Structural and Functional Characterization of the Ureidoacrylate Amidohydrolase RutB from Escherichia coli.

We present a detailed structure-function analysis of the ureidoacrylate amidohydrolase RutB from Eschericha coli, which is an essential enzyme of the Rut pathway for pyrimidine utilization. Crystals of selenomethionine-labeled RutB were produced, which allowed us to determine the first structure of the enzyme at a resolution of 1.9 Å and to identify it as a new member of the isochorismatase-like hydrolase family. RutB was co-crystallized with the substrate analogue ureidopropionate, revealing the mode of substrate binding. Mutation of residues constituting the catalytic triad (D24A, D24N, K133A, C166A, C166S, C166T, C166Y) resulted in complete inactivation of RutB, whereas mutation of other residues close to the active site (Y29F, Y35F, N72A, W74A, W74F, E80A, E80D, S92A, S92T, S92Y, Q105A, Y136A, Y136F) leads to distinct changes of the turnover number (kcat) and/or the Michaelis constant (KM). The results of our structural and mutational studies allowed us to assign specific functions to individual residues and to formulate a plausible reaction mechanism for RutB.

Retracing the Rapid Evolution of an Herbicide-Degrading Enzyme by Protein Engineering.

The mechanisms underlying the rapid evolution of novel enzymatic activities from promiscuous side activities are poorly understood. Recently emerged enzymes catalyzing the catabolic degradation of xenobiotic substances that have been spread out into the environment during the last decades provide an exquisite opportunity to study these mechanisms. A prominent example is the herbicide atrazine (2-chloro-4-ethylamino-6-isopropylamino-1,3,5-triazine), which is degraded through a number of enzymatic reactions constituting the Atz pathway. Here, we analyzed the evolution of the hydroxyatrazine ethylaminohydrolase AtzB, a Zn(II)-dependent metalloenzyme that adopts the amidohydrolase fold and catalyzes the second step of the Atz pathway. We searched for promiscuous side activities of AtzB, which might point to the identity of its progenitor. These investigations revealed that AtzB has low promiscuous guanine deaminase activity. Furthermore, we found that the two closest AtzB homologues, which have not been functionally annotated up to now, are guanine deaminases with modest promiscuous hydroxyatrazine hydrolase activity. Based on sequence comparisons with the closest AtzB homologues, the guanine deaminase activity of AtzB could be increased by three orders of magnitude through the introduction of only four active site mutations. Interestingly, introducing the inverse four mutations into the AtzB homologues significantly enhanced their hydroxyatrazine hydrolase activity, and in one case is even equivalent to that of wild-type AtzB. Molecular dynamics simulations elucidated the structural and molecular basis for the mutation-induced activity changes. The example of AtzB highlights how novel enzymes with high catalytic proficiency can evolve from low promiscuous side activities by only few mutational events within a short period of time.

The Burden of Disease in Germany at the National and Regional Level.

BACKGROUND: .Summary measures such as disability-adjusted life years (DALY) are becoming increasingly important for the standardized assessment of the burden of disease due to death and disability. The BURDEN 2020 pilot project was designed as an independent burden-of-disease study for Germany, which was based on nationwide data, but which also yielded regional estimates. METHODS: DALY is defined as the sum of years of life lost due to death (YLL) and years lived with disability (YLD). YLL is the difference between the age at death due to disease and the remaining life expectancy at this age, while YLD quantifies the number of years individuals have spent with health impairments. Data are derived mainly from causes of death statistics, population health surveys, and claims data from health insurers. RESULTS: In 2017, there were approximately 12 million DALY in Germany, or 14 584 DALY per 100 000 inhabitants. Conditions which caused the greatest number of DALY were coronary heart disease (2321 DALY), low back pain (1735 DALY), and lung cancer (1197 DALY). Headache and dementia accounted for a greater disease burden in women than in men, while lung cancer and alcohol use disorders accounted for a greater disease burden in men than in women. Pain disorders and alcohol use disorders were the leading causes of DALY among young adults of both sexes. The disease burden rose with age for some diseases, including cardiovascular diseases, dementia, and diabetes mellitus. For some diseases and conditions, the disease burden varied by geographical region. CONCLUSION: The results indicate a need for age- and sex-specific prevention and for differing interventions according to geographic region. Burden of disease studies yield comprehensive population health surveillance data and are a useful aid to decision-making in health policy.

