PBTK modeling of the pyrrolizidine alkaloid retrorsine to predict liver toxicity in mouse and rat

Retrorsine is a hepatotoxic pyrrolizidine alkaloid (PA) found in herbal supplements and medicines, food and livestock feed. Dose-response studies enabling the derivation of a point of departure including a benchmark dose for risk assessment of retrorsine in humans and animals are not available. Addressing this need, a physiologically based toxicokinetic (PBTK) model of retrorsine was developed for mouse and rat. Comprehensive characterization of retrorsine toxicokinetics revealed: both the fraction absorbed from the intestine (78%) and the fraction unbound in plasma (60%) are high, hepatic membrane permeation is dominated by active uptake and not by passive diffusion, liver metabolic clearance is 4-fold higher in rat compared to mouse and renal excretion contributes to 20% of the total clearance. The PBTK model was calibrated with kinetic data from available mouse and rat studies using maximum likelihood estimation. PBTK model evaluation showed convincing goodness-of-fit for hepatic retrorsine and retrorsine-derived DNA adducts. Furthermore, the developed model allowed to translate in vitro liver toxicity data of retrorsine to in vivo dose-response data. Resulting benchmark dose confidence intervals (mg/kg bodyweight) are 24.1–88.5 in mice and 79.9–104 in rats for acute liver toxicity after oral retrorsine intake. As the PBTK model was built to enable extrapolation to different species and other PA congeners, this integrative framework constitutes a flexible tool to address gaps in the risk assessment of PA

Fear of COVID-19 among homeless individuals in Germany in mid-2021.

AIMS: To investigate the prevalence and the correlates of fear of COVID-19 among homeless individuals. METHODS: We used data from the "national survey on psychiatric and somatic health of homeless individuals during the COVID-19 pandemic" (NAPSHI-study) which took place in several large cities in Germany in Mid-2021 (n = 666 in the analytical sample). Mean age equaled 43.3 years (SD: 12.1 years), ranging from 18 to 80 years. Multiple linear regressions were performed. RESULTS: In our study, 70.9% of the homeless individuals reported no fear of COVID-19. Furthermore, 14.0% reported a little fear of COVID-19, 8.4% reported some fear of COVID-19 and 6.7% reported severe fear of COVID-19. Multiple linear regressions revealed that fear of COVID-19 was higher among individuals aged 50-64 years (compared to individuals aged 18-29 years: β = 0.28, p < 0.05), among individuals with a higher perceived own risk of contracting the coronavirus 1 day (β = 0.28, p < 0.001) as well as among individuals with a higher agreement that a diagnosis of the coronavirus would ruin his/her life (β = 0.15, p < 0.001). CONCLUSIONS: Only a small proportion of homeless individuals reported fear of COVID-19 in mid-2021 in Germany. Such knowledge about the correlates of higher levels of fear of COVID-19 may be helpful for addressing certain risk groups (e.g., homeless individuals aged 50-64 years). In a further step, avoiding extraordinarily high levels of fear of COVID-19 may be beneficial to avoid irrational thinking and acting regarding COVID-19 in this group

Determinants of health-related quality of life (HRQoL) among homeless individuals during the COVID-19 pandemic

OBJECTIVE: Thus far, there is very limited knowledge regarding homeless individuals during the COVID-19 pandemic, particularly related to the health-related quality of life (HRQoL). Thus, our aim was to evaluate HRQoL and to clarify the determinants of HRQoL among homeless individuals during the COVID-19 pandemic in Germany. METHODS: Data were taken from the national survey on psychiatric and somatic health of homeless individuals during the COVID-19 pandemic-NAPSHI (n = 616). The established EQ-5D-5L was used to quantify problems in five health dimensions, and its visual analogue scale (EQ-VAS) was used to record self-rated health status. Sociodemographic factors were included in regression analysis. RESULTS: Pain/discomfort was the most frequently reported problem (45.3%), thereafter anxiety/depression (35.9%), mobility (25.4%), usual activities (18.5%) and self-care (11.4%). Average EQ-VAS score was 68.97 (SD: 23.83), and the mean EQ-5D-5L index was 0.85 (SD: 0.24). Regressions showed that higher age and having a health insurance were associated with several problem dimensions. Being married was associated with higher EQ-VAS scores. CONCLUSIONS: Overall, our study findings showed a quite high HRQoL among homeless individuals during the COVID-19 pandemic in Germany. Some important determinants of HRQoL were identified (e.g., age or marital status). Longitudinal studies are required to confirm our findings

Additive Antinociceptive Effects of a Combination of Vitamin C and Vitamin E after Peripheral Nerve Injury

