MODELING THE MORTALITY TREND UNDER MODERN SOLVENCY REGIMES

Stochastic modeling of mortality/longevity risks is necessary for internal models of (re)insurers under the new solvency regimes, such as Solvency II and the Swiss Solvency Test. In this paper, we propose a mortality model which fulfills all requirements imposed by these regimes. We show how the model can be calibrated and applied to the simultaneous modeling of both mortality and longevity risk for several populations. The main contribution of this paper is a stochastic trend component which explicitly models changes in the long-term mortality trend assumption over time. This allows to quantify mortality and longevity risk over the one-year time horizon prescribed by the solvency regimes without relying on nested simulations. We illustrate the practical ability of our model by calculating solvency capital requirements for some example portfolios, and we compare these capital requirements with those from the Solvency II standard formul

Introducing a unique animal ID and digital life history museum for wildlife metadata

Funding: C.R. acknowledges funding from the Gordon and Betty Moore Foundation (GBMF9881) and the National Geographic Society (NGS-82515R-20). G.B., R.K., S.C.D. and D.E.-S. acknowledge funding from NASA. A.S. and F.I. acknowledge support from the European Commission through the Horizon 2020 Marie Skłodowska-Curie Actions Individual Fellowships (grant no. 101027534 and no. 101107666, respectively). S.C.D. acknowledges funding from NASA Ecological Forecasting Program Grant 80NSSC21K1182. A.M.M.S. was supported by an ARC DP DP210103091. This project is funded in part by the Gordon and Betty Moore Foundation through Grant GBMF10539 to M.W., as well as the Academy for the Protection of Zoo Animals and Wildlife e.V., Germany.1. Over the past five decades, a large number of wild animals have been individually identified by various observation systems and/or temporary tracking methods, providing unparalleled insights into their lives over both time and space. However, so far there is no comprehensive record of uniquely individually identified animals nor where their data and metadata are stored, for example photos, physiological and genetic samples, disease screens, information on social relationships. 2. Databases currently do not offer unique identifiers for living, individual wild animals, similar to the permanent ID labelling for deceased museum specimens. 3. To address this problem, we introduce two new concepts: (1) a globally unique animal ID (UAID) available to define uniquely and individually identified animals archived in any database, including metadata archived at the time of publication; and (2) the digital ‘home’ for UAIDs, the Movebank Life History Museum (MoMu), storing and linking metadata, media, communications and other files associated with animals individually identified in the wild. MoMu will ensure that metadata are available for future generations, allowing permanent linkages to information in other databases. 4. MoMu allows researchers to collect and store photos, behavioural records, genome data and/or resightings of UAIDed animals, encompassing information not easily included in structured datasets supported by existing databases. Metadata is uploaded through the Animal Tracker app, the MoMu website, by email from registered users or through an Application Programming Interface (API) from any database. Initially, records can be stored in a temporary folder similar to a field drawer, as naturalists routinely do. Later, researchers and specialists can curate these materials for individual animals, manage the secure sharing of sensitive information and, where appropriate, publish individual life histories with DOIs. The storage of such synthesized lifetime stories of wild animals under a UAID (unique identifier or ‘animal passport’) will support basic science, conservation efforts and public participation.Peer reviewe

Precipitation with polyethylene glycol followed by washing and pelleting by ultracentrifugation enriches extracellular vesicles from tissue culture supernatants in small and large scales

