The baryon density of the Universe from an improved rate of deuterium burning.

Light elements were produced in the first few minutes of the Universe through a sequence of nuclear reactions known as Big Bang nucleosynthesis (BBN)1,2. Among the light elements produced during BBN1,2, deuterium is an excellent indicator of cosmological parameters because its abundance is highly sensitive to the primordial baryon density and also depends on the number of neutrino species permeating the early Universe. Although astronomical observations of primordial deuterium abundance have reached percent accuracy3, theoretical predictions4-6 based on BBN are hampered by large uncertainties on the cross-section of the deuterium burning D(p,γ)3He reaction. Here we show that our improved cross-sections of this reaction lead to BBN estimates of the baryon density at the 1.6 percent level, in excellent agreement with a recent analysis of the cosmic microwave background7. Improved cross-section data were obtained by exploiting the negligible cosmic-ray background deep underground at the Laboratory for Underground Nuclear Astrophysics (LUNA) of the Laboratori Nazionali del Gran Sasso (Italy)8,9. We bombarded a high-purity deuterium gas target10 with an intense proton beam from the LUNA 400-kilovolt accelerator11 and detected the γ-rays from the nuclear reaction under study with a high-purity germanium detector. Our experimental results settle the most uncertain nuclear physics input to BBN calculations and substantially improve the reliability of using primordial abundances to probe the physics of the early Universe.

Proton-Capture Rates on Carbon Isotopes and Their Impact on the Astrophysical

The ^{12}C/^{13}C ratio is a significant indicator of nucleosynthesis and mixing processes during hydrogen burning in stars. Its value mainly depends on the relative rates of the ^{12}C(p,γ)^{13}N and ^{13}C(p,γ)^{14}N reactions. Both reactions have been studied at the Laboratory for Underground Nuclear Astrophysics (LUNA) in Italy down to the lowest energies to date (E_{c.m.}=60 keV) reaching for the first time the high energy tail of hydrogen burning in the shell of giant stars. Our cross sections, obtained with both prompt γ-ray detection and activation measurements, are the most precise to date with overall systematic uncertainties of 7%-8%. Compared with most of the literature, our results are systematically lower, by 25% for the ^{12}C(p,γ)^{13}N reaction and by 30% for ^{13}C(p,γ)^{14}N. We provide the most precise value up to now of 3.6±0.4 in the 20-140 MK range for the lowest possible ^{12}C/^{13}C ratio that can be produced during H burning in giant stars.

Pharmacogenetic information in Swiss drug labels - a systematic analysis.

Implementation of pharmacogenetics (PGx) and individualization of drug therapy is supposed to obviate adverse drug reactions or therapy failure. Health care professionals (HCPs) use drug labels (DLs) as reliable information about drugs. We analyzed the Swiss DLs to give an overview on the currently available PGx instructions. We screened 4306 DLs applying natural language processing focusing on drug metabolism (pharmacokinetics) and we assigned PGx levels following the classification system of PharmGKB. From 5979 hits, 2564 were classified as PGx-relevant affecting 167 substances. 55% (n = 93) were classified as "actionable PGx". Frequently, PGx information appeared in the pharmacokinetics section and in DLs of the anatomic group "nervous system". Unstandardized wording, appearance of PGx information in different sections and unclear instructions challenge HCPs to identify and interpret PGx information and translate it into practice. HCPs need harmonization and standardization of PGx information in DLs to personalize drug therapies and tailor pharmaceutical care.

Direct Measurement of the

One of the main neutron sources for the astrophysical s process is the reaction ^{13}C(α,n)^{16}O, taking place in thermally pulsing asymptotic giant branch stars at temperatures around 90 MK. To model the nucleosynthesis during this process the reaction cross section needs to be known in the 150-230 keV energy window (Gamow peak). At these sub-Coulomb energies, cross section direct measurements are severely affected by the low event rate, making us rely on input from indirect methods and extrapolations from higher-energy direct data. This leads to an uncertainty in the cross section at the relevant energies too high to reliably constrain the nuclear physics input to s-process calculations. We present the results from a new deep-underground measurement of ^{13}C(α,n)^{16}O, covering the energy range 230-300 keV, with drastically reduced uncertainties over previous measurements and for the first time providing data directly inside the s-process Gamow peak. Selected stellar models have been computed to estimate the impact of our revised reaction rate. For stars of nearly solar composition, we find sizeable variations of some isotopes, whose production is influenced by the activation of close-by branching points that are sensitive to the neutron density, in particular, the two radioactive nuclei ^{60}Fe and ^{205}Pb, as well as ^{152}Gd.