Out of sight for the endoscopist? Gastrointestinal bleeding after aortic repair.

BACKGROUND AND STUDY AIM: Secondary Aortoenteric Fistulas (sAEF) are difficult to diagnose and usually result in fatal gastrointestinal (GI) bleeding following aortic repair. Outcomes are largely dependent on a timely diagnosis, but AEFs remain challenging to identify endoscopically and are usually diagnosed on computed tomography (CT) scans. The aim of our study was optimize diagnosis of AEF by identifying patients developing GI bleeding after aortic repair, investigate their clinical course and identify factors specific to different bleeding sources. METHODS: A retrospective, single-center study capturing all patients developing upper or lower GI bleeding after aortic surgery between January 2009 and March 2020 was performed. Electronic health records were screened for diagnostic codes of the relevant procedures. Bleeding was classified into three groups: AEF with demonstrable fistula, ischemic - macroscopic ulceration plus histological confirmation or imaging and "other" due to other recognized conventional cause, such as peptic ulcer disease. RESULTS: 47 GI bleeding episodes in 39 patients were identified. Of these, 10 episodes (21%) were caused by AEF, 16 (34%) by ischemic ulceration and 21 (45%) due to other causes. Patients with AEF exhibited more frequent hemodynamic instability requiring vasopressors and had higher mortality, while ischemic ulcerations were associated with more recent operation or hypotensive episode. CONCLUSIONS: GI bleeding complications are uncommon following aortic surgery. AEF and ischemic ulceration are however frequent bleeding causes in this cohort. In patients presenting with fulminant bleeding, primary CT-scanning should be considered.

Clinical and biochemical endpoints and predictors of response to plasma exchange in septic shock: results from a randomized controlled trial.

BACKGROUND: Recently, a randomized controlled trial (RCT) demonstrated rapid but individually variable hemodynamic improvement with therapeutic plasma exchange (TPE) in patients with septic shock. Prediction of clinical efficacy in specific sepsis treatments is fundamental for individualized sepsis therapy. METHODS: In the original RCT, patients with septic shock of < 24 h duration and norepinephrine (NE) requirement ≥ 0.4 µg/kg/min received standard of care (SOC) or SOC + one single TPE. Here, we report all clinical and biological endpoints of this study. Multivariate mixed-effects modeling of NE reduction was performed to investigate characteristics that could be associated with clinical response to TPE. RESULTS: A continuous effect of TPE on the reduction in NE doses over the initial 24 h was observed (SOC group: estimated NE dose reduction of 0.005 µg/kg/min per hour; TPE group: 0.018 µg/kg/min per hour, p = 0.004). Similarly, under TPE, serum lactate levels, continuously decreased over the initial 24 h in the TPE group, whereas lactate levels increased under SOC (p = 0.001). A reduction in biomarkers and disease mediators (such as PCT (p = 0.037), vWF:Ag (p < 0.001), Angpt-2 (p = 0.009), sTie-2 (p = 0.005)) along with a repletion of exhausted protective factors (such as AT-III (p = 0.026), Protein C (p = 0.012), ADAMTS-13 (p = 0.008)) could be observed in the TPE but not in the SOC group. In a multivariate mixed effects model, increasing baseline lactate levels led to greater NE dose reduction effects with TPE as opposed to SOC (p = 0.004). CONCLUSIONS: Adjunctive TPE is associated with the removal of injurious mediators and repletion of consumed protective factors altogether leading to preserved hemodynamic stabilization in refractory septic shock. We identified that baseline lactate concentration as a potential response predictor might guide future designing of large RCTs that will further evaluate TPE with regard to hard endpoints. Trial registration Retrospectively registered 18th January 2020 at clinicaltrials.gov (Identifier: NCT04231994 ).

