Statistical inference for the reserve risk

The major part of the liability of an insurance company's balance belongs to the reserves. Reserves are built to pay for all future, known or unknown, claims that happened so far. Hence an accurate prediction of the outstanding claims to determine the reserve is important. For non-life insurance companies, Mack (1993) proposed a distribution-free approach to calculate the first two moments of the reserve. In this cumulative dissertation, we derive first asymptotic theory for the unconditional and conditional limit distribution of the reserve risk. Therefore, we enhance the assumptions from Mack's model and derive a fully stochastic framework. The distribution of the reserve risk can be split up into two additive random parts covering the process and parameter uncertainty. The process uncertainty part dominates asymptotically and is in general non-Gaussian distributed unconditional and conditional on the whole observed loss triangle or the last observed diagonal of the loss triangle. In contrast, the parameter uncertainty part is measurable with respect to the whole observed upper loss triangle. Properly inflated, the parameter uncertainty part is Gaussian distributed conditional on the last observed diagonal of the loss triangle, and unconditional, it leads to a non-Gaussian distribution. Hence, the parameter uncertainty part is asymptotically negligible. In total, the reserve risk has asymptotically the same distribution as the process uncertainty part since this part dominates asymptotically leading to a non-Gaussian distribution conditional and unconditional. Using the theoretical asymptotic distribution results regarding the distribution of the reserve risk, we can now establish bootstrap consistency results, where the derived distribution of the reserve risk serves as a benchmark. Splitting the reserve risk into two additive parts enables a rigorous investigation of the validity of the Mack bootstrap. If the parametric family of distributions of the individual development factors is correctly specified, we prove that the (conditional) distribution of the asymptotically dominating process uncertainty part is correctly mimicked by the proposed Mack bootstrap approach. On the contrary, the corresponding (conditional) distribution of the estimation uncertainty part is generally not correctly captured by the Mack bootstrap. To address this issue, we propose an alternative Mack bootstrap, which uses a different centering and is designed to capture also the distribution of the estimation uncertainty part correctly

Studies on anti-inflammatory and vasoactive effects of mPGES-1 inhibition

Inflammation is the basis for various serious illnesses such as rheumatic diseases, cardiovascular diseases, and cancer. Prostaglandin E2 (PGE2) is a pro-inflammatory lipid mediator produced by cyclooxygenases (COX1/2) and the microsomal prostaglandin E synthase 1 (mPGES-1). Nonsteroidal anti-inflammatory drugs (NSAIDS) targeting COX successfully reduce pain and inflammation. However, gastrointestinal and cardiovascular side effects associated with blockade of all prostaglandins limit their use. Selective inhibition of mPGES-1 is an alternative therapeutic strategy to impede PGE2 production while sparing or even upregulating other lipid mediators. When and where the shunting of PGH2 to other prostanoids occurs and whether it interferes with or contributes to the therapeutic effects of mPGES-1 inhibition is not fully understood. The overall aim of this thesis was to study the anti-inflammatory and vasoactive effects of mPGES-1 inhibition in models of inflammation and cardiovascular disease and to investigate the possible shunting of PGH2 to PGD2 and PGI2. The methodological approach was principally based on liquid chromatography-tandem mass spectrometry, biochemical assays as well as wire-myography. In Paper I five new mPGES-1 inhibitors were characterized. The inhibitors selectively suppressed PGE2 formation in in-vitro and in-vivo assays, reduced acute paw swelling in rats, and reduced adrenergic vasoconstriction. The results of this study serve as a basis for the application of these inhibitors in pre-clinical research. Depletion of mPGES-1 may lead to the re-direction of PGH2 into the PGD2/15-deoxy-Δ12,14-PGJ2 (15dPGJ2) pathway, which has been described to be anti-inflammatory and pro-resolving. In Paper II, we studied the biosynthesis and metabolism of 15dPGJ2 via conjugation to glutathione in immune cells and upon inhibition of mPGES-1. The results of this study demonstrate the formation of 15dPGJ2-glutathione and 15dPGJ2-cysteine conjugates in immune cells, the involvement of MGST3 in this pathway and the preservation of the PGD2/15dPGJ2 pathway upon inhibition of mPGES-1. Another important aspect of mPGES-1 inhibition is the redirection of excess PGH2 into the PGI2 pathway. A decrease in PGI2 levels as a result of COX-2 inhibition has been associated with increased cardiovascular risk in patients treated with selective NSAIDs. In Paper III we aimed to study the effects of mPGES-1 inhibition on human resistance arteries. Inhibition of mPGES- 1 significantly reduced adrenergic vasoconstriction and enhanced relaxation. Our results suggest that multiple pathways in addition to shunting to PGI2 may be involved in the vasoactive effects of mPGES-1 inhibition in human microcirculation. In Paper IV we studied the effects of mPGES-1 inhibition in a mouse model of MI. The results of this study indicate that pharmacological inhibition of mPGES-1 could improve cardiac function after MI and increase the PGI2/PGE2 metabolite ratio in urine compared with controls. The results from this thesis contribute to a better understanding of the mechanisms underlying the effects seen after inhibition of mPGES-1 in models of inflammation and cardiovascular disease

