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The thrombopoietin receptor agonist eltrombopag was successfully used against human cytomegalovirus (HCMV)-associated thrombocytopenia refractory to immunomodulatory and antiviral drugs. These effects were ascribed to the effects of eltrombopag on megakaryocytes. Here, we tested whether eltrombopag may also exert direct antiviral effects. Therapeutic eltrombopag concentrations inhibited HCMV replication in human fibroblasts and adult mesenchymal stem cells infected with six different virus strains and drug-resistant clinical isolates. Eltrombopag also synergistically increased the anti-HCMV activity of the mainstay drug ganciclovir. Time-of-addition experiments suggested that eltrombopag interfered with HCMV replication after virus entry. Eltrombopag was effective in thrombopoietin receptor-negative cells, and the addition of Fe3+ prevented the anti-HCMV effects, indicating that it inhibits HCMV replication via iron chelation. This may be of particular interest for the treatment of cytopenias after hematopoietic stem cell transplantation, as HCMV reactivation is a major reason for transplantation failure. Since therapeutic eltrombopag concentrations are effective against drug-resistant viruses, and synergistically increase the effects of ganciclovir, eltrombopag is also a drug-repurposing candidate for the treatment of therapy-refractory HCMV diseas.
The thrombopoietin receptor agonist eltrombopag was successfully used against human cytomegalovirus (HCMV)-associated thrombocytopenia refractory to immunomodulatory and antiviral drugs. These effects were ascribed to effects of eltrombopag on megakaryocytes. Here, we tested whether eltrombopag may also exert direct antiviral effects. Therapeutic eltrombopag concentrations inhibited HCMV replication in human fibroblasts and adult mesenchymal stem cells infected with six different virus strains and drug-resistant clinical isolates. Eltrombopag also synergistically increased the anti-HCMV activity of the mainstay drug ganciclovir. Time-of-addition experiments suggested that eltrombopag interferes with HCMV replication after virus entry. Eltrombopag was effective in thrombopoietin receptor-negative cells, and addition of Fe3+ prevented the anti-HCMV effects, indicating that it inhibits HCMV replication via iron chelation. This may be of particular interest for the treatment of cytopenias after haematopoietic stem cell transplantation, as HCMV reactivation is a major reason for transplantation failure. Since therapeutic eltrombopag concentrations are effective against drug-resistant viruses and synergistically increase the effects of ganciclovir, eltrombopag is also a drug repurposing candidate for the treatment of therapy-refractory HCMV disease.
Objective: Combination antiretroviral therapy (cART) has markedly increased survival and quality of life in people living with HIV. With the advent of new treatment options, including single-tablet regimens, durability and efficacy of first-line cART regimens are evolving.
Methods: We analyzed data from the prospective multicenter German Clinical Surveillance of HIV Disease (ClinSurv) cohort of the Robert-Koch Institute. Kaplan–Meier and Cox proportional hazards models were run to examine the factors associated with treatment modification. Recovery after treatment initiation was analyzed comparing pre-cART viral load and CD4+ T-cell counts with follow-up data.
Results: We included 8788 patients who initiated cART between 2005 and 2017. The sample population was predominantly male (n = 7040; 80.1%), of whom 4470 (63.5%) were reporting sex with men as the transmission risk factor. Overall, 4210 (47.9%) patients modified their first-line cART after a median time of 63 months (IQR 59–66). Regimens containing integrase strand transfer inhibitors (INSTI) were associated with significantly lower rates of treatment modification (adjusted hazard ratio 0.44; 95% CI 0.39–0.50) compared to protease inhibitor (PI)-based regimens. We found a decreased durability of first-line cART significantly associated with being female, a low CD4+ T-cell count, cART initiation in the later period (2011–2017), being on a multi-tablet regimen (MTR).
Conclusions: Drug class and MTRs are significantly associated with treatment modification. INSTI-based regimens showed to be superior compared to PI-based regimens in terms of durability.
Correction to: Infection (2020) 48:723–733 https://doi.org/10.1007/s15010-020-01469-6. The original version of this article unfortunately contained a mistake. In this article the authors Dirk Schürmann at affiliation Charité, University Medicine, Berlin, Olaf Degen at affiliation University Clinic Hamburg Eppendorf, Hamburg and Heinz-August Horst at affiliation University Hospital Schleswig–Holstein, Kiel, Germany were missing from the author list. The original article has been corrected.