Successful Prediction of Total α-Induced Reaction Cross Sections at Astrophysically Relevant Sub-Coulomb Energies Using a Novel Approach.

The prediction of stellar (γ,α) reaction rates for heavy nuclei is based on the calculation of (α,γ) cross sections at sub-Coulomb energies. These rates are essential for modeling the nucleosynthesis of so-called p nuclei. The standard calculations in the statistical model show a dramatic sensitivity to the chosen α-nucleus potential. The present study explains the reason for this dramatic sensitivity which results from the tail of the imaginary α-nucleus potential in the underlying optical model calculation of the total reaction cross section. As an alternative to the optical model, a simple barrier transmission model is suggested. It is shown that this simple model in combination with a well-chosen α-nucleus potential is able to predict total α-induced reaction cross sections for a wide range of heavy target nuclei above A≳150 with uncertainties below a factor of 2. The new predictions from the simple model do not require any adjustment of parameters to experimental reaction cross sections whereas in previous statistical model calculations all predictions remained very uncertain because the parameters of the α-nucleus potential had to be adjusted to experimental data. The new model allows us to predict the reaction rate of the astrophysically important ^{176}W(α,γ)^{180}Os reaction with reduced uncertainties, leading to a significantly lower reaction rate at low temperatures. The new approach could also be validated for a broad range of target nuclei from A≈60 up to A≳200.

Erratum: Three New Low-Energy Resonances in the

This corrects the article DOI: 10.1103/PhysRevLett.115.252501.

Direct Capture Cross Section and the E_{p}=71 and 105 keV Resonances in the

The ^{22}Ne(p,γ)^{23}Na reaction, part of the neon-sodium cycle of hydrogen burning, may explain the observed anticorrelation between sodium and oxygen abundances in globular cluster stars. Its rate is controlled by a number of low-energy resonances and a slowly varying nonresonant component. Three new resonances at E_{p}=156.2, 189.5, and 259.7 keV have recently been observed and confirmed. However, significant uncertainty on the reaction rate remains due to the nonresonant process and to two suggested resonances at E_{p}=71 and 105 keV. Here, new ^{22}Ne(p,γ)^{23}Na data with high statistics and low background are reported. Stringent upper limits of 6×10^{-11} and 7×10^{-11} eV (90% confidence level), respectively, are placed on the two suggested resonances. In addition, the off-resonant S factor has been measured at unprecedented low energy, constraining the contributions from a subthreshold resonance and the direct capture process. As a result, at a temperature of 0.1 GK the error bar of the ^{22}Ne(p,γ)^{23}Na rate is now reduced by 3 orders of magnitude.

Days spent in acute care hospitals at the end of life of cancer patients in four Swiss cantons: a retrospective database study (SAKK 89/09).

Number of days spent in acute hospitals (DAH) at the end of life is regarded as an important care quality indicator for cancer patients. We analysed DAH during 90 days prior to death in patients from four Swiss cantons. Claims data from an insurance provider with about 20% market share and patient record review identified 2086 patients as dying of cancer. We calculated total DAH per patient. Multivariable generalised linear modelling served to evaluate potential explanatory variables. Mean DAH was 26 days. In the multivariable model, using complementary and alternative medicine (DAH = 33.9; +8.8 days compared to non-users) and canton of residence (for patient receiving anti-cancer therapy, Zürich DAH = 22.8 versus Basel DAH = 31.4; for other patients, Valais DAH = 22.7 versus Ticino DAH = 33.7) had the strongest influence. Age at death and days spent in other institutions were additional significant predictors. DAH during the last 90 days of life of cancer patients from four Swiss cantons is high compared to most other countries. Several factors influence DAH. Resulting differences are likely to have financial impact, as DAH is a major cost driver for end-of-life care. Whether they are supply- or demand-driven and whether patients would prefer fewer days in hospital remains to be established.