Julia Steinmetz Ryder scrapbook

Photographic scrapbook of Julia Steinmetz Ryder who was a student at Rollins College from 1902-1905. Scrapbook contains black-and-white photographs of Julia and her friends and family

A connectedness analysis of German financial institutions during the financial crisis in 2008

For core financial market activities like risk management and asset pricing, it appears to be crucial to investigate the “connectedness” among financial institutions. In times of economic crises, a suitable measure of connectedness can provide valuable insights of financial markets and helps to understand how institutions influence each other. In particular, depending on contractual obligations between financial institutions, the financial distress at a bank with large systemic impact is likely to cause also distress at other institutions. In the literature, the latter phenomenon is generally tagged by ’contagion’ and can eventually result in severe economic crises. The purpose of this paper is to investigate the connectedness among German financial institutions during the global financial crisis 2007-2009, where the authors focus particularly on 2008 and its height in September 2008 with the bankruptcy of Lehman Brothers. They make use of the definition of connectedness, as it was recently proposed by Diebold and Yilmaz (2014). Their approach relies on analyzing multiple time series of volatilities by a vector autoregressive (VAR) model and a generalized forecast error variance decompositions. It provides several meaningful measures of connectedness and allows for static (average), as well as dynamic (daily time-varying) analyses. The authors show that the connectedness in Germany can be described well by the model. Keywords: сonnectedness, contagion, generalized variance decomposition, networks, spillover effects. JEL Classification: C32, C58, G32, G3

Spatial clusters of life expectancy and association with cardiovascular disease mortality and cancer mortality in the contiguous United States: 1980-2014

The average life expectancy varies greatly from county to county in USA and there are also spatial variations in the county mortality rates for cardiovascular disease (CVD) and cancer, the top two causes of death. An association between these two groups of diseases has not been identified by cluster analysis previously. The main objective in this study was to investigate and quantify the associations between mortality due to CVD, cancer mortality and life expectancy based on US county data between 1980 and 2014. Regression analysis was used to adjust life expectancy for the mortality due to CVD and that due to cancer. In addition to the spatial life expectancy trends, we also studied existing trends over time with the software JOINPOINT to see how life expectancy is influenced by changes in mortality due to CVD and cancer mortality. The study setting was the 48 contiguous US states, while participants were 3,100 counties and their populations of all ages during the period 1980-2014. The main outcomes are spatial clusters of unusually low or high levels of life expectancy in addition to identifying which county level life expectancy locations were significantly associated with mortality due to CVD and/or cancer. Life expectancy has been improving steadily from 1980 to 2014, but the rate of increase per year (indicated by variation of the trend slope) changed significantly at five joinpoints, the latest of which occurred in 2010 when the slope changed from 0.29 (1980-1982) to 0.03 (2010-2014). Our results reveal that there are significant, purely spatial clusters in some geographical areas where life expectancy rates are significantly higher (or lower) than in the rest of the contiguous US. It is also shown that there is a significant association between the life expectancy level and the corresponding CVD mortality, and there is also a significant association between life expectancy level and the corresponding overall cancer mortality. The general trends (regression slopes) over time for the USA in life expectancy mortality, CVD mortality and cancer mortality have changed significantly after 2009-2010

Palmitate-Triggered COX2/PGE2-Related Hyperinflammation in Dual-Stressed PdL Fibroblasts Is Mediated by Repressive H3K27 Trimethylation

