The impact of the pandemic on the perception of stress and danger, and the adjustment of psychiatric and general medical staff of German military hospitals.

Introduction: The COVID-19 pandemic changed not only the working conditions but also the private conditions we live in. Health care professionals especially were confronted with multiple stressors, e.g., the risk of infection, lack of staff, and high workloads. Methods: To estimate some of the pandemic-related impacts this anonymous personnel survey was conducted in two German military hospitals (Hamburg and Berlin). This study presents a comparative analysis of the hospital staff in general vs. the psychiatric personnel (N = 685) at two measurement time points (MTPs) in April 2021 (n = 399) and December 2021 (n = 286). The survey contains the German version of the Covid Stress Scale (CSS) to assess the perceived level of pandemic-related stress, the Patient Health Questionnaire (German Version: PHQ-D) to screen for three major mental disorders, and the adjustment disorder-New Module (ADNM) to estimate the problems of adaptation to change. Results: The results showed a process of adaptation over the two MTPs with significant stress reduction at MTP2 in the general staff. The psychiatric staff did not report significantly higher pandemic-related symptoms. Quite the contrary, not only did the CSS show significantly lower xenophobia, traumatic stress, and compulsive checking, but the PHQ also showed lower stress symptoms and somatic symptoms at both MTPs. Also, the ADNM scores delivered evidence for a more effective adaptation process in psychiatric personnel (e.g., depressive mood, avoidance, anxiety). Discussion: The presented results must be interpreted while taking the unique situations of German military clinics into account. The supply of protective material was sufficient and there was no dramatic shortage of psychiatric staff during the pandemic. The inpatients were quite often (40%) elective treatments for trauma-related disorders, which could be discontinued in the case of a COVID-19 infection. The results of this study showed good adaptative skills among the psychiatric staff in military hospitals, which could be interpreted as a sign of good resilience. This might have led to lower stress-related symptoms during the COVID-19 pandemic.

Contact tracing & super-spreaders in the branching-process model.

In recent years, it became clear that super-spreader events play an important role, particularly in the spread of airborne infections. We investigate a novel model for super-spreader events, not based on a heterogeneous contact graph but on a random contact rate: Many individuals become infected synchronously in single contact events. We use the branching-process approach for contact tracing to analyze the impact of super-spreader events on the effect of contact tracing. Here we neglect a tracing delay. Roughly speaking, we find that contact tracing is more efficient in the presence of super-spreaders if the fraction of symptomatics is small, the tracing probability is high, or the latency period is distinctively larger than the incubation period. In other cases, the effect of contact tracing can be decreased by super-spreaders. Numerical analysis with parameters suited for SARS-CoV-2 indicates that super-spreaders do not decrease the effect of contact tracing crucially in case of that infection.

Aptamers Against COVID-19: An Untested Opportunity.

Given the lack of success in the development of effective drugs to treat COVID-19, which show "game-changing" potential, it is necessary to explore drugs with different modes of action. Single mode-of-action drugs have not been succeeded in curing COVID-19, which is a highly complex disease. This is the case for direct antivirals and anti-inflammatory drugs, both of which treat different phases of the disease. Aptamers are molecules that deliver different modes of action, allowing their effects to be bundled, which, when combined, support their therapeutic efficacy. In this minireview, we summarise the current activities in the development of aptamers for the treatment of COVID-19 and long-COVID. A special emphasis is placed on the capability of their multiple modes of action, which is a promising approach for treating complex diseases such as COVID-19.

Case Report: Neutralization of Autoantibodies Targeting G-Protein-Coupled Receptors Improves Capillary Impairment and Fatigue Symptoms After COVID-19 Infection.

Clinical features of Coronavirus disease 2019 (COVID-19) are caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Acute infection management is a substantial healthcare issue, and the development of long-Covid syndrome (LCS) is extremely challenging for patients and physicians. It is associated with a variety of characteristics as impaired capillary microcirculation, chronic fatigue syndrome (CFS), proinflammatory cytokines, and functional autoantibodies targeting G-protein-coupled receptors (GPCR-AAbs). Here, we present a case report of successful healing of LCS with BC 007 (Berlin Cures, Berlin, Germany), a DNA aptamer drug with a high affinity to GPCR-AAbs that neutralizes these AAbs. A patient with a documented history of glaucoma, recovered from mild COVID-19, but still suffered from CFS, loss of taste, and impaired capillary microcirculation in the macula and peripapillary region. He was positively tested for various targeting GPCR-AAbs. Within 48 h after a single BC 007 treatment, GPCR-AAbs were functionally inactivated and remained inactive during the observation period of 4 weeks. This observation was accompanied by constant improvement of the fatigue symptoms of the patient, taste, and retinal capillary microcirculation. Therefore, the removal of GPCR-AAb might ameliorate the characteristics of the LCD, such as capillary impairment, loss of taste, and CFS.

Lack of efficacy of mono-mode of action therapeutics in COVID-19 therapy - How the lack of predictive power of preclinical cell and animal studies leads developments astray.