Extracellular vesicles (EVs) provide a complex means of intercellular signalling between cells at local and distant sites, both within and between different organs. According to their cell-type specific signatures, EVs can function as a novel class of biomarkers for a variety of diseases, and can be used as drug-delivery vehicles. Furthermore, EVs from certain cell types exert beneficial effects in regenerative medicine and for immune modulation. Several techniques are available to harvest EVs from various body fluids or cell culture supernatants. Classically, differential centrifugation, density gradient centrifugation, size-exclusion chromatography and immunocapturing-based methods are used to harvest EVs from EV-containing liquids. Owing to limitations in the scalability of any of these methods, we designed and optimised a polyethylene glycol (PEG)based precipitation method to enrich EVs from cell culture supernatants. We demonstrate the reproducibility and scalability of this method and compared its efficacy with more classical EV-harvesting methods. We show that washing of the PEG pellet and the re-precipitation by ultracentrifugation remove a huge proportion of PEG co-precipitated molecules such as bovine serum albumine (BSA). However, supported by the results of the size exclusion chromatography, which revealed a higher purity in terms of particles per milligram protein of the obtained EV samples, PEG-prepared EV samples most likely still contain a certain percentage of other non-EV associated molecules. Since PEG-enriched EVs revealed the same therapeutic activity in an ischemic stroke model than corresponding cells, it is unlikely that such co-purified molecules negatively affect the functional properties of obtained EV samples. In summary, maybe not being the purification method of choice if molecular profiling of pure EV samples is intended, the optimised PEG protocol is a scalable and reproducible method, which can easily be adopted by laboratories equipped with an ultracentrifuge to enrich for functional active EVs

Time travelling with Triticum: An Ecotron experiment to study the wheat of the future

2. Zero hunger3. Good health and well-being12. Responsible consumption and production13. Climate action15. Life on land17. Partnerships for the goal

Real‐world outcomes using PD‐1 antibodies and BRAF + MEK inhibitors for adjuvant melanoma treatment from 39 skin cancer centers in Germany, Austria and Switzerland

Abstract Background Programmed death‐1 (PD‐1) antibodies and BRAF + MEK inhibitors are widely used for adjuvant therapy of fully resected high‐risk melanoma. Little is known about treatment efficacy outside of phase III trials. This real‐world study reports on clinical outcomes of modern adjuvant melanoma treatment in specialized skin cancer centers in Germany, Austria and Switzerland. Methods Multicenter, retrospective study investigating stage III–IV melanoma patients receiving adjuvant nivolumab (NIV), pembrolizumab (PEM) or dabrafenib + trametinib (D + T) between 1/2017 and 10/2021. The primary endpoint was 12‐month recurrence‐free survival (RFS). Further analyses included descriptive and correlative statistics, and a multivariate linear‐regression machine learning model to assess the risk of early melanoma recurrence. Results In total, 1198 patients from 39 skin cancer centers from Germany, Austria and Switzerland were analysed. The vast majority received anti PD‐1 therapies (n = 1003). Twelve‐month RFS for anti PD‐1 and BRAF + MEK inhibitor‐treated patients were 78.1% and 86.5%, respectively (hazard ratio [HR] 1.998 [95% CI 1.335–2.991]; p = 0.001). There was no statistically significant difference in overall survival (OS) in anti PD‐1 (95.8%) and BRAF + MEK inhibitor (96.9%) treated patients (p > 0.05) during the median follow‐up of 17 months. Data indicates that anti PD‐1 treated patients who develop immune‐related adverse events (irAEs) have lower recurrence rates compared to patients with no irAEs (HR 0.578 [95% CI 0.443–0.754], p = 0.001). BRAF mutation status did not affect overall efficacy of anti PD‐1 treatment (p > 0.05). In both, anti PD‐1 and BRAF + MEK inhibitor treated cohorts, data did not show any difference in 12‐month RFS and 12‐month OS comparing patients receiving total lymph node dissection (TLND) versus sentinel lymph node biopsy only (p > 0.05). The recurrence prediction model reached high specificity but only low sensitivity with an AUC = 0.65. No new safety signals were detected. Overall, recorded numbers and severity of adverse events were lower than reported in pivotal phase III trials. Conclusions Despite recent advances in adjuvant melanoma treatment, early recurrence remains a significant clinical challenge. This study shows that TLND does not reduce the risk of early melanoma recurrence and should only be considered in selected patients. Data further highlight that variables collected during clinical routine are unlikely to allow for a clinically relevant prediction of individual recurrence risk

Tränenflüssigkeit als mögliche Quelle für Biomarker bei Patienten mit einem idiopathischem Parkinson-Syndrom

