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Background: Strokes cause an estimated annual health care burden of 170 billion euros across Europe. Atrial fibrillation is one of the major risk factors for stroke and increases the individual risk 4.2-fold. But prevention with anticoagulants may reduce this risk by 70%. Screening methods are employed to detect previously undetected atrial fibrillation. Screening studies in various European countries show a high degree of undetected atrial fibrillation. This study aims to assess the cost-effectiveness of systematic screening with a smartphone application, named Preventicus Heartbeats. It is a hands-on screening tool for use on smartphone to diagnose AF with high sensitivity and specificity., Methods: A previously published model for calculating screening cost-effectiveness was extended to 6 European countries covering a wide range in terms of treatment costs and epidemiologic parameters., Results: The use of screening lowers the cost per case in countries with comparatively high levels of health care costs (Switzerland: -€75; UK: -€7). Moderate higher costs per case were observed in 4 countries (Greece: €6; Netherlands: €15). Low levels of health care costs result in less or no potential for further cost reduction (Poland: €20; Serbia: €33). In all countries considered, the model showed an increase in effectiveness measures both in the number of strokes avoided and the quality adjusted life years. The number of strokes avoided per 1000 participants ranged from 2.52 (Switzerland) to 4.44 (Poland). Quality-adjusted life-years per case gained from screening ranged from 0.0105 (Switzerland) to 0.0187 (Poland). The screening procedure dominated in two countries (Switzerland, UK). For the remaining countries, the incremental cost effectiveness ratio ranged from €489/QALY (Greece) to €2548/QALY (Serbia)., Conclusion: The model results showed a strong dependence of the results on the country-specific costs for stroke treatment. The use of the investigated screening method is close to cost-neutral or cost-reducing in the Western European countries and Greece. In countries with low price levels, higher cost increases due to AF screening are to be expected. Lower costs of anticoagulation, which are expected due to the upcoming patent expiry of direct anticoagulants, have a positive effect on the cost result., (© 2022. The Author(s).)

Introduction: Until recently, adjuvant treatment options for higher stage resectable cutaneous melanoma were limited. Two studies with a similar set-up, published 2017, led to registration of targeted therapy for BRAF-mutated melanoma with dabrafenib and trametinib as well as of the immunotherapy with nivolumab irrespective of BRAF-mutation status. Both options have been positively assessed in Germany since 2019 for the adjuvant treatment of BRAF-V600 mutated melanoma. This study evaluates the cost-effectiveness of both treatment alternatives (dabrafenib/trametinib and nivolumab) against observation as a comparative therapy from the perspective of German statutory health funds., Methods: Partitioned survival analysis based on published survival curves for the investigated treatment options was used for a cohort model for the health states relapse free survival, progression, and death. The partitioned survival analysis approach was based on the survival curves published for the key studies Combi AD and Checkmate-238. The modelling was performed for the remaining lifetime for a cohort with starting age of 50 years. For extrapolation of the survival curves, convergence to general population mortality rates was assumed in the long term. Within the progression state, a Markov model uses three levels of progressions (locoregional, distant metastases with 1st and 2nd line treatment). Lifetime treatment costs were calculated using the German statutory health fund reimbursement scheme. Quality adjusted life years (QALYs) associated to the health states were adopted from previously published utilities based on the Combi AD study., Results: The treatment with dabrafenib/trametinib yielded an increase in quality adjusted life years of 2.28 QALY at an incremental lifetime cost of 86.1 T€. The incremental cost effectiveness ratio of dabrafenib/trametinib and nivolumab was comparable with 37.8 T€/QALY and 30.0 T€/QALY, respectively. Several sensitivity analyses proved the result to be insensitive. General model parameters like discount rate and length of the time horizon had stronger influence. For nivolumab, the model showed lower discounted lifetime costs (118.1 T€) compared to dabrafenib/trametinib [155.1 T€], associated with a lower gain in QALYs (1.64 years) compared to observation., Conclusion: Both dabrafenib/trametinib and nivolumab turned out to be cost effective within internationally accepted Incremental Cost Effectiveness Ratio (ICER) thresholds with comparable cost effectiveness ratios., (© 2022. The Author(s).)