The paper explores factors that influence the design of financing contracts between venture capital investors and European venture capital funds. 122 Private Placement Memoranda and 46 Partnership Agreements are investigated in respect to the use of covenant restrictions and compensation schemes. The analysis focuses on the impact of two key factors: the reputation of VC-funds and changes in the overall demand for venture capital services. We find that established funds are more severely restricted by contractual covenants. This contradicts the conventional wisdom which assumes that established market participants care more about their reputation, have less incentive to behave opportunistically and therefore need less covenant restrictions. We also find that managers of established funds are more often obliged to invest own capital alongside with investors money. We interpret this as evidence that established funds have actually less reason to care about their reputation as compared to young funds. One reason for this surprising result could be that managers of established VC funds are older and closer to retirement and therefore put less weight on the effects of their actions on future business opportunities. We also explore the effects of venture capital supply on contract design. Gompers and Lerner (1996) show that VC-funds in the US are able to reduce the number of restrictive covenants in years with high supply of venture capital and interpret this as a result of increased bargaining power by VC-funds. We do not find similar evidence for Europe. Instead, we find that VC-funds receive less base compensation and higher performance related compensation in years with strong capital inflows into the VC industry. This may be interpreted as a signal of overconfidence: Strong investor demand seems to coincide with overoptimistic expectations by fund managers which make them willing to accept higher powered incentive schemes. JEL: G32 Keywords: Venture Capital, Contracting, Limited Partnership, Funds, Principal Agent, Compensation, Covenants, Reputation, Bargaining Power
The paper explores factors that influence the design of financing contracts between venture capital investors and European venture capital funds. 122 Private Placement Memoranda and 46 Partnership Agreements are investigated in respect to the use of covenant restrictions and compensation schemes. The analysis focuses on the impact of two key factors: the reputation of VC-funds and changes in the overall demand for venture capital services. We find that established funds are more severely restricted by contractual covenants. This contradicts the conventional wisdom which assumes that established market participants care more about their reputation, have less incentive to behave opportunistically and therefore need less covenant restrictions. We also find that managers of established funds are more often obliged to invest own capital alongside with investors money. We interpret this as evidence that established funds have actually less reason to care about their reputation as compared to young funds. One reason for this surprising result could be that managers of established VC funds are older and closer to retirement and therefore put less weight on the effects of their actions on future business opportunities. We also explore the effects of venture capital supply on contract design. Gompers and Lerner (1996) show that VC-funds in the US are able to reduce the number of restrictive covenants in years with high supply of venture capital and interpret this as a result of increased bargaining power by VC-funds. We do not find similar evidence for Europe. Instead, we find that VC-funds receive less base compensation and higher performance related compensation in years with strong capital inflows into the VC industry. This may be interpreted as a signal of overconfidence: Strong investor demand seems to coincide with overoptimistic expectations by fund managers which make them willing to accept higher powered incentive schemes.
In this article, we investigate risk return characteristics and diversification benefits when private equity is used as a portfolio component. We use a unique dataset describing 642 US-American portfolio companies with 3620 private equity investments. Information about precisely dated cash flows at the company level enables for the first time a cash flow equivalent and simultaneous investment simulation in stocks, as well as the construction of stock portfolios for benchmarking purposes. With respect to the methodology involved, we construct private equity, stock-benchmark and mixed-asset portfolios using bootstrap simulations. For the late 1990s we find a dramatic increase in the extent to which private equity outperforms stock investment. In earlier years private equity was underperforming its stock benchmarks. Within the overall class of private equity, returns on earlier private equity investment categories, like venture capital, show on average higher variations and even higher rates of failure. It is in this category in particular that high average portfolio returns are generated solely by the ability to select a few extremely well performing companies, thus compensating for lost investments. There is a high marginal diversifiable risk reduction of about 80% when the portfolio size is increased to include 15 investments. When the portfolio size is increased from 15 to 200 there are few marginal risk diversification effects on the one hand, but a large increase in managing expenditure on the other, so that an actual average portfolio size between 20 and 28 investments seems to be well balanced. We provide empirical evidence that the non-diversifiable risk that a constrained investor, who is exclusively investing in private equity, has to hold exceeds that of constrained stock investors and also the market risk. From the viewpoint of unconstrained investors with complete investment freedom, risk can be optimally reduced by constructing mixed asset portfolios. According to the various private equity subcategories analyzed, there are big differences in optimal allocations to this asset class for minimizing mixed-asset portfolio variance or maximizing performance ratios. We observe optimal portfolio weightings to be between 3% and 65%.