The interrelationships between periodontal disease, obesity-related hyperlipidemia and mechanical forces and their modulating effects on the epigenetic profile of periodontal ligament (PdL) cells are assumed to be remarkably complex. The PdL serves as a connective tissue between teeth and alveolar bone and is involved in pathogen defense and the inflammatory responses to mechanical stimuli occurring during tooth movement. Altered inflammatory signaling could promote root resorption and tooth loss. Hyperinflammatory COX2/PGE2 signaling was reported for human PdL fibroblasts (HPdLFs) concomitantly stressed with Porphyromonas gingivalis lipopolysaccharides and compressive force after exposure to palmitic acid (PA). The aim of this study was to investigate the extent to which this was modulated by global and gene-specific changes in histone modifications. The expression of key epigenetic players and global H3Kac and H3K27me3 levels were quantitatively evaluated in dual-stressed HPdLFs exposed to PA, revealing a minor force-related reduction in repressive H3K27me3. UNC1999-induced H3K27me3 inhibition reversed the hyperinflammatory responses of dual-stressed PA cultures characterized by increased COX2 expression, PGE2 secretion and THP1 adhesion. The reduced expression of the gene encoding the anti-inflammatory cytokine IL-10 and the increased presence of H3K27me3 at its promoter-associated sites were reversed by inhibitor treatment. Thus, the data highlight an important epigenetic interplay between the different stimuli to which the PdL is exposed

Tuberculosis in Swiss captive Asian elephants: microevolution of Mycobacterium tuberculosis characterized by multilocus variable-number tandem-repeat analysis and whole-genome sequencingle-number tandem-repeat analysis and whole-genome sequencing

Zoonotic tuberculosis is a risk for human health, especially when animals are in close contact with humans. Mycobacterium tuberculosis was cultured from several organs, including lung tissue and gastric mucosa, of three captive elephants euthanized in a Swiss zoo. The elephants presented weight loss, weakness and exercise intolerance. Molecular characterization of the M. tuberculosis isolates by spoligotyping revealed an identical profile, suggesting a single source of infection. Multilocus variable-number of tandem-repeat analysis (MLVA) elucidated two divergent populations of bacteria and mixed infection in one elephant, suggesting either different transmission chains or prolonged infection over time. A total of eight M. tuberculosis isolates were subjected to whole-genome sequence (WGS) analysis, confirming a single source of infection and indicating the route of transmission between the three animals. Our findings also show that the methods currently used for epidemiological investigations of M. tuberculosis infections should be carefully applied on isolates from elephants. Moreover the importance of multiple sampling and analysis of within-host mycobacterial clonal populations for investigations of transmission is demonstrated

Interventions to reduce stress and prevent burnout in healthcare professionals supported by digital applications: a scoping review

Aim: Healthcare professionals are at increased risk of burnout, primarily due to workplace-related stressors. The COVID-19 pandemic has further increased this risk. Different interventions exist with varying degrees of effectiveness; little is reported on the content and implementation of such programs. This review fills this gap, with attention to recent programs using digital components. Methods: PubMed, Embase, PsycInfo, and Google Scholar were searched between January 24th and 28th, 2022, limited to the last 5 years (≥2017). Articles were included if they (1) focused on stress reduction or burnout prevention for nurses and medical doctors within workplace health promotion for nurses or medical doctors, (2) included a digital program component, (3) were conducted in high-income country contexts, and (4) were clinical studies published in English or German. Data was extracted using a priori designed spreadsheets. A group of at least 2 authors at each stage carried out the screening, selection, and data extraction. Results: The search strategy identified 153 articles, all except 7 were excluded. Two studies were conducted in the USA, two in Spain, one in the Netherlands, Poland, and Korea each. Four studies used a randomized study design, all but one had a control group. A wide range of outcome measures was used. The types of interventions included an adapted mindfulness-based stress reduction program combined with aspects of behavioral therapies, cognitive behavioral therapy, or acceptance and commitment therapy. The digital components used were apps (4 studies), a digital platform, blended learning, and a web-based intervention (1 study each). Six studies focused on individual interventions, one included organizational interventions. Conclusion: Despite an acute burnout crisis in the healthcare sector, only seven recent interventions were found that integrated digital components. Several problems emerged during the implementation of the interventions that made it clear that organizational support is urgently needed for successful implementation. Although interventions for stress reduction and burnout prevention should combine individual and organizational measures to be as successful as possible, this was only partially the case in one of the intervention programs. The results of this scoping review can be used to further develop or optimize stress and burnout prevention programs

Original Contribution 2 PGD 2 and PGE 2 regulate gene expression of Prx 6 in primary macrophages via Nrf2