Compared to the medical, economic and social implications of COVID-19 vaccinations, little attention has been paid to the ecological balance to date. This study is an attempt to estimate the environmental impact of two mRNA vaccines in terms of CO 2 equivalents with respect to their different freezing strategies and supply chain organization. Although it is impossible to accurately calculate the actual environmental impact of the new biochemical synthesis technology, it becomes apparent that transport accounts for up to 99% of the total carbon footprint. The emissions for air freight, road transportation and last-mile delivery are nearly as 19 times the emissions generated from ultra-deep freeze technologies, the production of dry ice, glass and medical polymers for packaging. The carbon footprint of a single mRNA vaccine dose injected into a patient is about 0.01 to 0.2 kg CO 2 equivalents, depending on the cooling technology and the logistic routes to the vaccination sites in Germany.

Background: With atrial fibrillation (AF) the risk of stroke is 4.2-fold increased to a comparable population without AF. This risk decreases by up to 70% if AF is detected early enough and effective stroke preventive measures are taken as recommended by international guidelines. Long-term studies found large number of subjects with undiagnosed AF. Preventicus Heartbeats" is a hands-on screening tool for use on smartphone to diagnose AF with high sensitivity and specificity. The aim of this study is to research the cost-effectiveness of systematic screening for AF with this smartphone application., Method: Employing a Markov model we analysed the cost-effectiveness of the "Preventicus Heartbeats" screening for Germany, i.e. from the perspective of German statutory sick funds., Results: For a cohort of 10,000 insured 75-year-old the use of the diagnostic app could avoid 60 strokes in the remaining lifetime thereof 32 strokes in the next four years. Former models have applied similar cohorts. The same cohort showed an increase in quality-adjusted life years (QALY) in the remaining lifetime of 165 QALYs in the scenario with screening versus. without screening and a decrease in discounted lifetime costs (including risk compensation effects) of €129 per participant (€148 for male, €114 for female participants)., Conclusions: The modelling demonstrates the health benefits and economic effects of an implementation of a systematic screening on AF with "Preventicus Heartbeats", given the perspective of the German payer, the statutory health care system.

Yields of atomic iodine I q+ (q≥ 2) fragments resulting from photoexcitation and photoionisation of the target cations CH x I + (x = 0-3) have been measured in the photon-energy range 610 eV to 670 eV, which comprises the threshold for iodine 3d ionisation. The measured ion-yield spectra show two strong and broad resonance features due to the excitation of the 3d 3/2,5/2 electrons into εf states similar to atomic iodine. In the 3d pre-edge range, electrons are excited into molecular orbitals consisting of iodine, carbon, and hydrogen atomic orbitals. These transitions have been identified by comparison with literature data and by simulations using time-dependent density functional theory (TDDFT) with the KMLYP functional. The ion-yield spectrum for CH 3 I + resembles the spectrum of IH + [Klumpp et al., Phys. Rev. A, 2018, 97, 033401] because the highest occupied molecular orbitals (HOMO) of the H and CH 3 fragments both contain a single vacancy, only. For the molecular cations with higher number of vacancies in the valence molecular orbitals CH x I + (x = 0-2), a stronger hybridisation of the molecular orbitals occurs between the organic fragment and the iodine resulting in a change of bonding from a single σ bond in CH 3 I + to a triple bond including two π orbitals in CI + . This is reflected in the resonance energies of the observed absorption lines below the iodine 3d excitation threshold.

Ion yields following X-ray absorption of the cationic series NH y + (y = 0-3) were measured to identify the characteristic absorption resonances in the energy range of the atomic nitrogen K-edge. Significant changes in the position of the absorption resonances were observed depending on the number of hydrogen atoms bound to the central nitrogen atom. Configuration interaction (CI) calculations were performed to obtain line assignments in the frame of molecular group theory. To validate the calculations, our assignment for the atomic cation N + , measured as a reference, was compared with published theoretical and experimental data.

