Abstract: Plants, fungi and algae are important components of global biodiversity and are fundamental to all ecosystems. They are the basis for human well-being, providing food, materials and medicines. Specimens of all three groups of organisms are accommodated in herbaria, where they are commonly referred to as botanical specimens. The large number of specimens in herbaria provides an ample, permanent and continuously improving knowledge base on these organisms and an indispensable source for the analysis of the distribution of species in space and time critical for current and future research relating to global biodiversity. In order to make full use of this resource, a research infrastructure has to be built that grants comprehensive and free access to the information in herbaria and botanical collections in general. This can be achieved through digitization of the botanical objects and associated data. The botanical research community can count on a long-standing tradition of collaboration among institutions and individuals. It agreed on data standards and standard services even before the advent of computerization and information networking, an example being the Index Herbariorum as a global registry of herbaria helping towards the unique identification of specimens cited in the literature. In the spirit of this collaborative history, 51 representatives from 30 institutions advocate to start the digitization of botanical collections with the overall wall-to-wall digitization of the flat objects stored in German herbaria. Germany has 70 herbaria holding almost 23 million specimens according to a national survey carried out in 2019. 87% of these specimens are not yet digitized. Experiences from other countries like France, the Netherlands, Finland, the US and Australia show that herbaria can be comprehensively and cost-efficiently digitized in a relatively short time due to established workflows and protocols for the high-throughput digitization of flat objects. Most of the herbaria are part of a university (34), fewer belong to municipal museums (10) or state museums (8), six herbaria belong to institutions also supported by federal funds such as Leibniz institutes, and four belong to non-governmental organizations. A common data infrastructure must therefore integrate different kinds of institutions. Making full use of the data gained by digitization requires the set-up of a digital infrastructure for storage, archiving, content indexing and networking as well as standardized access for the scientific use of digital objects. A standards-based portfolio of technical components has already been developed and successfully tested by the Biodiversity Informatics Community over the last two decades, comprising among others access protocols, collection databases, portals, tools for semantic enrichment and annotation, international networking, storage and archiving in accordance with international standards. This was achieved through the funding by national and international programs and initiatives, which also paved the road for the German contribution to the Global Biodiversity Information Facility (GBIF). Herbaria constitute a large part of the German botanical collections that also comprise living collections in botanical gardens and seed banks, DNA- and tissue samples, specimens preserved in fluids or on microscope slides and more. Once the herbaria are digitized, these resources can be integrated, adding to the value of the overall research infrastructure. The community has agreed on tasks that are shared between the herbaria, as the German GBIF model already successfully demonstrates. We have compiled nine scientific use cases of immediate societal relevance for an integrated infrastructure of botanical collections. They address accelerated biodiversity discovery and research, biomonitoring and conservation planning, biodiversity modelling, the generation of trait information, automated image recognition by artificial intelligence, automated pathogen detection, contextualization by interlinking objects, enabling provenance research, as well as education, outreach and citizen science. We propose to start this initiative now in order to valorize German botanical collections as a vital part of a worldwide biodiversity data pool.

Abstract: Patients suffering from chronic kidney disease (CKD) are in general at high risk for severe coronavirus disease (COVID-19) but dialysis-dependency (CKD5D) is poorly understood. We aimed to describe CKD5D patients in the different intervals of the pandemic and to evaluate pre-existing dialysis dependency as a potential risk factor for mortality. Methods In this multicentre cohort study, data from German study sites of the Lean European Open Survey on SARS-CoV-2-infected patients (LEOSS) were used. We multiply imputed missing data, performed subsequent analyses in each of the imputed data sets and pooled the results. Cases (CKD5D) and controls (CKD not requiring dialysis) were matched 1:1 by propensity-scoring. Effects on fatal outcome were calculated by multivariable logistic regression. Results The cohort consisted of 207 patients suffering from CKD5D and 964 potential controls. Multivariable regression of the whole cohort identified age ( 〉  85 years adjusted odds ratio (aOR) 7.34, 95% CI 2.45–21.99), chronic heart failure (aOR 1.67, 95% CI 1.25–2.23), coronary artery disease (aOR 1.41, 95% CI 1.05–1.89) and active oncological disease (aOR 1.73, 95% CI 1.07–2.80) as risk factors for fatal outcome. Dialysis-dependency was not associated with a fatal outcome—neither in this analysis (aOR 1.08, 95% CI 0.75–1.54) nor in the conditional multivariable regression after matching (aOR 1.34, 95% CI 0.70–2.59). Conclusions In the present multicentre German cohort, dialysis dependency is not linked to fatal outcome in SARS-CoV-2-infected CKD patients. However, the mortality rate of 26% demonstrates that CKD patients are an extreme vulnerable population, irrespective of pre-existing dialysis-dependency.