Idiopathic Parkinson's disease is the second most common neurodegenerative disorder worldwide with a growing prevalence in the continuously aging population. Until today, the diagnosis of Parkinson's disease is mainly based on the evaluation of distinctive clinical features and the differentiation from atypical parkinsonian syndromes and Parkinson's disease mimics. Despite remarkable developments in the field of diagnostics, the evaluation of Parkinson's disease patients can be challenging, particularly in oligosymptomatic early stages when distinctive clinical features are not that obvious. Therefore, biomarkers could contribute to an improved diagnostic accuracy. Tear fluid is an easily accessible body fluid reflecting pathophysiological changes in systemic and ocular diseases and is already used as a biomarker source for several ophthalmological disorders. Here, we analyzed the tear fluid of patients with Parkinson's disease and age-matched controls to describe disease-related changes in tear fluid and identify putative biomarkers for the diagnosis of Parkinson's disease. Therefore, unstimulated tear fluid samples of a pilot cohort with 36 Parkinson's disease patients and 18 controls were collected via Schirmer tear test strips and then analyzed via a Bottom-up liquid chromatography electrospray ionization tandem mass spectrometry workflow, followed by functional analysis encompassing protein-protein interaction as well as cellular component and pathway analysis. This mass spectrometric analysis lead to the identification of 571 tear proteins, whereby 31 proteins were exclusively detected in the Parkinson's disease group and 7 only in the control group. Whereas 21 proteins were significantly increased in the Parkinson's disease versus control group, 19 proteins were significantly decreased. Core networks of proteins involved in immune response, lipid metabolism and oxidative stress were distinctly altered in Parkinson's disease patients. Several proteins that are already well known in neurodegenerative disorders were identified. To our best knowledge, this is the first description of tear fluid proteome in Parkinson's disease patients. Tear protein level alterations suggest the contribution of different disease-related mechanisms in ocular pathology in Parkinson's disease and propose candidate proteins to be validated as potential biomarkers in larger cohorts.2022-03-3

On the economics of the longevity risk transfer market

We present a model of a longevity risk transfer market with different market players (primary insurers, reinsurers, and capital market investors) and investigate how market dynamics and the market players' roles evolve with progressing market saturation. We find that reinsurers' appetite for longevity risk is the key driver in the early stage of market development. Since diversification benefits with other businesses decrease with every transaction, the reinsurance market is intrinsically antimonopolistic. With the increasing saturation of the reinsurance sector as a whole, its competitiveness shrinks leading to rising expected risk‐adjusted returns for capital market investors. We show that in a saturated market, reinsurers should assume the entire longevity risk from primary insurers, diversify it within their business mix, and subsequently pass on only specific (nondiversifiable) components of the longevity risk to the capital markets. Our findings provide valuable suggestions on how to make the best use of the market's limited risk absorption capacity

On the pricing of longevity-linked securities

For annuity providers, longevity risk, i.e. the risk that future mortality trends differ from those anticipated, constitutes an important risk factor. In order to manage this risk, new financial products, so-called longevity derivatives, may be needed, even though a first attempt to issue a longevity bond in 2004 was not successful. While different methods of how to price such securities have been proposed in recent literature, no consensus has been reached. This paper reviews, compares and comments on these different approaches. In particular, we use data from the United Kingdom to derive prices for the proposed first longevity bond and an alternative security design based on the different methods.Longevity risk Stochastic mortality Longevity derivatives

Analysis of the Ion Channel Gating Mechanism in Solution by Nuclear Magnetic Resonance (NMR) Spectroscopy

Ion channels activated by cyclic nucleotides play crucial roles in signal transduction pathways. Upon binding of cyclic nucleotides to the intracellular cyclic nucleotide-binding domain (CNBD) of HCN or CNG channels (hyperpolarization-activated and cyclic nucleotide-gated channels or cyclic nucleotide-gated channels) an opening of the membrane pore occurs.To analyze the underlying gating mechanism highly resolved structures of the cyclic nucleotide-binding domains are necessary. Until now, structures of CNBDs from eukaryotic HCN channels as well as prokaryotic CNG channels are known. However, CNBD crystal structures of the HCN channels reveal no significant differences between apo and holo state1,2. In contrast, CNBD structures of the prokaryotic Mesorhizobium loti K1 channel, solved by liquid state NMR spectroscopy, show substantial rearrangements upon binding of a cyclic nucleotide3,4.Further elucidation of the gating mechanism will be done by structural analysis of an eukaryotic CNBD using liquid state NMR spectroscopy