Prostaglandin 26 Free radicals 27 Peroxiredoxin 6 (Prx 6) is a bifunctional enzyme with both glutathione peroxidase and acidic Ca 2+ -28 independent phospholipase A 2 activities. We have recently shown that exposure of murine bone marrow-29 derived macrophages to LPS and IFN-γ leads to induction of COX-2 expression and secretion of PGE 2 , up-30 regulating Prx 6 mRNA levels. This study was designed to investigate various prostaglandins (PGs) for their 31 ability to induce gene expression of Prx's, in particular Prx 6, and to determine the underlying regulatory 32 mechanisms. We provide evidence that both conventional and cyclopentenone PGs enhance Prx 6 mRNA 33 expression. Treatment with either activators or inhibitors of adenylate cyclase as well as cAMP analogs 34 indicated that Prx 6 gene expression is regulated by adenylate cyclase in response to PGD 2 or PGE 2 . 35 Furthermore, our study revealed that JAK2, PI3K, PKC, and p38 MAPK contribute to the PGD 2 -or PGE 2 -36 dependent Prx 6 induction. Using stimulated macrophages from Nrf2-deficient mice or activators of Nrf2 and 37 PPARγ, we found that Nrf2, but not PPARγ, is involved in the PG-dependent increase in Prx 6 mRNA 38 expression. In summary, our data suggest multiple signaling pathways of Prx 6 regulation by PGs and 39 identified Nrf2 as a critical player mediating transcriptional induction. 40 © 2011 Elsevier Inc. All rights reserved

The role of sand lances (Ammodytes sp.) in the Northwest Atlantic ecosystem: a synthesis of current knowledge with implications for conservation and management

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Staudinger, M. D., Goyert, H., Suca, J. J., Coleman, K., Welch, L., Llopiz, J. K., Wiley, D., Altman, I., Applegate, A., Auster, P., Baumann, H., Beaty, J., Boelke, D., Kaufman, L., Loring, P., Moxley, J., Paton, S., Powers, K., Richardson, D., Robbins, J., Runge, J., Smith, B., Spiegel, C., & Steinmetz, H. The role of sand lances (Ammodytes sp.) in the Northwest Atlantic ecosystem: a synthesis of current knowledge with implications for conservation and management. Fish and Fisheries, 00, (2020): 1-34, doi:10.1111/faf.12445.The American sand lance (Ammodytes americanus, Ammodytidae) and the Northern sand lance (A. dubius, Ammodytidae) are small forage fishes that play an important functional role in the Northwest Atlantic Ocean (NWA). The NWA is a highly dynamic ecosystem currently facing increased risks from climate change, fishing and energy development. We need a better understanding of the biology, population dynamics and ecosystem role of Ammodytes to inform relevant management, climate adaptation and conservation efforts. To meet this need, we synthesized available data on the (a) life history, behaviour and distribution; (b) trophic ecology; (c) threats and vulnerabilities; and (d) ecosystem services role of Ammodytes in the NWA. Overall, 72 regional predators including 45 species of fishes, two squids, 16 seabirds and nine marine mammals were found to consume Ammodytes. Priority research needs identified during this effort include basic information on the patterns and drivers in abundance and distribution of Ammodytes, improved assessments of reproductive biology schedules and investigations of regional sensitivity and resilience to climate change, fishing and habitat disturbance. Food web studies are also needed to evaluate trophic linkages and to assess the consequences of inconsistent zooplankton prey and predator fields on energy flow within the NWA ecosystem. Synthesis results represent the first comprehensive assessment of Ammodytes in the NWA and are intended to inform new research and support regional ecosystem‐based management approaches.This manuscript is the result of follow‐up work stemming from a working group formed at a two‐day multidisciplinary and international workshop held at the Parker River National Wildlife Refuge, Massachusetts in May 2017, which convened 55 experts scientists, natural resource managers and conservation practitioners from 15 state, federal, academic and non‐governmental organizations with interest and expertise in Ammodytes ecology. Support for this effort was provided by USFWS, NOAA Stellwagen Bank National Marine Sanctuary, U.S. Department of the Interior, U.S. Geological Survey, Northeast Climate Adaptation Science Center (Award # G16AC00237), an NSF Graduate Research Fellowship to J.J.S., a CINAR Fellow Award to J.K.L. under Cooperative Agreement NA14OAR4320158, NSF award OCE‐1325451 to J.K.L., NSF award OCE‐1459087 to J.A.R, a Regional Sea Grant award to H.B. (RNE16‐CTHCE‐l), a National Marine Sanctuary Foundation award to P.J.A. (18‐08‐B‐196) and grants from the Mudge Foundation. The contents of this paper are the responsibility of the authors and do not necessarily represent the views of the National Oceanographic and Atmospheric Administration, U.S. Fish and Wildlife Service, New England Fishery Management Council and Mid‐Atlantic Fishery Management Council. This manuscript is submitted for publication with the understanding that the United States Government is authorized to reproduce and distribute reprints for Governmental purposes. Any use of trade, firm or product names is for descriptive purposes only and does not imply endorsement by the U.S. Government