Abstract: Population-based serological studies allow to estimate prevalence of SARS-CoV-2 infections despite a substantial number of mild or asymptomatic disease courses. This became even more relevant for decision making after vaccination started. The KoCo19 cohort tracks the pandemic progress in the Munich general population for over two years, setting it apart in Europe. Methods Recruitment occurred during the initial pandemic wave, including 5313 participants above 13 years from private households in Munich. Four follow-ups were held at crucial times of the pandemic, with response rates of at least 70%. Participants filled questionnaires on socio-demographics and potential risk factors of infection. From Follow-up 2, information on SARS-CoV-2 vaccination was added. SARS-CoV-2 antibody status was measured using the Roche Elecsys® Anti-SARS-CoV-2 anti-N assay (indicating previous infection) and the Roche Elecsys® Anti-SARS-CoV-2 anti-S assay (indicating previous infection and/or vaccination). This allowed us to distinguish between sources of acquired antibodies. Results The SARS-CoV-2 estimated cumulative sero-prevalence increased from 1.6% (1.1-2.1%) in May 2020 to 14.5% (12.7-16.2%) in November 2021. Underreporting with respect to official numbers fluctuated with testing policies and capacities, becoming a factor of more than two during the second half of 2021. Simultaneously, the vaccination campaign against the SARS-CoV-2 virus increased the percentage of the Munich population having antibodies, with 86.8% (85.5-87.9%) having developed anti-S and/or anti-N in November 2021. Incidence rates for infections after (BTI) and without previous vaccination (INS) differed (ratio INS/BTI of 2.1, 0.7-3.6). However, the prevalence of infections was higher in the non-vaccinated population than in the vaccinated one. Considering the whole follow-up time, being born outside Germany, working in a high-risk job and living area per inhabitant were identified as risk factors for infection, while other socio-demographic and health-related variables were not. Although we obtained significant within-household clustering of SARS-CoV-2 cases, no further geospatial clustering was found. Conclusions Vaccination increased the coverage of the Munich population presenting SARS-CoV-2 antibodies, but breakthrough infections contribute to community spread. As underreporting stays relevant over time, infections can go undetected, so non-pharmaceutical measures are crucial, particularly for highly contagious strains like Omicron.

Abstract: Currently, there are no approved treatments for early disease stages of COVID-19 and few strategies to prevent disease progression after infection with SARS-CoV-2. The objective of this study is to evaluate the safety and efficacy of convalescent plasma (CP) or camostat mesylate administered within 72 h of diagnosis of SARS-CoV-2 infection in adult individuals with pre-existing risk factors at higher risk of getting seriously ill with COVID-19. Camostat mesylate acts as an inhibitor of the host cell serine protease TMPRSS2 and prevents the virus from entering the cell. CP represents another antiviral strategy in terms of passive immunization. The working hypothesis to be tested in the RES-Q-HR study is that the early use of CP or camostat mesylate reduces the likelihood of disease progression to (modified) WHO stages 4b-8 in SARS-CoV-2-positive adult patients at high risk of moderate or severe COVID-19 progression. Trial design This study is a 4-arm (parallel group), multicenter, randomized (2:2:1:1 ratio), partly double-blind, controlled trial to evaluate the safety and efficacy of convalescent plasma (CP) or camostat mesylate with control or placebo in adult patients diagnosed with SARS-CoV-2 infection and high risk for progression to moderate/severe COVID-19. Superiority of the intervention arms will be tested. Participants The trial is conducted at 10–15 tertiary care centers in Germany. Individuals aged 18 years or above with ability to provide written informed consent with SARS-CoV-2 infection, confirmed by PCR within 3 days or less before enrolment and the presence of at least one SARS-CoV-2 symptom (such as fever, cough, shortness of breath, sore throat, headache, fatigue, smell/and or taste disorder, diarrhea, abdominal symptoms, exanthema) and symptom duration of not more than 3 days. Further inclusion criteria comprise: Presence of at least one of the following criteria indicating increased risk for severe COVID-19: Age 〉  75 years Chronic obstructive pulmonary disease (COPD) and/or pulmonary fibrosis BMI 〉  40 kg/m 2 Age 〉  65 years with at least one other risk factor (BMI 〉  35 kg/m 2 , coronary artery disease (CAD), chronic kidney disease (CKD) with GFR 〈  60 ml/min but ≥ 30 ml/min, diabetes mellitus, active tumor disease) BMI 〉  35 kg/m 2 with at least one other risk factor (CAD, CKD with GFR 〈  60 ml/min but ≥ 30 ml/min, diabetes mellitus, active tumor disease) Exclusion criteria: Age 〈  18 years Unable to give informed consent Pregnant women or breastfeeding mothers Previous transfusion reaction or other contraindication to a plasma transfusion Known hypersensitivity to camostat mesylate and/or severe pancreatitis Volume stress due to CP administration would be intolerable Known IgA deficiency Life expectancy 〈  6 months Duration SARS-CoV-2 typical symptoms 〉  3 days SARS-CoV-2 PCR detection older than 3 days SARS-CoV-2 associated clinical condition ≥ WHO stage 3 (patients hospitalized for other reasons