Addressing the 'hypoxia paradox' in severe COVID-19: literature review and report of four cases treated with erythropoietin analogues

Since fall 2019, SARS-CoV-2 spread world-wide, causing a major pandemic with estimated ~ 220 million subjects affected as of September 2021. Severe COVID-19 is associated with multiple organ failure, particularly of lung and kidney, but also grave neuropsychiatric manifestations. Overall mortality reaches > 2%. Vaccine development has thrived in thus far unreached dimensions and will be one prerequisite to terminate the pandemic. Despite intensive research, however, few treatment options for modifying COVID-19 course/outcome have emerged since the pandemic outbreak. Additionally, the substantial threat of serious downstream sequelae, called 'long COVID' and 'neuroCOVID', becomes increasingly evident. Main body of the abstract Among candidates that were suggested but did not yet receive appropriate funding for clinical trials is recombinant human erythropoietin. Based on accumulating experimental and clinical evidence, erythropoietin is expected to (1) improve respiration/organ function, (2) counteract overshooting inflammation, (3) act sustainably neuroprotective/neuroregenerative. Recent counterintuitive findings of decreased serum erythropoietin levels in severe COVID-19 not only support a relative deficiency of erythropoietin in this condition, which can be therapeutically addressed, but also made us coin the term 'hypoxia paradox'. As we review here, this paradox is likely due to uncoupling of physiological hypoxia signaling circuits, mediated by detrimental gene products of SARS-CoV-2 or unfavorable host responses, including microRNAs or dysfunctional mitochondria. Substitution of erythropoietin might overcome this 'hypoxia paradox' caused by deranged signaling and improve survival/functional status of COVID-19 patients and their long-term outcome. As supporting hints, embedded in this review, we present 4 male patients with severe COVID-19 and unfavorable prognosis, including predicted high lethality, who all profoundly improved upon treatment which included erythropoietin analogues. Short conclusion Substitution of EPO may among other beneficial EPO effects in severe COVID-19 circumvent downstream consequences of the 'hypoxia paradox'. A double-blind, placebo-controlled, randomized clinical trial for proof-of-concept is warranted

Managing risk in open source software adoption

By 2016 an estimated 95% of all commercial software packages will include Open Source Software (OSS). This extended adoption is yet not avoiding failure rates in OSS projects to be as high as 50%. Inadequate risk management has been identified among the top mistakes to avoid when implementing OSS-based solutions. Understanding, managing and mitigating OSS adoption risks is therefore crucial to avoid potentially significant adverse impact on the business. In this position paper we portray a short report of work in progress on risk management in OSS adoption processes. We present a risk-aware technical decision-making management platform integrated in a business-oriented decision-making framework, which together support placing technical OSS adoption decisions into organizational, business strategy as well as the broader OSS community context. The platform will be validated against a collection of use cases coming from different types of organizations: big companies, SMEs, public administration, consolidated OSS communities and emergent small OSS products.Postprint (published version

Semen inhibits Zika virus infection of cells and tissues from the anogenital region

Zika virus (ZIKV) causes severe birth defects and can be transmitted via sexual intercourse. Semen from ZIKV-infected individuals contains high viral loads and may therefore serve as an important vector for virus transmission. Here we analyze the effect of semen on ZIKV infection of cells and tissues derived from the anogenital region. ZIKV replicates in all analyzed cell lines, primary cells, and endometrial or vaginal tissues. However, in the presence of semen, infection by ZIKV and other flaviviruses is potently inhibited. We show that semen prevents ZIKV attachment to target cells, and that an extracellular vesicle preparation from semen is responsible for this anti-ZIKV activity. Our findings suggest that ZIKV transmission is limited by semen. As such, semen appears to serve as a protector against sexual ZIKV transmission, despite the availability of highly susceptible cells in the anogenital tract and high viral loads in this bodily fluid.Peer reviewe

Zur staatlichen Marktregulierung in der Bundesrepublik

Available from Bibliothek des Instituts fuer Weltwirtschaft, ZBW, Duesternbrook Weg 120, D-24105 Kiel B 218002 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Biomarker Records of Environmental Shifts on the Labrador Shelf During the Holocene

AbstractThe ultimate demise of the Laurentide Ice Sheet (LIS) and the preceding and succeeding oceanographic changes along the western Labrador Sea offer insights critically important to improve climate predictions of expected future climate warming and further melting of the Greenland ice cap. However, while the final disappearance of the LIS during the Holocene is rather well constrained, the response of sea ice during the resulting meltwater events is not fully understood. Here, we present reconstructions of paleoceanographic changes over the past 9.3 Kyr BP on the northwestern Labrador Shelf, with a special focus on the interaction between the final meltwater event around 8.2 Kyr BP and sea ice and phytoplankton productivity (e.g., IP25, HBI III (Z), brassicasterol, dinosterol, biogenic opal, total organic carbon). Our records indicate low sea‐ice cover and high phytoplankton productivity on the Labrador Shelf prior to 8.9 Kyr BP, sea‐ice formation was favored by decreased surface salinities due to the meltwater events from Lake Agassiz‐Ojibway and the Hudson Bay Ice Saddle from 8.55 Kyr BP onwards. For the past ca. 7.5 Kyr BP sea ice is mainly transported to the study area by local ocean currents such as the inner Labrador and Baffin Current. Our findings provide new insights into the response of sea ice to increased meltwater discharge as well as shifts in atmospheric and oceanic circulation.Key Points: Sea ice on the Labrador Shelf mainly follows the solar insolation and meltwater input from the decaying Laurentide Ice Sheet Sea ice increased following the Lake Agassiz outburst and Hudson Bay Ice Saddle Collapse between 8.5 and 8.2 Kyr BP Low sea ice conditions during the Holocene Thermal Maximum were replaced by an increase following the Neoglacial cooling trend Ocean Frontier InstituteNSERChttps://doi.org/10.4095/221564https://doi.org/10.1594/PANGAEA.949244https://doi.org/10.5281/zenodo.8247131https://doi.org/10.1594/PANGAEA.949065https://doi.org/10.1594/PANGAEA.94905

