„Medizinische Notwendigkeit“: Herausforderungen eines unscharfen Begriffs

Definition of the problem

“Medical necessity” (MedN) is the central regulatory concept for decisions about which services are covered by German statutory health insurance. Despite its seeming objectivity and dependence on physicians’ expert judgment, the concept is by no means clearly defined.

Arguments

In this first of five planned papers on the conceptual analysis of MedN from the perspectives of philosophy and ethics of medicine, law, and (social) medicine, the focus lies on systemizing ongoing controversies.

Conclusion

Our goal is to come up with a so far missing foundation for detailed debates. We aim to clarify MedN’s conceptual structure, function, contextuality, and ambiguities as well as the fundamental limits of conceptual investigations for the normative questions at issue of regulating medical services.

     

Unique reduced graphene oxide as efficient anode material in Li ion battery

Unique reduced graphene oxide named solar reduced graphene oxide (SRGO) was found to be an excellent anode material in Li ion battery. SRGO exhibited first cycle discharge- and charge-capacities as high as 1480 and 880 mAh \(\hbox {g}^{-1}\), respectively. Moreover, the columbic efficiency was found to be >95% and the specific capacity retention even after 60 cycles was >500 mAh \(\hbox {g}^{-1}\).     

Revisiting the Roles of Filaggrin in Atopic Dermatitis

The discovery in 2006 that loss-of-function mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris and can predispose to atopic dermatitis (AD) galvanized the dermatology research community and shed new light on a skin protein that was first identified in 1981. However, although outstanding work has uncovered several key functions of filaggrin in epidermal homeostasis, a comprehensive understanding of how filaggrin deficiency contributes to AD is still incomplete, including details of the upstream factors that lead to the reduced amounts of filaggrin, regardless of genotype. In this review, we re-evaluate data focusing on the roles of filaggrin in the epidermis, as well as in AD. Filaggrin is important for alignment of keratin intermediate filaments, control of keratinocyte shape, and maintenance of epidermal texture via production of water-retaining molecules. Moreover, filaggrin deficiency leads to cellular abnormalities in keratinocytes and induces subtle epidermal barrier impairment that is sufficient enough to facilitate the ingress of certain exogenous molecules into the epidermis. However, although FLG null mutations regulate skin moisture in non-lesional AD skin, filaggrin deficiency per se does not lead to the neutralization of skin surface pH or to excessive transepidermal water loss in atopic skin. Separating facts from chaff regarding the functions of filaggrin in the epidermis is necessary for the design efficacious therapies to treat dry and atopic skin.     

Dynamic programming algorithms for multi-stage safety stock optimization

The task of multi-stage safety stock optimization is very complex. Therefore, simplifying models with specific assumptions are considered. In this paper, the inventory system is controlled by a base-stock policy where each stockpoint of the inventory system follows a periodically reviewed order-up-to policy. End item demands are assumed to be normally distributed. To reduce the occurrences or size and duration of internal and external stockouts, appropriate service level constraints are specified for all items. Applying such a control policy within systems of serial, convergent or divergent structure, solution properties hold which reduce the solution set to a limited number of cut-levels. Dynamic programming allows to evaluate the relevant alternatives with little computational effort. For the serial system, both a forward and a backward recursion with different types of service levels are presented and extended to a backward algorithm for divergent and a forward algorithm for convergent systems. Bounds for the complexity of the algorithms are discussed and numerical examples are presented to demonstrate differences in size and allocation of safety stocks according to the prespecified type of service level.     

Quasi‐Continuous Wave Near‐Infrared Excitation of Upconversion Nanoparticles for Optogenetic Manipulation of C. elegans

Optogenetics is an emerging powerful tool to investigate workings of the nervous system. However, the use of low tissue penetrating visible light limits its therapeutic potential. Employing deep penetrating near‐infrared (NIR) light for optogenetics would be beneficial but it cannot be used directly. This issue can be tackled with upconversion nanoparticles (UCNs) acting as nanotransducers emitting at shorter wavelengths extending to the UV range upon NIR light excitation. Although attractive, implementation of such NIR‐optogenetics is hindered by the low UCN emission intensity that necessitates high NIR excitation intensities, resulting in overheating issues. A novel quasi‐continuous wave (quasi‐CW) excitation approach is developed that significantly enhances multiphoton emissions from UCNs, and for the first time NIR light‐triggered optogenetic manipulations are implemented in vitro and in C. elegans. The approach developed here enables the activation of channelrhodopsin‐2 with a significantly lower excitation power and UCN concentration along with negligible phototoxicity as seen with CW excitation, paving the way for therapeutic optogenetics.     

