Cost-savings and potential cost-savings through the distribution of generic antiretroviral drugs within the statutory health insurance market of Germany between January 2017 and June 2019

Background: Recent patent losses for antiretroviral drugs (ARV) have led to the debate of cost-saving through the replacement of patented drugs with generic drugs. The split of recommended single-tablet regimens (STR) into their single substance partners is one of the considerations mentioned in said debate. Particularly, generic tenofovir disoproxil/emtricitabine (TDF/FTC) is expected to hold untapped cost-saving potential, which may curb increasing overall expenditures for combined antiretroviral therapy (cART) within the statutory health insurance (SHI) of Germany. Methods: Data of ARV reimbursed by the SHI were used to describe the trends of defined daily doses (DDD) as well as the revenue within the German ARV market. They were also used to determine the cost-savings of moving to generic drugs. The time period observed was between January 2017 and June 2019. The potential cost-savings were determined with following assumption in mind: the maximum possible use of generic ARV, including 1) the split of STR and replacing all substance partners with generic ones, and 2) replacing patented tenofovir alafenamide/emtricit- abine (TAF/FTC) with generic TDF/FTC. Results: Throughout the observation period, the DDD of generic ARV increased nearly five-fold while their revenue increased more than four-fold. Total cost-saving showed a sharp increase over the same period, with generic TDF/FTC accounting for a share of around 70%. The largest potential cost-saving could have been achieved through replacing patented TAF/FTC with generic TDF/FTC, peaking at nearly 10% of total revenue, but showing decreasing trends in general. Conclusion: The progressive distribution of generic ARV ensured increasing cost-savings, but consequently curbed the potential cost-savings. Unique price reductions of generic TDF/FTC have played a pivotal role for these effects. In any case, substituting with generic ARV should not fail to adhere to the treatment guidelines and continue to con- sider the medical requirements for the treatment.Peer Reviewe

In-vivo Raman spectroscopy: from basics to applications

For more than two decades, Raman spectroscopy has found widespread use in biological and medical applications. The instrumentation and the statistical evaluation procedures have matured, enabling the lengthy transition from ex-vivo demonstration to in-vivo examinations. This transition goes hand-in-hand with many technological developments and tightly bound requirements for a successful implementation in a clinical environment, which are often difficult to assess for novice scientists in the field. This review outlines the required instrumentation and instrumentation parameters, designs, and developments of fiber optic probes for the in-vivo applications in a clinical setting. It aims at providing an overview of contemporary technology and clinical trials and attempts to identify future developments necessary to bring the emerging technology to the clinical end users. A comprehensive overview of in-vivo applications of fiber optic Raman probes to characterize different tissue and disease types is also given

Magnetic microcalorimeter with paramagnetic temperature sensors and integrated dc-SQUID readout for high-resolution X-ray emission spectroscopy

We present two variants of a magnetic microcalorimeter with paramagnetic temperature sensors and integrated dc-SQUID readout for high-resolution X-ray emission spectroscopy. Each variant employs two overhanging gold absorbers with a sensitive area of 150$\mu$m x 150$\mu$m and a thickness of 3$\mu$m, thus providing a quantum efficiency of 98% for photons up to 5keV and 50% for photons up to 10keV. The first variant turned out to be fully operational, but, at the same time, to suffer from Joule power dissipation of the Josephson junction shunt resistors, athermal phonon loss, and slew rate limitations of the overall setup. Overall, it only achieved an energy resolution $\Delta E_\mathrm{FWHM} = 8.9eV$. In the second variant, we introduced an innovative `tetrapod absorber geometry' as well as a membrane-technique for protecting the temperature sensors against the power dissipation of the shunt resistors. By this, the second variant achieves an outstanding energy resolution of $\Delta E_\mathrm{FWHM} =1.25(18)eV$ and hence provides, to our knowledge, the present best energy resolving power $E/\Delta E_\mathrm{FWHM}$ among all existing energy-dispersive detectors for soft and tender X-rays.Comment: submitted to Applied Physics Letter

Multimodal nonlinear imaging of atherosclerotic plaques differentiation of triglyceride and cholesterol deposits