Fatigue is one of the most common symptoms in multiple sclerosis (MS), with a major impact on patients' quality of life. Currently, treatment proceeds by trial and error with limited success, probably due to the presence of multiple different underlying mechanisms. Recent neuroscientific advances offer the potential to develop tools for differentiating these mechanisms in individual patients and ultimately provide a principled basis for treatment selection. However, development of these tools for differential diagnosis will require guidance by pathophysiological and cognitive theories that propose mechanisms which can be assessed in individual patients. This article provides an overview of contemporary pathophysiological theories of fatigue in MS and discusses how the mechanisms they propose may become measurable with emerging technologies and thus lay a foundation for future personalised treatments., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Postoperative, new-onset atrial fibrillation (POAF) is one of the most common complications after cardiosurgical procedures. Vernakalant has been reported to be effective in the conversion of POAF. The aim of this study was to evaluate the efficacy and safety of vernakalant for atrial fibrillation after cardiac operations, and to investigate predictors for the success of vernakalant treatment. Patients and Methods: Post-cardiac surgery patients with new-onset of atrial fibrillation (AF) were consecutively enrolled in this study. Demographic data as well as intraoperative and postoperative parameters were analyzed. Vernakalant administration was primarily started 5.5 hours after new-onset POAF: 3 mg/kg intravenously over 10 min, and in case of non-conversion, a second dose of 2 mg/kg intravenously over 10 min. Results: 129 consecutive patients (70.2 ± 9.1 years) were included: 61 patients with coronary artery bypass graft (CABG) surgery, 49 patients with isolated valve procedures, and 19 patients with combined procedures (CABG and valve). Conversion in sinus rhythm was achieved after the first vernakalant dose in 57 patients (44%), and after the second dose in 41 patients (32%). The mean time to conversion was 13.7 ± 14.1 min. The patients receiving valve procedures depicted a significantly lower conversion rate. The following variables lowered conversion rate: no preoperative beta blocker, postoperative troponin levels >500 ng/L, and systolic blood pressure >140 mmHg. At the first follow-up, 92% of the converted patients showed sinus rhythm, while 80% of the non-responders showed sinus rhythm (P < .01). Conclusions: The POAF was effectively converted by vernakalant. The conversion rate of POAF after valve surgery was lower when compared to isolated CABG.

While there is scientific consensus that global and local mean sea level (GMSL and LMSL) has risen since the late nineteenth century, the relative contribution of natural and anthropogenic forcing remains unclear. Here we provide a probabilistic upper range of long-term persistent natural GMSL/LMSL variability (P=0.99), which in turn, determines the minimum/maximum anthropogenic contribution since 1900. To account for different spectral characteristics of various contributing processes, we separate LMSL into two components: a slowly varying volumetric component and a more rapidly changing atmospheric component. We find that the persistence of slow natural volumetric changes is underestimated in records where transient atmospheric processes dominate the spectrum. This leads to a local underestimation of possible natural trends of up to ∼1 mm per year erroneously enhancing the significance of anthropogenic footprints. The GMSL, however, remains unaffected by such biases. On the basis of a model assessment of the separate components, we conclude that it is virtually certain (P=0.99) that at least 45% of the observed increase in GMSL is of anthropogenic origin.

Objectives: Transfusion of allogeneic blood is still common in orthopedic surgery. This analysis evaluates from the perspective of a German hospital the potential cost savings of Epoetin alfa (EPO) compared to predonated autologous blood transfusions or to a nobloodconservationstrategy (allogeneic blood transfusion strategy)during elective hip and knee replacement surgery., Methods: Individual patients (N = 50,000) were simulated based on data from controlled trials, the German DRG institute (InEK) and various publications and entered into a stochastic model (Monte-Carlo) of three treatment arms: EPO, preoperative autologous donation and nobloodconservationstrategy. All three strategies lead to a different risk for an allogeneic blood transfusion. The model focused on the costs and events of the three different procedures. The costs were obtained from clinical trial databases, the German DRG system, patient records and medical publications: transfusion (allogeneic red blood cells: €320/unit and autologous red blood cells: €250/unit), pneumonia treatment (€5,000), and length of stay (€300/day). Probabilistic sensitivity analyses were performed to determine which factors had an influence on the model's clinical and cost outcomes., Results: At acquisition costs of €200/40,000 IU EPO is cost saving compared to autologous blood donation, and cost-effective compared to a nobloodconservationstrategy. The results were most sensitive to the cost of EPO, blood units and hospital days., Conclusions: EPO might become an attractive blood conservation strategy for anemic patients at reasonable costs due to the reduction in allogeneic blood transfusions, in the modeled incidence of transfusion-associated pneumonia andthe prolongedlength of stay.