than COVID-19 may be included if they fulfill all inclusion and none of the exclusion criteria) Previously or currently hospitalized due to SARS-CoV-2 Previous antiviral therapy for SARS-CoV-2 ALT or AST 〉  5 x ULN at screening Liver cirrhosis 〉 Child A (patients with Child B/C cirrhosis are excluded from the trial) Chronic kidney disease with GFR  〈  30 ml/min Concurrent or planned anticancer treatment during trial period Accommodation in an institution due to legal orders (§40(4) AMG). Any psycho-social condition hampering compliance with the study protocol. Evidence of current drug or alcohol abuse Use of other investigational treatment within 5 half-lives of enrolment is prohibited Previous use of convalescent plasma for COVID-19 Concomitant proven influenza A infection Patients with organ or bone marrow transplant in the three months prior to screening visit Intervention and comparator Participants will be randomized to the following 4 groups: Convalescent plasma (CP), 2 units at screening/baseline visit (day 0) or day 1; CP is defined by the presence of neutralizing anti-SARS-CoV-2 antibodies with titers ≥ 1:160; individuals with body weight ≥ 150 kg will receive a third unit of plasma on day 3 Camostat mesylate (200 mg per capsule, one capsule taken each in the morning, afternoon and evening on days 1–7) Standard of care (SOC, control for CP) Placebo (identical in appearance to camostat mesylate capsules, one capsule taken each morning, afternoon and evening on days 1–7; for camostat mesylate control group) Participants will be monitored after screening/baseline on day 3, day 5, day 8, and day 14. On day 28 and day 56, telephone visits and on day 90, another outpatient visit are scheduled. Adverse events and serious adverse events will be monitored and reported until the end of the study. An independent data safety monitoring committee will review trial progression and safety. Main outcomes The primary endpoint of the study is the cumulative number of individuals who progress to or beyond category 4b on the modified WHO COVID-19 ordinal scale (defined as hospitalization with COVID-19 pneumonia and additional oxygen demand via nasal cannula or mask) within 28 days after randomization. Randomization Participants will be randomized using the Alea-Tool ( aleaclinical.com ) in a 2:2:1:1 ratio to the treatment arms (1) CP, (2) camostat mesylate, (3) standard of care (SoC), and (4) placebo matching camostat mesylate. Randomization will be stratified by study center. Blinding (masking) The camostat mesylate treatment arm and the respective placebo will be blinded for participants, caregivers, and those assessing outcomes. The treatment arms convalescent plasma and standard of care will not be blinded and thus are open-labeled, unblinded. Numbers to be randomized (sample size) Overall, n  = 994 participants will be randomized to the following groups: n  = 331 to convalescent plasma (CP), n  = 331 to camostat mesylate, n  = 166 to standard of care (SoC), and n  = 166 to placebo matching camostat mesylate. Trial status The RES-Q-HR protocol (V04F) was approved on the 18 December 2020 by the local ethics committee and by the regulatory institutions PEI/BfARM on the 2 December 2020. The trial was opened for recruitment on 26 December 2020; the first patient was enrolled on 7 January 2021 and randomized on 8 January 2021. Recruitment shall be completed by June 2021. The current protocol version RES-Q HR V05F is from 4 January 2021, which was approved on the 18 January 2021. Trial registration EudraCT Number 2020-004695-18 . Registered on September 29, 2020. ClinicalTrial.gov NCT04681430 . Registered on December 23, 2020, prior to the start of the enrollment (which was opened on December 26, 2020). Full protocol The full protocol (V05F) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Abstract: Introduction While lithium (Li) has been well established for the treatment of bipolar disorder, geriatric patients require special attention when it comes to issues of drug safety. Declining renal function, amongst other medical conditions, and polypharmacy may pose increased risks. Only a few previous studies have addressed the management of Li in geriatric patients. Methods Twenty-four German medical experts on geriatric medicine and Li treatment participated in a Delphi survey, consisting of two rounds of questionnaires and a final formulation of treatment recommendations. Three major issues of Li therapy were outlined: initiation of treatment, monitoring of ongoing therapy, and withdrawal due to medical reasons. Final recommendations were consented to at a threshold of at least 80% expert agreement. Results Final consensus was achieved on 21 clinical recommendations. The approved recommendations covered aspects of necessary laboratory checks, concomitant medication, and target Li serum concentration in geriatric patients. Concerning the termination of Li therapy, an agreement was reached on the appropriate time span for tapering and on potential alternatives to Li. No consensus was achieved on whether concomitant dementia or frailty should be considered contraindications for Li treatment and the appropriate threshold of the estimated glomerular function rate for withdrawing Li. Conclusion According to the view of German experts, Li may be used in geriatric patients, but it should be monitored carefully. However, the lack of consent in several specific treatment situations underlines the need for research on specific issues of Li therapy.