Improved Direct Measurement of the 64.5 keV Resonance Strength in the

The ^{17}O(p,α)^{14}N reaction plays a key role in various astrophysical scenarios, from asymptotic giant branch stars to classical novae. It affects the synthesis of rare isotopes such as ^{17}O and ^{18}F, which can provide constraints on astrophysical models. A new direct determination of the E_{R}=64.5 keV resonance strength performed at the Laboratory for Underground Nuclear Astrophysics (LUNA) accelerator has led to the most accurate value to date ωγ=10.0±1.4_{stat}±0.7_{syst} neV, thanks to a significant background reduction underground and generally improved experimental conditions. The (bare) proton partial width of the corresponding state at E_{x}=5672 keV in ^{18}F is Γ_{p}=35±5_{stat}±3_{syst} neV. This width is about a factor of 2 higher than previously estimated, thus leading to a factor of 2 increase in the ^{17}O(p, α)^{14}N reaction rate at astrophysical temperatures relevant to shell hydrogen burning in red giant and asymptotic giant branch stars. The new rate implies lower ^{17}O/^{16}O ratios, with important implications on the interpretation of astrophysical observables from these stars.

Three New Low-Energy Resonances in the

The ^{22}Ne(p,γ)^{23}Na reaction takes part in the neon-sodium cycle of hydrogen burning. This cycle affects the synthesis of the elements between ^{20}Ne and ^{27}Al in asymptotic giant branch stars and novae. The ^{22}Ne(p,γ)^{23}Na reaction rate is very uncertain because of a large number of unobserved resonances lying in the Gamow window. At proton energies below 400 keV, only upper limits exist in the literature for the resonance strengths. Previous reaction rate evaluations differ by large factors. In the present work, the first direct observations of the ^{22}Ne(p,γ)^{23}Na resonances at 156.2, 189.5, and 259.7 keV are reported. Their resonance strengths are derived with 2%-7% uncertainty. In addition, upper limits for three other resonances are greatly reduced. Data are taken using a windowless ^{22}Ne gas target and high-purity germanium detectors at the Laboratory for Underground Nuclear Astrophysics in the Gran Sasso laboratory of the National Institute for Nuclear Physics, Italy, taking advantage of the ultralow background observed deep underground. The new reaction rate is a factor of 20 higher than the recent evaluation at a temperature of 0.1 GK, relevant to nucleosynthesis in asymptotic giant branch stars.

Trends in incidence and medical resource utilisation in patients with chronic lymphocytic leukaemia: insights from the UK Clinical Practice Research Datalink (CPRD).

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in European adults. We aimed to evaluate time trends in CLL incidence and medical resource utilisation of CLL patients in the UK. We conducted a retrospective, observational cohort analysis using the UK Clinical Practice Research Datalink (CPRD) comprising mainly primary care data. We included adult patients with newly diagnosed CLL between January 2000 and June 2012. Descriptive and trend analyses of CLL incidence and medical resource utilisation were performed. A total of 2576 patients with CLL met the eligibility criteria. At diagnosis, the majority of patients (71.7 %) were above 65 years of age. The European age-standardised CLL incidence rate in the CPRD was 6.2/100,000 (95 % confidence interval [CI] 6.0, 6.5/100,000) person-years. There was no statistically significant increase over time. The CLL patients had on average 74.6 general practitioner visits during a median follow-up of 3.3 years. Between 2000 and 2012, the average number of recorded hospitalisations and referrals per year corrected for duration of follow-up significantly (p < 0.001) increased by 8.1 % (95 % CI 6.8 %, 9.3 %) and 16.4 % (95 % CI 15.4 %, 17.3 %), respectively. Referrals and hospitalisations in the second year compared to the first year following the CLL diagnosis significantly decreased. CLL incidence rates in the CPRD were stable over the period from 2000 to 2012. Medical resource utilisation in UK primary care was well documented, but further research is needed to describe secondary and tertiary care medical resource utilisation e.g. chemotherapy administration, which is inadequately captured in the CPRD.