Predictors of response to intra-arterial vasodilatory therapy of non-occlusive mesenteric ischemia in patients with severe shock: results from a prospective observational study.

BACKGROUND: Non-occlusive mesenteric ischemia (NOMI) is a life-threatening condition occurring in patients with shock and is characterized by vasoconstriction of the mesenteric arteries leading to intestinal ischemia and multi-organ failure. Although minimal invasive local intra-arterial infusion of vasodilators into the mesenteric circulation has been suggested as a therapeutic option in NOMI, current knowledge is based on retrospective case series and it remains unclear which patients might benefit. Here, we prospectively analyzed predictors of response to intra-arterial therapy in patients with NOMI. METHODS: This is a prospective single-center observational study to analyze improvement of ischemia (indicated by reduction of blood lactate > 2 mmol/l from baseline after 24 h, primary endpoint) and 28-day mortality (key secondary endpoint) in patients with NOMI undergoing intra-arterial vasodilatory therapy. Predictors of response to therapy concerning primary and key secondary endpoint were identified using a) clinical parameters as well as b) data from 2D-perfusion angiography and c) experimental biomarkers of intestinal injury. RESULTS: A total of 42 patients were included into this study. At inclusion patients had severe shock, indicated by high doses of norepinephrine (NE) (median (interquartile range (IQR)) 0.37 (0.21-0.60) µg/kg/min), elevated lactate concentrations (9.2 (5.2-13) mmol/l) and multi-organ failure. Patients showed a continuous reduction of lactate following intra-arterial prostaglandin infusion (baseline: (9.2 (5.2-13) mmol/l vs. 24 h: 4.4 (2.5-9.1) mmol/l, p < 0.001) with 22 patients (52.4%) reaching a lactate reduction > 2 mmol/l at 24 h following intervention. Initial higher lactate concentrations and lower NE doses at baseline were independent predictors of an improvement of ischemia. 28-day mortality was 59% in patients with a reduction of lactate > 2 mmol/l 24 h after inclusion, while it was 85% in all other patients (hazard ratio 0.409; 95% CI, 0.14-0.631, p = 0.005). CONCLUSIONS: A reduction of lactate concentrations was observed following implementation of intra-arterial therapy, and lactate reduction was associated with better survival. Our findings concerning outcome predictors in NOMI patients undergoing intra-arterial prostaglandin therapy might help designing a randomized controlled trial to further investigate this therapeutic approach. Trial registration Retrospectively registered on January 22, 2020, at clinicaltrials.gov (REPERFUSE, NCT04235634), https://clinicaltrials.gov/ct2/show/NCT04235634?cond=NOMI&draw=2&rank=1 .

Cerebrospinal fluid findings in COVID-19: a multicenter study of 150 lumbar punctures in 127 patients.