Abstract: OBJECTIVES The aim of this study was to analyse the outcome of patients between 50 and 69 years of age undergoing biological or mechanical aortic valve replacement. METHODS Data were collected from the German Aortic Valve Registry. Data were analysed regarding baseline characteristics and outcome parameters such as 5-year survival, stroke and reintervention. RESULTS In total,   3046 patients undergoing isolated surgical aortic valve replacement between 2011 and 2012 were investigated and a propensity score matching was performed. Within this period, 2239 patients received a biological prostheses, while 807 patients received a mechanical prosthesis. Mean age in the biological group was 63.07 (±5.11) and 57.34 (±4.67) in the mechanical group (standardized mean difference 1.172). In the overall cohort, there were more female patients in the biological group (32.7% vs 28.4%) and log EuroSCORE I was higher (5.41% vs 4.26%). After propensity matching (610 pairs), there was no difference in the mortality at 5-year follow-up (12.1% biological vs 9.2% mechanical P = 0.05) nor for reoperation/reintervention (2.5% biological vs 2.0% mechanical, P = 0.546). Patients undergoing mechanical aortic valve replacement suffered from a higher stroke rate 3.3% vs 1.5% (P = 0.04) at 5-year follow-up. CONCLUSIONS Aortic valve replacement with biological or mechanical prostheses showed similar 5-year outcomes for survival and reoperation in a propensity-matched cohort, but significantly increased stroke rate after mechanical aortic valve replacement. This could influence the choice of a mechanical valve in younger patients.

Abstract: OBJECTIVES Chronic kidney disease (CKD) is a key risk factor in patients undergoing transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement (SAVR). We analysed the impact of estimated glomerular filtration rate (eGFR) and CKD stages on their mid-term survival. METHODS Data from 29 893 patients enrolled in the German Aortic Valve registry from January 2011 to December 2015 receiving TAVI (n = 12 834) or SAVR (n = 17 059) at 88 sites were included. The impact of renal impairment, as measured by eGFR and CKD stages, was investigated. The primary end-point was 1-year cumulative all-cause mortality. RESULTS Higher CKD stages were significantly associated to lower in-hospital, 30-day- and 1-year survival rates. Both TAVI- and SAVR-treated patients in CKD 3a, 3b, 4 and 5 stages showed significant and gradually increasing HR values for 1-year all-cause mortality. The same trend persisted in multivariable analysis, although HR values for CKD 3a and 5 did not reach significance in TAVI patients, whereas CKD 4 + 5 did not reach statistical significance in SAVR. Likewise, eGFR as a continuous variable was a significant predictor for 1-year mortality, with the best cut-off points being 47.4 ml/min/1.73 m2 for TAVI and 59.8 ml/min/1.73 m2 for SAVR. Significant 8.6% and 9.0% increases in 1-year mortality were observed for every 5-ml reduction in eGFR for TAVI and SAVR, respectively. CONCLUSIONS CKD ≥3b and CKD ≥3a are the independent major risk factors for mortality in patients undergoing TAVI and SAVR, respectively. In the overall population of patients with severe aortic stenosis, an appropriate stratification based on CKD substage may contribute to a better selection of patients suitable for such therapies.