivascular endothelial growth factor as an approach for macular edema.

Macular edema is an abnormal thickening of the macula associated with the accumulation of excess fluid in the extracellular space of the neurosensory retina. The following chapter looks at the basic pathomechanisms of macular edema as well as major pathologic conditions leading to it: special focus is on diabetic retinopathy, retinal venous occlusions and a number of inflammatory disorders. Currently available data on up-to-date pharmacologic treatment options such as steroids and anti-VEGF compounds is presented and discussed.

A cost-effectiveness analysis of fixed-combination therapies in patients with open-angle glaucoma: a European perspective.

OBJECTIVE: To compare the efficacy and cost implications of the use of the intraocular pressure-lowering prostaglandin analogues bimatoprost, travoprost, and latanoprost as fixed-combination therapies with timolol, a beta-adrenergic receptor antagonist. METHODS: A decision analytic cost-effectiveness model was constructed. Since no head-to-head studies comparing the three treatment options exist, the analysis was based on an indirect comparison. Hence, the model was based on efficacy data from five randomized, controlled, clinical studies. The studies were comparable with respect to study design, time horizon, patient population and type of end point presented. The measure of effectiveness was the percentage reduction of the intraocular pressure level from baseline. The cost evaluated was the cost of medication and clinical visits to the ophthalmologist. All drug costs were market prices inclusive of value-added tax, and visit costs were priced using official physician fees. Cost-effectiveness analyses were carried out in five European countries: Spain, Italy, United Kingdom, Norway and Sweden. The time horizon for the analyses was 3 months. RESULTS: The analysis showed that fixed-combination bimatoprost/timolol was more effective and less costly than fixed-combination travoprost/timolol and fixed-combination latanoprost/timolol in three out of the five countries analyzed. In two countries, bimatoprost/timolol was less costly than latanoprost/timolol, and cost the same as travoprost/timolol. CONCLUSIONS: This cost-effectiveness analysis showed that the fixed combination of bimatoprost 0.03%/timolol 0.5% administered once daily was a cost-effective treatment option for patients with primary open-angle glaucoma. This study was limited by available clinical data: without a head-to-head trial, indirect comparisons were necessary. In the United Kingdom, Sweden, Norway, Italy, and Spain, from a health service viewpoint, bimatoprost/timolol was a slightly more effective as well as less costly treatment strategy when compared to both travoprost/timolol and latanoprost/timolol.