Impact of genetic variability and treatment-related factors on outcome in early breast cancer patients receiving (neo-) adjuvant chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide, and docetaxel.

To assess the impact of patient-related factors, including genetic variability in genes involved in the metabolism of chemotherapeutic agents, on breast cancer-specific survival (BCSS) and recurrence-free interval (RFI). We selected early breast cancer patients treated between 2000 and 2010 with 4-6 cycles of (neo-)adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) or 3 cycles FEC followed by 3 cycles docetaxel. Tumor stage/subtype; febrile neutropenia and patient-related factors such as selected single nucleotide polymorphisms and baseline laboratory parameters were evaluated. Multivariable Cox regression was performed. Of 991 patients with a mean follow-up of 5.2 years, 152 (15.3 %) patients relapsed and 63 (6.4 %) patients died. Advanced stage and more aggressive subtype were associated with poorer BCSS and RFI in multivariable analysis (p < 0.0001). Associations with worse BCSS in multivariable analysis were: homozygous carriers of the rs1057910 variant C-allele in CYP2C9 (hazard ratio [HR] 30.4; 95 % confidence interval [CI] 6.1-151.5; p < 0.001) and higher white blood cell count (WBC) (HR 1.2; 95 % CI 1.0-1.3; p = 0.014). The GT genotype of the ABCB1 variant rs2032582 was associated with better BCSS (HR 0.5; 95 % CI 0.3-0.9, p = 0.021). Following associations with worse RFI were observed: higher WBC (HR 1.1; 95 % CI 1.0-1.2; p = 0.026), homozygous carriers of the rs1057910 variant C-allele in CYP2C9 (HR 10.9; 95 % CI 2.5-47.9; p = 0.002), CT genotype of the CYBA variant rs4673 (HR 1.8; 95 % CI 1.2-2.7; p = 0.006), and G-allele homozygosity for the UGT2B7 variant rs3924194 (HR 3.4; 95 % CI 1.2-9.7, p = 0.023). Patient-related factors including genetic variability and baseline white blood cell count, impacted on outcome in early breast cancer.

First direct measurement of the 2H(α,γ)6Li cross section at big bang energies and the primordial lithium problem.

Recent observations of (6)Li in metal poor stars suggest a large production of this isotope during big bang nucleosynthesis (BBN). In standard BBN calculations, the (2)H(α,γ)(6)Li reaction dominates (6)Li production. This reaction has never been measured inside the BBN energy region because its cross section drops exponentially at low energy and because the electric dipole transition is strongly suppressed for the isoscalar particles (2)H and α at energies below the Coulomb barrier. Indirect measurements using the Coulomb dissociation of (6)Li only give upper limits owing to the dominance of nuclear breakup processes. Here, we report on the results of the first measurement of the (2)H(α,γ)(6)Li cross section at big bang energies. The experiment was performed deep underground at the LUNA 400 kV accelerator in Gran Sasso, Italy. The primordial (6)Li/(7)Li isotopic abundance ratio has been determined to be (1.5 ± 0.3) × 10(-5), from our experimental data and standard BBN theory. The much higher (6)Li/(7)Li values reported for halo stars will likely require a nonstandard physics explanation, as discussed in the literature.

Geographic disparities in access to cancer care: do patients in outlying areas talk about their access problems to their general practitioners and medical oncologists and how does that impact on the choice of chemotherapy?