Toward a molecular design of porous carbon materials

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A Database and Evaluation Methodology for Optical Flow

The quantitative evaluation of optical flow algorithms by Barron et al. (1994) led to significant advances in performance. The challenges for optical flow algorithms today go beyond the datasets and evaluation methods proposed in that paper. Instead, they center on problems associated with complex natural scenes, including nonrigid motion, real sensor noise, and motion discontinuities. We propose a new set of benchmarks and evaluation methods for the next generation of optical flow algorithms. To that end, we contribute four types of data to test different aspects of optical flow algorithms: (1) sequences with nonrigid motion where the ground-truth flow is determined by tracking hidden fluorescent texture, (2) realistic synthetic sequences, (3) high frame-rate video used to study interpolation error, and (4) modified stereo sequences of static scenes. In addition to the average angular error used by Barron et al., we compute the absolute flow endpoint error, measures for frame interpolation error, improved statistics, and results at motion discontinuities and in textureless regions. In October 2007, we published the performance of several well-known methods on a preliminary version of our data to establish the current state of the art. We also made the data freely available on the web at . Subsequently a number of researchers have uploaded their results to our website and published papers using the data. A significant improvement in performance has already been achieved. In this paper we analyze the results obtained to date and draw a large number of conclusions from them.     

Sphingolipid Catabolism and Glycerophospholipid Levels Are Altered in Erythrocytes and Plasma from Multiple Sclerosis Patients

Multiple sclerosis (MS) is an autoimmune, inflammatory, degenerative disease of the central nervous system. Changes in lipid metabolism have been suggested to play important roles in MS pathophysiology and progression. In this work we analyzed the lipid composition and sphingolipid-catabolizing enzymes in erythrocytes and plasma from MS patients and healthy controls. We observed reduction of sphingomyelin (SM) and elevation of its products—ceramide (CER) and shingosine (SPH). These changes were supported by the detected up-regulation of the activity of acid sphingomyelinase (ASM) in MS plasma and alkaline ceramidase (ALCER) in erythrocytes from MS patients. In addition, Western blot analysis showed elevated expression of ASM, but not of ALCER. We also compared the ratios between saturated (SAT), unsaturated (UNSAT) and polyunsaturated fatty acids and suggest, based on the significant differences observed for this ratio, that the UNSAT/SAT values could serve as a marker distinguishing erythrocytes and plasma of MS from controls. In conclusion, the application of lipid analysis in the medical practice would contribute to definition of more precise diagnosis, analysis of disease progression, and evaluation of therapeutic strategies. Based on the molecular changes of blood lipids in neurodegenerative pathologies, including MS, clinical lipidomic analytical approaches could become a promising contemporary tool for personalized medicine.     

Preclinical Assessment of the Combination of PSMA-Targeting Radionuclide Therapy with PARP Inhibitors for Prostate Cancer Treatment

Prostate specific membrane antigen targeted radionuclide therapy (PSMA-TRT) is a promising novel treatment for prostate cancer (PCa) patients. However, PSMA-TRT cannot be used for curative intent yet, thus additional research on how to improve the therapeutic efficacy is warranted. A potential way of achieving this, is combining TRT with poly ADP-ribosylation inhibitors (PARPi), which has shown promising results for TRT of neuroendocrine tumor cells. Currently, several clinical trials have been initiated for this combination for PCa, however so far, no evidence of synergism is available for PCa. Therefore, we evaluated the combination of PSMA-TRT with three classes of PARPi in preclinical PCa models. In vitro viability and survival assays were performed using PSMA-expressing PCa cell lines PC3-PIP and LNCaP to assess the effect of increasing concentrations of PARPi veliparib, olaparib or talazoparib in combination with PSMA-TRT compared to single PARPi treatment. Next, DNA damage analyses were performed by quantifying the number of DNA breaks by immunofluorescent stainings. Lastly, the potential of the combination treatments was studied in vivo in mice bearing PC3-PIP xenografts. Our results show that combining PSMA-TRT with PARPi did not synergistically affect the in vitro clonogenic survival or cell viability. DNA-damage analysis revealed only a significant increase in DNA breaks when combining PSMA-TRT with veliparib and not in the other combination treatments. Moreover, PSMA-TRT with PARPi treatment did not improve tumor control compared to PSMA-TRT monotherapy. Overall, the data presented do not support the assumption that combining PSMA-TRT with PARPi leads to a synergistic antitumor effect in PCa. These results underline that extensive preclinical research using various PCa models is imperative to validate the applicability of the combination strategy for PCa, as it is for other cancer types.     

Dynamic Hotlinks

Consider a directed rooted tree T=(V,E) representing a collection V of n web pages connected via a set E of links all reachable from a source home page, represented by the root of T. Each web page i carries a weight w _i representative of the frequency with which it is visited. By adding hotlinks, shortcuts from a node to one of its descendants, we are interested in minimizing the expected number of steps needed to visit pages from the home page. We give the first linear time algorithm for assigning hotlinks so that the number of steps to access a page i from the root of the tree reaches the entropy bound, i.e. is at most O(log (W/w _i )) where W=∑ _i∈T w _i . The best previously known algorithm for this task runs in time O(n ²). We also give the first efficient data structure for maintaining hotlinks when nodes are added, deleted or their weights modified, in amortized time O(log (W/w _i )) per update. The data structure can be made adaptive, i.e. reaches the entropy bound in the amortized sense without knowing the weights w _i in advance.