Biomarker Records of Environmental Shifts on the Labrador Shelf During the Holocene

The ultimate demise of the Laurentide Ice Sheet (LIS) and the preceding and succeeding oceanographic changes along the western Labrador Sea offer insights critically important to improve climate predictions of expected future climate warming and further melting of the Greenland ice cap. However, while the final disappearance of the LIS during the Holocene is rather well constrained, the response of sea ice during the resulting meltwater events is not fully understood. Here, we present reconstructions of paleoceanographic changes over the past 9.3 Kyr BP on the northwestern Labrador Shelf, with a special focus on the interaction between the final meltwater event around 8.2 Kyr BP and sea ice and phytoplankton productivity (e.g., IP25, HBI III (Z), brassicasterol, dinosterol, biogenic opal, total organic carbon). Our records indicate low sea-ice cover and high phytoplankton productivity on the Labrador Shelf prior to 8.9 Kyr BP, sea-ice formation was favored by decreased surface salinities due to the meltwater events from Lake Agassiz-Ojibway and the Hudson Bay Ice Saddle from 8.55 Kyr BP onwards. For the past ca. 7.5 Kyr BP sea ice is mainly transported to the study area by local ocean currents such as the inner Labrador and Baffin Current. Our findings provide new insights into the response of sea ice to increased meltwater discharge as well as shifts in atmospheric and oceanic circulation

Cellular Infiltrates and NF kappa B Subunit c-Rel Signaling in Kidney Allografts of Patients With Clinical Operational Tolerance

Background. Nuclear factor kappa B (NF kappa B) plays a potential role in tolerance by orchestrating onset and resolution of inflammation and regulatory T cell differentiation through subunit c-Rel. We characterized cellular infiltrates and expression of NF kappa B1, c-Rel and its upstream regulators phosphatidylinositol 3-kinase/RAC-alpha serine/threonine kinase, in allograft biopsies from patients with spontaneous clinical operational tolerance (COT). Methods. Paraffin-fixed kidney allograft biopsies from 40 patients with COT (n=4), interstitial rejection (IR; n=12), borderline changes (BC; n=12), and long-term allograft function without rejection (NR; n=12) were used in the study. Cellular infiltrates and immunohistochemical expression of key proteins of the NF kappa B pathway were evaluated in the cortical tubulointerstitium and in cellular infiltrates using digital image analysis software. Results were given as mean +/- SEM. Results. Biopsies from patients with COT exhibited a comparable amount of cellular infiltrate to IR, BC, and NR (COT, 191 +/- 81; IR, 291 +/- 62; BC, 178 +/- 45; and NR, 210 +/- 42 cells/mm(2)) but a significantly higher proportion of forkhead box P3-positive cells (COT, 11%+/- 1.7%; IR, 3.5%+/- 0.70%; BC, 3.4%+/- 0.57%; and NR, 3.7%+/- 0.78% of infiltrating cells; P=0.02). c-Rel expression in cellular infiltrates was significantly elevated in IR, BC, and NR when analyzing the number of positive cells per mm(2) (P=0.02) and positive cells per infiltrating cells (P=0.04). In contrast, tubular PI3K and c-Rel expression were significantly higher in IR and BC but not in NR compared with COT (P=0.03 and P=0.006, respectively). With RAC-alpha serine-threonine kinase, similar tendencies were observed (P=0.2). Conclusions. Allografts from COT patients show significant cellular infiltrates but a distinct expression of proteins involved in the NF kappa B pathway and a higher proportion of forkhead box P3-positive cells.Deutsche Forschungsgemeinschaft [SFB 938]Deutsche Forschungsgemeinschaf

Managing risk in open source software adoption

By 2016 an estimated 95% of all commercial software packages will include Open Source Software (OSS). This extended adoption is yet not avoiding failure rates in OSS projects to be as high as 50%. Inadequate risk management has been identified among the top mistakes to avoid when implementing OSS-based solutions. Understanding, managing and mitigating OSS adoption risks is therefore crucial to avoid potentially significant adverse impact on the business. In this position paper we portray a short report of work in progress on risk management in OSS adoption processes. We present a risk-aware technical decision-making management platform integrated in a business-oriented decision-making framework, which together support placing technical OSS adoption decisions into organizational, business strategy as well as the broader OSS community context. The platform will be validated against a collection of use cases coming from different types of organizations: big companies, SMEs, public administration, consolidated OSS communities and emergent small OSS products