Der Fischadler (pandion haliaefus), der nahezu weltweit verbreitet ist, kommt in Deutschland vorwiegend im Nordosten als Brutvogel vor. Er ernährt sich fast ausschließlich von lebend erbeuteten Fischen. Bis Mitte des 20. Jahrhunderts wurde er deshalb in vielen Teilen Europas als vermeintlicher Nahrungskonkurrent des Menschen verfolgt und ausgerottet (z. B. SCHMIDT 1995a). Weitere Bestandseinbußen erlitt der Fischadler in den 1960er und 70er Jahren durch Kontamination mit den auf land- und forstwirtschaftlichen Flächen ausgebrachten Pestiziden, vornehmlich DDT. Das führte zur Dünnschaligkeit und zum Bruch der Eier. Seine dadurch über eine lange Zeit bedingte Seltenheit führte bei Ornithologen und Naturschützern zu der Annahme, der Fischadler sei eine scheue und anspruchsvolle Vogelart. Schutzmaßnahmen in den mitteleuropäischen Kerngebieten seiner Verbreitung, in Mecklenburg und Brandenburg, haben in den vergangenen 20 Jahren zu einer deutlichen Bestandserholung geführt. So kommt es jährlich zu neuen Ansiedlungen auch in Regionen, die den bisherigen Vorstellungen über den von dieser Vogelart bevorzugten Lebensraum kaum entsprechen. Im Folgenden soll über eine Ansiedlung des Fischadlers im Landkreis Bitterfeld berichtet werden. Diese Region war einerseits einer hohen Umweltbelastung durch chemische Industrie und Braunkohletagebau ausgesetzt, andererseits existieren aber auch noch Reste von fast ursprünglichen Naturräumen, und es wurde durch menschliches Wirken eine "Natur aus zweiter Hand" geschaffen. Besonderes Augenmerk wird bei diesen Ausführungen auf praktische Artenschutzmaßnahmen gelegt, die dem Fischadler die Ansiedlung zur Brut in einer Bergbaufolgelandschaft ermöglicht haben.
Die vorliegende empirische Studie analysiert die Vertragsgestaltung zwischen Investoren und europäischen Venture Capital-Fonds. Im Zentrum steht die Analyse der Vergütung des Fondsmanagements sowie der zum Einsatz kommenden Vertragsklauseln. Deren Ausgestaltung ist entscheidend für die Überwindung der Prinzipal-Agenten-Beziehung innewohnenden Agency-Probleme. Hierzu werden 122 Fondsprospekte sowie 46 Gesellschafterverträge von europäischen Venture Capital-Fonds ausgewertet, die in den Jahren 1996 bis 2001, der ersten großen Boomphase des europäischen Venture Capital-Marktes, aufgelegt wurden. Während die jährliche Vergütung des Fondsmanagements auf den ersten Blick sehr standardisiert erscheint, ergeben sich bei einer Barwertbetrachtung aller zu leistenden Management Fees über die gesamte Fondslaufzeit deutliche Anzeichen für Preisdifferenzierung. In Bezug auf den Einsatz von Vertragsklauseln kann eine Zunahme im Zeitablauf und mithin eine zunehmende Komplexität des Vertragsdesigns festgestellt werden. Vor dem Hintergrund der Erfahrungen aus dem US-amerikanischen Venture Capital-Markt kann diese Entwicklung jedoch noch nicht als abgeschlossen gelten. Der europäische Markt bewegt sich in Bezug auf die Verwendung vertraglicher Restriktionen auf dem Niveau, das in den USA bereits Anfang der neunziger Jahre erreicht war.
We analyze governance with a dataset on investments of venture capitalists in 3848 portfolio firms in 39 countries from North and South America, Europe and Asia spanning 1971-2003. We find that cross-country differences in Legality have a significant impact on the governance structure of investments in the VC industry: better laws facilitate faster deal screening and deal origination, a higher probability of syndication and a lower probability of potentially harmful co-investment, and facilitate board representation of the investor. We also show better laws reduce the probability that the investor requires periodic cash flows prior to exit, which is in conjunction with an increased probability of investment in high-tech companies. Klassifikation: G24, G31, G32.