The diverse experiences regarding the failure of tested drugs in the fight against COVID-19 made it clear that one should at least question the requirement to apply classical preclinical development strategies that demand cell and animal efficacy models to be tested before going into clinical trials. Most animals are not susceptible to infection with SARS-CoV-2, and so this led to one-sided virus replication experiments in cells and the use of animal models that have little in common with the complex pathogenesis of COVID-19 in humans. Therefore, non-clinical development strategies were designed to meet regulatory requirements, but they did not truly reflect the situation in the clinic. This has led the search for effective agents astray in many cases. As proof of this statement, we now bring together the results of such required preclinical experiments and compare with the results in clinical trials. Two clear conclusions that can be drawn from the experience to date: The required preclinical models are unsuitable for the development of innovative treatments medical devices in the case of COVID-19 and mono-action strategies (e.g. direct antivirals) are of very little or no benefit to patients under randomized,blinded conditions. Our hypothesis is that the complex situation of COVID-19 may benefit from multi-mode drugs. Here, the molecular class of aptamers could be a solution.

Should I stay or should I go?

Analysing the characteristics of the SARS-CoV-2 virus makes it possible to estimate the length of quarantine that reduces the impact on society and the economy, while minimising infections.

The impact of digital contact tracing on the SARS-CoV-2 pandemic-a comprehensive modelling study.

Contact tracing is one of several strategies employed in many countries to curb the spread of SARS-CoV-2. Digital contact tracing (DCT) uses tools such as cell-phone applications to improve tracing speed and reach. We model the impact of DCT on the spread of the virus for a large epidemiological parameter space consistent with current literature on SARS-CoV-2. We also model DCT in combination with random testing (RT) and social distancing (SD). Modelling is done with two independently developed individual-based (stochastic) models that use the Monte Carlo technique, benchmarked against each other and against two types of deterministic models. For current best estimates of the number of asymptomatic SARS-CoV-2 carriers (approximately 40%), their contagiousness (similar to that of symptomatic carriers), the reproductive number before interventions ( R 0 at least 3) we find that DCT must be combined with other interventions such as SD and/or RT to push the reproductive number below one. At least 60% of the population would have to use the DCT system for its effect to become significant. On its own, DCT cannot bring the reproductive number below 1 unless nearly the entire population uses the DCT system and follows quarantining and testing protocols strictly. For lower uptake of the DCT system, DCT still reduces the number of people that become infected. When DCT is deployed in a population with an ongoing outbreak where O (0.1%) of the population have already been infected, the gains of the DCT intervention come at the cost of requiring up to 15% of the population to be quarantined (in response to being traced) on average each day for the duration of the epidemic, even when there is sufficient testing capability to test every traced person.

Aptamer BC 007's Affinity to Specific and Less-Specific Anti-SARS-CoV-2 Neutralizing Antibodies.

COVID-19 is a pandemic respiratory disease that is caused by the highly infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Anti-SARS-CoV-2 antibodies are essential weapons that a patient with COVID-19 has to combat the disease. When now repurposing a drug, namely an aptamer that interacts with SARS-CoV-2 proteins for COVID-19 treatment (BC 007), which is, however, a neutralizer of pathogenic autoantibodies in its original indication, the possibility of also binding and neutralizing anti-SARS-CoV-2 antibodies must be considered. Here, the highly specific virus-neutralizing antibodies have to be distinguished from the ones that also show cross-reactivity to tissues. The last-mentioned could be the origin of the widely reported SARS-CoV-2-induced autoimmunity, which should also become a target of therapy. We, therefore, used enzyme-linked immunosorbent assay (ELISA) technology to assess the binding of well-characterized publicly accessible anti-SARS-CoV-2 antibodies (CV07-209 and CV07-270) with BC 007. Nuclear magnetic resonance spectroscopy, isothermal calorimetric titration, and circular dichroism spectroscopy were additionally used to test the binding of BC 007 to DNA-binding sequence segments of these antibodies. BC 007 did not bind to the highly specific neutralizing anti-SARS-CoV-2 antibody but did bind to the less specific one. This, however, was a lot less compared to an autoantibody of its original indication (14.2%, range 11.0-21.5%). It was also interesting to see that the less-specific anti-SARS-CoV-2 antibody also showed a high background signal in the ELISA (binding on NeutrAvidin-coated or activated but noncoated plastic plate). These initial experiments suggest that the risk of binding and neutralizing highly specific anti-SARS CoV-2 antibodies by BC 007 should be low.

Forward thinking on backward tracing

SARS, MERS and now SARS-CoV-2 are unlikely to be the last emerging infections we face during our lifetimes. Tracing contacts both forward and backward through our heterogeneous populations will prove essential to future response strategies.

Functional autoantibodies against G-protein coupled receptors in patients with persistent Long-COVID-19 symptoms.