Cardiovascular diseases in general and atherothrombosis as the most common of its individual disease entities is the leading cause of death in the developed countries. Therefore, visualization and characterization of inner arterial plaque composition is of vital diagnostic interest, especially for the early recognition of vulnerable plaques. Established clinical techniques provide valuable morphological information but cannot deliver information about the chemical composition of individual plaques. Therefore, spectroscopic imaging techniques have recently drawn considerable attention. Based on the spectroscopic properties of the individual plaque components, as for instance different types of lipids, the composition of atherosclerotic plaques can be analyzed qualitatively as well as quantitatively. Here, we compare the feasibility of multimodal nonlinear imaging combining two-photon fluorescence (TPF), coherent anti-Stokes Raman scattering (CARS) and second-harmonic generation (SHG) microscopy to contrast composition and morphology of lipid deposits against the surrounding matrix of connective tissue with diffraction limited spatial resolution. In this contribution, the spatial distribution of major constituents of the arterial wall and atherosclerotic plaques like elastin, collagen, triglycerides and cholesterol can be simultaneously visualized by a combination of nonlinear imaging methods, providing a powerful label-free complement to standard histopathological methods with great potential for in vivo application

Systematic evaluation of particle loss during handling in the percutaneous transluminal angioplasty for eight different drug-coated balloons

Paclitaxel drug coated balloons (DCBs) should provide optimal drug transfer exclusively to the target tissue. The aim of this study was to evaluate the particle loss by handling during angioplasty. A robotic arm was developed for systematic and reproducible drug abrasion experiments. The contact force on eight different commercially available DCB types was gradually increased, and high-resolution microscopic images of the deflated and inflated balloons were recorded. Three types of DCBs were classified: no abrasion of the drug in both statuses (deflated and inflated), significant abrasion only in the inflated status, and significant abrasion in both statuses. Quantitative measurements via image processing confirmed the qualitative classification and showed changes of the drug area between 2.25 and 45.73% (13.28 ± 14.29%) in the deflated status, and between 1.66 and 40.41% (21.43 ± 16.48%) in the inflated status. The structures and compositions of the DCBs are different, some are significantly more susceptible to drug loss. Particle loss by handling during angioplasty leads to different paclitaxel doses in the target regions for same DCB types. Susceptibility to involuntary drug loss may cause side effects, such as varying effective paclitaxel doses, which may explain variations in studies regarding the therapeutic outcome

The impact of fat deterioration on formation of acrylamide in fried foods

The current study investigates to what extent the reaction products of thermal degradation directly influence acrylamide formation in French fries. The frying tests at 170 and 180 °C are carried out with rapeseed oil for 32 h with 128 frying cycles. Acrylamide content in French fries is determined by LC-MS/MS. Oxidative and thermal degradation is followed by measuring total polar compounds (TPC), di- and polymerized triacylglycerols (DPTG), monomer oxidized triacylglycerols (MONOX), p-anisidine value (AnV), mono and di-acyl-glycerols (MAG and DAG), acid value (AV), epoxy fatty acids, iodine value (IV), saponification value, and fatty acid composition. During frying, the nature and degradation level of the frying medium have a direct impact on acrylamide formation. It can be shown that the pH-dependent reaction is strongly inhibited at acid values above 0.5 mg KOH g−1 oil. Acidity measured as AV or FFA is mainly caused by oxidation, and less so by hydrolysis of triacylglycerols (TAG) as assumed up to now. Obviously, acid functional groups formed by oxidation of unsaturated fatty acids bound in TAG can act not only as catalyst for dimerization of TAG but also interact with asparagine as most important precursor for acrylamide formation so that no reaction with carbonyl groups for the formation of acrylamide is necessary. Practical applications: The same acidic functional groups that are known to catalyze the formation of dimeric TAG under frying conditions (160–190 °C, access of oxygen) in a nonradical mechanism apparently can also deactivate asparagine by protonization as a potential precursor for the formation of acrylamide. It is recommended not to reduce acidity of used frying oil by active filter aids below AV ≥ 0.5 as it helps to reduce acrylamide contamination of fried food

Robot-assisted pancreatic surgery—optimized operating procedures: set-up, port placement, surgical steps