Accumulating evidence indicates that increased generation of reactive oxygen species (ROS) contributes to the development of exaggerated pain hypersensitivity during persistent pain. In the present study, we investigated the antinociceptive efficacy of the antioxidants vitamin C and vitamin E in mouse models of inflammatory and neuropathic pain. We show that systemic administration of a combination of vitamins C and E inhibited the early behavioral responses to formalin injection and the neuropathic pain behavior after peripheral nerve injury, but not the inflammatory pain behavior induced by Complete Freund's Adjuvant. In contrast, vitamin C or vitamin E given alone failed to affect the nociceptive behavior in all tested models. The attenuated neuropathic pain behavior induced by the vitamin C and E combination was paralleled by a reduced p38 phosphorylation in the spinal cord and in dorsal root ganglia, and was also observed after intrathecal injection of the vitamins. Moreover, the vitamin C and E combination ameliorated the allodynia induced by an intrathecally delivered ROS donor. Our results suggest that administration of vitamins C and E in combination may exert synergistic antinociceptive effects, and further indicate that ROS essentially contribute to nociceptive processing in special pain states

MoorIS: Contents and Future Possibilities for the Peatland Information System for Lower Saxony

Die Bundesrepublik Deutschland hat im Klimaschutzgesetz formuliert, bis zum Jahr 2045 eine Treibhausgasneutralität anzustreben. Die Änderung der Landnutzung auf Moorstandorten wird als integraler Bestandteil der Zielsetzung angesehen. Durch die landwirtschaftliche Nutzung von Moorstandorten werden 53 Millionen Tonnen Treibhausgase pro Jahr emittiert. Damit ist die Nutzung der entwässerten Moore der größte einzelne Treibhausgasemittent außerhalb des Energiesektors. Die Verfügbarkeit von Daten und Informationen für ein klimaschonendes Management der Moorflächen ist essentiell für die langfristige Reduktion der Emissionen aus Mooren und den Erhalt weiterer Landschaftsfunktionen wie der Biodiversität. Die Landesfläche Niedersachsens beheimatet ein Drittel der deutschen Moorflächen. Damit obliegt dem Bundesland eine wichtige Verantwortung in der Reduktion der Emissionen auf Mooren und kohlenstoffreichen Böden. Das Moorinformationssystem „MoorIS“ (https://mooris-niedersachsen.de/) stellt behördenübergreifende Daten und Informationen zu den niedersächsischen Mooren zur Verfügung. Diese umfassen neben landesweiten kartographischen Aufbereitungen und Bohrungen auch Informationen zu Moorgebieten und Moorprojekten, eine Übersicht und Arbeitshilfen für Moormanagementoptionen. Ergänzt wird dies durch moorkundliche Erläuterungen sowie Ausführungen zur Nutzung und Geschichte der niedersächsischen Moore. Das Zielpublikum des MoorIS umfasst vor allem Fachpublikum mit Vorkenntnissen zu Mooren. Das reicht von Verwaltungen, Entscheidungstragenden in Politik und Wirtschaft, über Verbände und Vereine im Natur- und Umweltschutz, Planungsbüros bis hin zu Forschung und Lehre. Gleichzeitig bietet die Webseite auch Informationen zu Niedersachsens Mooren für Nutzende mit wenig bis keinen Vorkenntnissen. Die Webseite umfasst vor allem landesweite Karten und Auszüge aus Datenbanken mehrerer Landesbehörden. In zukünftigen Erweiterungen des Informationssystems könnten Daten, die im Rahmen von Moorprojekten erhoben wurden, integriert werden. Damit würden vor allem lokale Informationen zum Boden und zur Hydrologie erfasst werden. Diese Integration von Daten Dritter erfordert eine enge behördliche Zusammenarbeit, um bestehende Standards und Datenstrukturen nutzen zu können und doppelte Datenhaltungen zu vermeiden. Im Moorinformationssystem wird die Bereitstellung von umfassenden sowie belastbaren Informationen angestrebt, sodass eine breite Informationsbasis für zukünftige Entscheidungen im Sinne des Schutzes der niedersächsischen Moore zur Verfügung stehen wird.Germany aims to become greenhouse gas neutral by 2045. An integral part of reaching this goal will be changing the land use of peatlands. The agricultural use of peatlands in Germany results in the emission of 53 Mio. T greenhouse gases each year, making peatlands the single largest emitter of GHGs outside of the energy sector. In order to reduce GHG Emissions from peatlands and to achieve other environmental objectives like biodiversity goals, stakeholders in peatland management will need access to reliable site data as well as information about climate-friendly management options. With over one third of the peatland area in Germany, Lower Saxony plays an important role in reducing GHG emissions from peatlands. The peatland information system for Lower Saxony (MoorIS) is a website, which bundles peatland data from different institutions, i.e. nature protection and geological institutes. The content of the website covers maps, detailed information on peatland areas and peatland projects, best practices documents on various climate-friendly management options as well as general texts on peatland management, ecology and regional land use. Furthermore, an online form, which will allow stakeholders to upload basic information about new peatland related projects, will allow users to contribute information to the website. The main target group for MoorIS is users with some previous peatland knowledge, i.e. administrative authorities, stakeholder in politics and industry, non-governmental organizations, planning offices. General texts on peatland topics will allow also users with little previous knowledge to acquire general background knowledge of peatlands in Lower Saxony. Currently, the website focusses on providing small-scale information in the form of maps and databases from various state institutions. However, future expansion of the website could integrate detailed project data. This addition would include local data, such as soil and hydrology data, compiled by management projects. The integration of additional data would entail cooperation with institutes that have existing databases to avoid the duplication of data. Overall, MoorIS aims to provide reliable and comprehensive data to enable stakeholders to plan and manage Lower Saxony’s peatlands in a climate-friendly manner.SUB Göttingen, DGMTrepor

Immunity against measles, mumps, rubella, and varicella among homeless individuals in Germany - A nationwide multi-center cross-sectional study.