Aims: Myocardial infarction networks have been shown to improve guideline adherent therapy and outcomes in patients presenting with acute ST-elevation myocardial infarction (STEMI). Our objective was to assess the short term cost effectiveness of a network structure., Methods and Results: Outcome data and reimbursement data for the index hospital stay were gathered in consecutive patients with acute STEMI (n = 536) admitted to any of the hospitals in a 350.000 inhabitant rural network area during the years 2002 (n = 185), 2005 (n = 163) and 2008 (n = 188). Network structure was established between 2002 and 2005 aiming for identical treatment of all acute STEMI patients during 24 h/7d a week with primary angioplasty. Patient baseline characteristics in the different years were quite comparable. From 2002 to 2005 regional hospital mortality in STEMI patients decreased from 16% to 9%. Lower mortality under network conditions was confirmed in 2008. Reimbursement data of different years were standardized to exclude effects not induced by the network. The mean initial costs per saved live during the index stay were €7727 with a 95%-confidence interval of €-3.500 to €36.700 (referenced to the German reimbursement in 2005)., Conclusion: The short term cost effectiveness of a myocardial infarction network organisation is within well accepted boundaries under conditions of the German reimbursement system.

Life tables used in life insurance determine the age of death distribution only at integer ages. Therefore, actuaries make fractional age assumptions to interpolate between integer age values when they have to value payments that are not restricted to integer ages. Traditional fractional age assumptions as well as the fractional independence assumption are easy to apply but result in a non-intuitive overall shape of the force of mortality. Other approaches proposed either require expensive optimization procedures or produce many discontinuities. We suggest a new, computationally inexpensive algorithm to select the parameters within the LFM-family introduced by Jones and Mereu (Insur Math Econ 27:261-276, 2000). In contrast to previously suggested methods, our algorithm enforces a monotone force of mortality between integer ages if the mortality rates are monotone and keeps the number of discontinuities small.

Extracts from Butcher's broom rhizome (Ruscus aculeatus) have been widely used in the oral treatment of lower leg edema in patients with chronic venous insufficiency. The aim of the present multi-center, double-blind, randomized, placebo-controlled trial was to confirm the efficacy and safety of a ruscus extract (Fagorutin Ruscus Kapseln) according to the latest scientific standards. 166 women suffering from chronic venous insufficiency (Widmer grade I and II, CEAP (Clinical signs, Etiological classification, Anatomic distribution, Pathophysiology) 3-4) were included. The data of 148 patients (30-89 years, 150-182 cm height, 49-97 kg body weight) with a mean disease duration of 14.6 years in the ruscus extract group and 15.1 years in the placebo group were eligible for the intent-to-treat-analysis. The primary parameter was the area under baseline of the leg volume changes over 12 weeks (AUB0-12). Secondary parameters were the changes in circumference of the lower leg and the ankle, changes in subjective symptoms and quality of life, the overall efficacy and tolerability and safety parameters. The study was carried out according to the guidelines for testing drugs for chronic venous insufficiency. There were significant differences between the treatment groups ruscus and placebo for the AUB0-12 (-827 ml x day), for the change of leg volume after 8 and 12 weeks of treatment (-16.5 ml and -20.5 ml), for changes in ankle and leg circumferences after 8 and 12 weeks of treatment, and for the changes in subjective symptoms, heavy tired legs and sensation of tension (week 12). For the changes in the symptoms heavy lower legs, sensation of tension, and tingling sensation a significant positive correlation with the changes in leg volume was shown. Overall assessment of efficacy was significantly better for ruscus extract compared to placebo. Overall tolerability for both treatments was assessed as good and very good. Of all 48 adverse events occurring in both treatment groups, 22 were reported in the ruscus group, one of them was considered to be related to the study medication (unlikely). Considering the study duration of three months it is concluded, that ruscus extract, in the recommended daily dosage according to the German monograph, is a safe and effective treatment for patients suffering from chronic venous insufficiency.