Geographic disparities in access to cancer care have been reported for several countries. The distance between the place of residence and the cancer care centre can be one cause of these disparities. Solutions to surmount the barriers can be found if patients talk about this to their care professionals. We investigated whether patients in Valais talk with their physicians about difficulties to access cancer care. We interviewed five general practitioners and five medical oncologists in Valais with semi-structured interviews to identify difficulties patients are talking about. Medical oncologists were also interviewed on their habits to adapt chemotherapy to access problems of their patients. Cancer patients in Valais do talk about their access problems. Medical oncologists in Valais do take access problems into account when discussing therapeutic options with the patients and use the scope they have within their therapeutic options. In Valais the family of cancer patients play an important role in access to cancer care. Special offers are in place when social support is insufficient. Whether some socio-economic minorities do not use the solutions in place cannot be answered and should be investigated in further studies.

First direct measurement of the 17O(p,γ)18F reaction cross section at Gamow energies for classical novae.

Classical novae are important contributors to the abundances of key isotopes, such as the radioactive (18)F, whose observation by satellite missions could provide constraints on nucleosynthesis models in novae. The (17)O(p,γ)(18)F reaction plays a critical role in the synthesis of both oxygen and fluorine isotopes, but its reaction rate is not well determined because of the lack of experimental data at energies relevant to novae explosions. In this study, the reaction cross section has been measured directly for the first time in a wide energy range E(c.m.)~/= 200-370 keV appropriate to hydrogen burning in classical novae. In addition, the E(c.m.)=183 keV resonance strength, ωγ=1.67±0.12 µeV, has been measured with the highest precision to date. The uncertainty on the (17)O(p,γ)(18)F reaction rate has been reduced by a factor of 4, thus leading to firmer constraints on accurate models of novae nucleosynthesis.

Addition of cetuximab to first-line chemotherapy in patients with advanced non-small-cell lung cancer: a cost-utility analysis.

BACKGROUND: Adding cetuximab to standard chemotherapy results in a moderate increase of overall survival in patients with advanced non-small-cell lung cancer (NSCLC), but the cost-effectiveness is unknown. MATERIALS AND METHODS: A Markov model was constructed based on the results of the First-Line ErbituX in lung cancer randomized trial, adding cetuximab to cisplatin-vinorelbine first-line chemotherapy in patients with advanced NSCLC. The primary outcome was the incremental cost-effectiveness ratio (ICER) of adding cetuximab, expressed as cost per quality-adjusted life year (QALY) gained, and relative to a willingness-to-pay threshold of €60 000/QALY. The impact of cetuximab intermittent dosing schedules on the ICER was also evaluated. RESULTS: Adding cetuximab to standard chemotherapy leads to a gain of 0.07 QALYs per patient at an additional cost of €26 088. The ICER for adding cetuximab to chemotherapy was €376 205 per QALY gained. Intermittent cetuximab dosing schedules resulted in ICERs per QALY gained between €31 300 and €83 100, under the assumption of equal efficacy. CONCLUSIONS: From a health economic perspective, the addition of cetuximab to standard first-line chemotherapy in patients with epidermal growth factor receptor-expressing advanced NSCLC cannot be recommended to date, due to a high ICER compared with other health care interventions. Treatment schedules resulting in more favorable cost-utility ratios should be evaluated.

Potential health economic impact of intravenous iron supplementation to erythropoiesis-stimulating agent treatment in patients with cancer- or chemotherapy-induced anemia.

BACKGROUND: Intravenous (i.v.) iron supplementation significantly improves the response to erythropoiesis-stimulating agent (ESA)-based therapies in patients with cancer- or chemotherapy-induced anemia. The economic implications of adding i.v. iron to ESA treatment are less well investigated. Published randomized controlled trials do not provide sufficient data for a comprehensive cost-effectiveness analysis. METHODS: Preliminary cost calculations from the Swiss health care system perspective based on a meta-analysis and published results of eight randomized controlled trials without correction for decreased ESA need provide a conservative cost-effectiveness estimate. RESULTS: The additional total cost of i.v. iron supplementation ranged from EUR 417 to EUR 901 per patient depending on the evaluated iron-carbohydrate complex. Considering a 24% absolute increase in the proportion of ESA responders, the incremental cost-effectiveness ratios per additional responder are EUR 1,704-3,686. In routine practice, better values may be achieved due to ESA dose savings. CONCLUSION: Supplementation of ESAs with i.v. iron appears to be an economically viable treatment option in anemic cancer patients. Additional research on ESA dose savings and cost-effectiveness is required.