Impairment of health after overcoming the acute phase of COVID-19 is being observed more and more frequently. Here different symptoms of neurological and/or cardiological origin have been reported. With symptoms, which are very similar to the ones reported but are not caused by SARS-CoV-2, the occurrence of functionally active autoantibodies (fAABs) targeting G-protein coupled receptors (GPCR-fAABs) has been discussed to be involved. We, therefore investigated, whether GPCR-fAABs are detectable in 31 patients suffering from different Long-COVID-19 symptoms after recovery from the acute phase of the disease. The spectrum of symptoms was mostly of neurological origin (29/31 patients), including post-COVID-19 fatigue, alopecia, attention deficit, tremor and others. Combined neurological and cardiovascular disorders were reported in 17 of the 31 patients. Two recovered COVID-19 patients were free of follow-up symptoms. All 31 former COVID-19 patients had between 2 and 7 different GPCR-fAABs that acted as receptor agonists. Some of those GPCR-fAABs activate their target receptors which cause a positive chronotropic effect in neonatal rat cardiomyocytes, the read-out in the test system for their detection (bioassay for GPCR-fAAB detection). Other GPCR-fAABs, in opposite, cause a negative chronotropic effect on those cells. The positive chronotropic GPCR-fAABs identified in the blood of Long-COVID patients targeted the ß2-adrenoceptor (ß2-fAAB), the α1-adrenoceptor (α1-fAAB), the angiotensin II AT1-receptor (AT1-fAAB), and the nociceptin-like opioid receptor (NOC-fAAB). The negative chronotropic GPCR-fAABs identified targeted the muscarinic M2-receptor (M2-fAAB), the MAS-receptor (MAS-fAAB), and the ETA-receptor (ETA-fAAB). It was analysed which of the extracellular receptor loops was targeted by the autoantibodies.

Use of Digital Media for Home-Based Sports Activities during the COVID-19 Pandemic: Results from the German SPOVID Survey.

Health authorities recommend digital tools for home-based sport and exercise routines to stay active and healthy during the COVID-19 pandemic. The study investigates the prevalence, duration, most popular activities, and social selectivity of home-based digital sport and its contribution to overall levels of sporting activity during the pandemic. It is based on cross-sectional survey data (n = 1508), representing the population >14 years living in Germany. Data collection took place in October 2020, using computer-assisted web interviewing. Results show that overall, 23% of respondents used digital media for sports activities at least one time during the COVID-19 pandemic. Numbers increased during the lockdown and decreased afterwards. People engaged in a variety of fitness workouts, most frequently practiced with the help of publicly accessible fitness videos from video-sharing platforms. Digital sports practitioners are younger, better educated, and financially better off. Females are overrepresented. Individuals engaged in digital sports achieved 30 min/week more sports activity during the pandemic compared to individuals solely involved in offline sports. Hence, home-based digital sports activities were a popular means to stay active, particularly in the period of the lockdown. Strong social disparities indicate that the possible health benefits of digital sports only reach out to particular population groups.

Contact tracing - Old models and new challenges.

Contact tracing is an effective method to control emerging infectious diseases. Since the 1980's, modellers are developing a consistent theory for contact tracing, with the aim to find effective and efficient implementations, and to assess the effects of contact tracing on the spread of an infectious disease. Despite the progress made in the area, there remain important open questions. In addition, technological developments, especially in the field of molecular biology (genetic sequencing of pathogens) and modern communication (digital contact tracing), have posed new challenges for the modelling community. In the present paper, we discuss modelling approaches for contact tracing and identify some of the current challenges for the field.

Aptamer BC 007 - Efficient binder of spreading-crucial SARS-CoV-2 proteins.

Corona virus disease 2019 (COVID-19) is a respiratory disease caused by a new coronavirus (SARS-CoV-2) which causes significant morbidity and mortality. The emergence of this novel and highly pathogenic SARS-CoV-2 and its rapid international spread poses a serious global public health emergency. To date 32,174,627 cases, of which 962,613 (2.99%) have died, have been reported (https://www.who.int/westernpacific/health-topics/coronavirus, accessed 23 Sep 2020). The outbreak was declared a Public Health Emergency of International Concern on 30 January 2020. There are still not many SARS-CoV-2-specific and effective treatments or vaccines available. A second round of infection is obviously unavoidable. Aptamers had already been at the centre of interest in the fight against viruses before now. The selection and development of a new aptamer is, however, a time-consuming process. We therefore checked whether a clinically developed aptamer, BC 007, which is currently in phase 2 of clinical testing for a different indication, would also be able to efficiently bind DNA-susceptible peptide structures from SARS-CoV-2-spreading crucial proteins, such as the receptor binding domain (RBD) of the spike protein and the RNA dependent RNA polymerase of SARS-CoV-2 (re-purposing). Indeed, several such sequence-sections have been identified. In particular for two of these sequences, BC 007 showed specific binding in a therapy-relevant concentration range, as shown in Nuclear magnetic resonance (NMR)- and Circular dicroism (CD)-spectroscopy and isothermal titration calorimetry (ITC). The excellent clinical toxicity and tolerability profile of this substance opens up an opportunity for rapid clinical testing of its COVID-19 effectiveness.