INTRODUCTION: Homeless individuals suffer a high burden of vaccine-preventable infectious diseases. Moreover, they are particularly susceptible to adverse infection outcomes with limited access to the health care system. Data on the seroprevalence of measles, mumps, rubella, and varicella within this cohort are missing. METHODS: The seroprevalence of measles, mumps, rubella, and varicella was determined within the homeless population in Germany. Predictors of lacking immune protection were determined using multivariable logistic regression analysis. RESULTS: Homeless individuals in Germany (n = 611) showed a seroprevalence of 88.5% (95% CI: 85.8-91.0) for measles, 83.8% (95% CI: 80.6-86.6) for mumps, 86.1% (95% CI: 83.1-88.7) for rubella, and 95.7% (95% CI 93.8-97.2) for varicella. Measles seroprevalences declined from individuals born in 1965 to individuals born in 1993, with seroprevalences not compatible with a 95% threshold in individuals born after 1980. For mumps, seroprevalences declined from individuals born in 1950 to individuals born in 1984. Here, seroprevalences were not compatible with a 92% threshold for individuals born after 1975. Seronegativity for measles, mumps and rubella was associated with age but not with gender or country of origin. DISCUSSION: Herd immunity for measles and mumps is not achieved in this homeless cohort, while there was sufficient immune protection for rubella and varicella. Declining immune protection rates in younger individuals warrant immunization campaigns also targeting marginalized groups such as homeless individuals. Given that herd immunity thresholds are not reached for individuals born after 1980 for measles, and after 1975 for mumps, vaccination campaigns should prioritize individuals within these age groups

Predictors of Loneliness among Homeless Individuals in Germany during the COVID-19 Pandemic

Purpose: The aim of the study was to identify the frequency of loneliness and to examine the factors associated with loneliness among homeless individuals in Germany during the COVID-19 pandemic. Methods: Data were taken from the &lsquo;national survey on the psychiatric and somatic health of homeless individuals during the COVID-19 pandemic&rsquo;. The data collection took place from 26th July to 17th September 2021 (the analytical sample included n = 491 observations). The well-established UCLA-3 tool was used to quantify loneliness. Independent variables included sex, age, marital status, the existence of children and pets, level of education, country of origin, duration of homelessness, alcohol and drug consumption, mental health concerns and concerns regarding COVID-19 illness. Multiple logistic regressions were used to examine the predictors of loneliness. Results: The frequency of loneliness was 41.7% for the total sample. Multiple logistic regression analysis stratified by gender showed that a higher likelihood of loneliness was associated with being born in Germany, being middle aged (40 to 49 years compared to 18 to 29 years), having mental health problems and a short period of homelessness (1 month compared to longer periods) among women. In men, a higher likelihood of loneliness was associated with a higher fear of COVID-19 and a short period of homelessness. Conclusions: Our study revealed a high frequency rate of loneliness among homeless individuals. The study results highlight the associations between some explanatory variables (i.e., the duration of homelessness and mental health problems). Identifying the factors associated with loneliness may help to adequately address the problems of homeless individuals at risk of loneliness. Longitudinal studies are required to confirm our findings

Quadruple mutation GCAC1809-1812TTCT acts as a biomarker in healthy European HBV carriers

Many mutation analyses of the HBV genome have been performed in the search for new prognostic markers. However, the Kozak sequence preceding precore was covered only infrequently in these analyses. In this study, the HBV core promoter/precore region was sequenced in serum samples from European inactive HBV carriers. Quadruple mutation GCAC1809-1812TTCT was found with a high prevalence of 42% in the Kozak sequence preceding precore among all HBV genotypes. GCAC1809-1812TTCT was strongly associated with coexistence of basal core promoter (BCP) double mutation A1762T/G1764A and lower HBV DNA levels. In vitro GCAC1809-1812TTCT lead to drastically diminished synthesis of pregenomic RNA (pgRNA), precore mRNA, core, HBsAg, and HBeAg. Calculation of the pgRNA secondary structure suggests a destabilization of the pgRNA structure by A1762T/G1764A that was compensated by GCAC1809-1812TTCT. In 125 patients with HBV-related cirrhosis, GCAC1809-1812TTCT was not detected. While a strong association of GCAC1809-1812TTCT with inactive carrier status was observed, BCP double mutation was strongly correlated with cirrhosis, but this was only observed in absence of GCAC1809-1812TTCT. In conclusion, our data reveal that GCAC1809-1812TTCT is highly prevalent in inactive carriers and acts as a compensatory mutation for BCP double mutation. GCAC1809-1812TTCT seems to be a biomarker of good prognosis in HBV infection