Trastuzumab beyond progression: a cost-utility analysis.

BACKGROUND: The continuation of trastuzumab beyond progression in combination with capecitabine as secondary chemotherapy for HER2-positive metastatic breast cancer (MBC) prolongs progression-free survival without a substantial increase in toxicity. PATIENTS AND METHODS: A Markov cohort simulation was used to follow the clinical course of typical patients with MBC. Information on response rates and major adverse effects was derived, and transition probabilities were estimated, based on the results of the Breast International Group 03-05 clinical trial. Direct costs were assessed from the perspective of the Swiss health care system. RESULTS: The addition of trastuzumab to capecitabine is estimated to cost on average an additional of €33,980 and to yield a gain of 0.35 quality-adjusted life years (QALYs), resulting in an incremental cost-effectiveness ratio of €98,329/QALYs gained. Probabilistic sensitivity analysis showed that the willingness-to-pay threshold of €60,000/QALY was reached in 12% of cases. CONCLUSION: The addition of trastuzumab to capecitabine in MBC patients is more expensive than what is typically regarded as cost-effective but falls within the value ranges found for established regimens in the treatment of MBC.

Cost-effectiveness of raltegravir in antiretroviral treatment-experienced HIV-1-infected patients in Switzerland.

OBJECTIVES: Raltegravir, a novel integrase inhibitor, has shown great efficacy in reducing HIV viral load among treatment-experienced patients. A cohort state-transition model was used to assess the long-term effect of raltegravir treatment on costs and quality-adjusted life expectancy from a Swiss perspective. METHODS: Patients were stratified into health states according to opportunistic infection status, HIV RNA level, and CD4 count, with each group assigned a treatment cost and utility (quality of life) score. Model inputs came from published studies, clinical trials, and database analyses. Results were used to calculate incremental cost-effectiveness ratio (ICER) of raltegravir use, expressed in Swiss francs (CHF) as incremental cost/quality-adjusted life-year (QALY) gained. Future costs and QALYs were discounted at 3% per year. RESULTS: Five years of raltegravir treatment increased discounted quality-adjusted life expectancy by 3.73 years over placebo, with additional discounted cost of CHF 170,347, resulting in an ICER of CHF 45,687/QALY. ICERs ranged from CHF 42,751 to 53,478/QALY for treatment duration of 3 and 10 years, respectively. Results were most sensitive to changes in raltegravir treatment duration, source of estimated quality of life weights, and raltegravir price. CONCLUSIONS: Adding raltegravir to optimized background therapy was a cost-effective strategy for treatment-experienced patients in Switzerland.

Reducing the burden of influenza-associated complications with antiviral therapy.

INTRODUCTION: Influenza imposes an annual burden on individuals, society, and healthcare systems. This burden is increased by the development of complications that are often more severe than the primary infection. Here, we examine the main complications associated with influenza and review the effectiveness of antiviral therapy in reducing the incidence of such events. MATERIAL AND METHODS: The content of this review is taken from the study of the authors' extensive collection of reference materials, examination of the bibliographical content of relevant papers, and the results of Medline searches. RESULTS: The most commonly encountered complications in adults are sinusitis, pharyngitis, bronchitis, and, particularly in the elderly, bacterial pneumonia. Such complications may exacerbate pulmonary complaints. Children are particularly prone to post-influenza croup and otitis media. Complications involving the central nervous system, heart, or skeletal muscle also occur in influenza patients. Influenza-associated complications impose sizeable healthcare costs in terms of outpatient contacts, hospitalizations, and antibiotic use. Vaccination is the primary prevention strategy for influenza and its complications, but has limitations. Neuraminidase inhibitors have demonstrated efficacy in reducing the incidence of influenza-associated complications in populations with different ages and risks. CONCLUSIONS: Influenza complications place a large burden on healthcare providers and society. Neuraminidase inhibitors can reduce the incidence of such complications, particularly in high-risk groups.