Even in most complex surgical settings, recent advances in minimal-invasive technologies have made the application of robotic-assisted devices more viable. Due to ever increasing experience and expertise, many large international centers now offer robotic-assisted pancreatic surgery as a preferred alternative. In general however, pancreatic operations are still associated with high morbidity and mortality, while robotic-assisted techniques still require significant learning curves. As a prospective post-marketing trial, we have established optimized operating procedures at our clinic. This manuscript intends to publicize our standardized methodology, including pre-operative preparation, surgical set-up as well as the surgeons' step-by-step actions when using pancreatic-assisted robotic surgery. This manuscript is based on our institutional experience as a high-volume pancreas operating center. We introduce novel concepts that should standardize, facilitate and economize the surgical steps in all types of robotic-assisted pancreatic surgery. The "One Fits All" principle enables single port placement irrespective of the pancreatic procedure, while the "Reversed 6-to-6 Approach" offers an optimized manual for pancreatic surgeons using the robotic console. Novel and standardized surgical concepts could guide new centers to establish a robust, efficient and safe robotic-assisted pancreatic surgery program

A Data-Driven Approach for Baggage Handling Operations at Airports

Before each flight departs, baggage has to be loaded into containers, which are then forwarded to the airplane. Planning the loading process consists of setting the start times for the loading process and depletion of the baggage storage as well as assigning handling facilities and workers. Flight delays and uncertain arrival times of passengers at the check-in counters require plans that are adjusted dynamically every few minutes and, hence, an efficient planning procedure. We propose a model formulation and a solution procedure that utilize historical flight data to generate reliable plans in a rolling planning fashion, allowing problem parameters to be updated in each reoptimization. To increase the tractability of the problem, we employ a column generation–based heuristic in which new schedules and work profiles are generated in subproblems, which are solved as dynamic programs. In a computational study, we demonstrate the robust performance of the proposed procedure based on real-world data from a major European airport. The results show that (i) the procedure outperforms both a constructive heuristic that mimics human decision making and a meta heuristic (tabu search) and (ii) being able to dynamically (re)allocate baggage handlers leads to improved solutions with considerably fewer left bags

Robotic-assisted pancreatic surgery in the elderly patient: experiences from a high-volume centre

Background: Robotic-assisted pancreatic surgery (RPS) has fundamentally developed over the past few years. For subgroups, e.g. elderly patients, applicability and safety of RPS still needs to be defined. Given prognosticated demographic developments, we aim to assess the role of RPS based on preoperative, operative and postoperative parameters. Methods: We included 129 patients undergoing RPS at our institution between 2017 and 2020. Eleven patients required conversion to open surgery and were excluded from further analysis. We divided patients into two groups; >= 70 years old (Group 1; n = 32) and < 70 years old (Group 2; n = 86) at time of resection. Results: Most preoperative characteristics were similar in both groups. However, number of patients with previous abdominal surgery was significantly higher in patients >= 70 years old (78% vs 37%, p = 70 years old stayed significantly longer at ICU (1.8 vs 0.9 days; p = 0.037), length of hospital stay and postoperative morbidity were equivalent between the groups. Conclusion: RPS is safe and feasible in elderly patients and shows non-inferiority when compared with younger patients. However, prospectively collected data is needed to define the role of RPS in elderly patients accurately. Trial registration Clinical Trial Register: Deutschen Register Klinischer Studien (DRKS; German Clinical Trials Register). Clinical Registration Number: DRKS00017229 (retrospectively registered, Date of Registration: 2019/07/19, Date of First Enrollment: 2017/10/18)

It is not just a ‘trade‐off’: : indications for sink‐ and source‐limitation to vegetative and regenerative growth in an old‐growth beech forest

Summary Controls on tree growth are key issues in plant physiology. The hypothesis of our study was that the interannual variability of wood and fruit production are primarily controlled directly by weather conditions (sink limitation), while carbon assimilation (source limitation) plays a secondary role. We analyzed the interannual variability of weather conditions, gross primary productivity (GPP) and net primary productivity (NPP) of wood and fruits of an old‐growth, unmanaged Fagus sylvatica forest over 14 yr, including six mast years. In a multiple linear regression model, c . 71% of the annual variation in wood‐NPP could be explained by mean air temperature in May, precipitation from April to May (positive influence) and fruit‐NPP (negative influence). GPP of June to July solely explained c . 42% of the variation in wood‐NPP. Fruit‐NPP was positively related to summer precipitation 2 yr before ( R 2 = 0.85), and negatively to precipitation in May ( R 2 = 0.83) in the fruit years. GPP had no influence on fruit‐NPP. Our results suggest a complex system of sink and source limitations to tree growth driven by weather conditions and going beyond a simple carbon‐mediated ‘trade‐off’ between regenerative and vegetative growth