BACKGROUND: Comprehensive data on the cerebrospinal fluid (CSF) profile in patients with COVID-19 and neurological involvement from large-scale multicenter studies are missing so far. OBJECTIVE: To analyze systematically the CSF profile in COVID-19. METHODS: Retrospective analysis of 150 lumbar punctures in 127 patients with PCR-proven COVID-19 and neurological symptoms seen at 17 European university centers RESULTS: The most frequent pathological finding was blood-CSF barrier (BCB) dysfunction (median QAlb 11.4 [6.72-50.8]), which was present in 58/116 (50%) samples from patients without pre-/coexisting CNS diseases (group I). QAlb remained elevated > 14d (47.6%) and even > 30d (55.6%) after neurological onset. CSF total protein was elevated in 54/118 (45.8%) samples (median 65.35 mg/dl [45.3-240.4]) and strongly correlated with QAlb. The CSF white cell count (WCC) was increased in 14/128 (11%) samples (mostly lympho-monocytic; median 10 cells/µl, > 100 in only 4). An albuminocytological dissociation (ACD) was found in 43/115 (37.4%) samples. CSF L-lactate was increased in 26/109 (24%; median 3.04 mmol/l [2.2-4]). CSF-IgG was elevated in 50/100 (50%), but was of peripheral origin, since QIgG was normal in almost all cases, as were QIgA and QIgM. In 58/103 samples (56%) pattern 4 oligoclonal bands (OCB) compatible with systemic inflammation were present, while CSF-restricted OCB were found in only 2/103 (1.9%). SARS-CoV-2-CSF-PCR was negative in 76/76 samples. Routine CSF findings were normal in 35%. Cytokine levels were frequently elevated in the CSF (often associated with BCB dysfunction) and serum, partly remaining positive at high levels for weeks/months (939 tests). Of note, a positive SARS-CoV-2-IgG-antibody index (AI) was found in 2/19 (10.5%) patients which was associated with unusually high WCC in both of them and a strongly increased interleukin-6 (IL-6) index in one (not tested in the other). Anti-neuronal/anti-glial autoantibodies were mostly absent in the CSF and serum (1509 tests). In samples from patients with pre-/coexisting CNS disorders (group II [N = 19]; including multiple sclerosis, JC-virus-associated immune reconstitution inflammatory syndrome, HSV/VZV encephalitis/meningitis, CNS lymphoma, anti-Yo syndrome, subarachnoid hemorrhage), CSF findings were mostly representative of the respective disease. CONCLUSIONS: The CSF profile in COVID-19 with neurological symptoms is mainly characterized by BCB disruption in the absence of intrathecal inflammation, compatible with cerebrospinal endotheliopathy. Persistent BCB dysfunction and elevated cytokine levels may contribute to both acute symptoms and 'long COVID'. Direct infection of the CNS with SARS-CoV-2, if occurring at all, seems to be rare. Broad differential diagnostic considerations are recommended to avoid misinterpretation of treatable coexisting neurological disorders as complications of COVID-19.

High Incidence of Epileptiform Potentials During Continuous EEG Monitoring in Critically Ill COVID-19 Patients.

Objective: To analyze continuous 1- or 2-channel electroencephalograms (EEGs) of mechanically ventilated patients with coronavirus disease 2019 (COVID-19) with regard to occurrence of epileptiform potentials. Design: Single-center retrospective analysis. Setting: Intensive care unit of Hannover Medical School, Hannover, Germany. Patients: Critically ill COVID-19 patients who underwent continuous routine EEG monitoring (EEG monitor: Narcotrend-Compact M) during sedation. Measurements and Main Results: Data from 15 COVID-19 patients (11 men, four women; age: 19-75 years) were evaluated. Epileptiform potentials occurred in 10 of 15 patients (66.7%). Conclusions: The results of the evaluation regarding the occurrence of epileptiform potentials show that there is an unusually high percentage of cerebral involvement in patients with severe COVID-19. EEG monitoring can be used in COVID-19 patients to detect epileptiform potentials.

Are depressive symptoms associated with quality of care in diabetes? Findings from a nationwide population-based study.

INTRODUCTION: We investigated whether the presence of depressive symptoms among adults with diagnosed diabetes is associated with adverse quality of diabetes care. RESEARCH DESIGN AND METHODS: The study population was drawn from the German national health survey 'German Health Update' 2014/2015-European Health Interview Survey and included 1712 participants aged ≥18 years with self-reported diabetes during the past 12 months. Depressive symptoms in the past 2 weeks were assessed by the eight-item depression module of the Patient Health Questionnaire (PHQ-8), with PHQ-8 sum score values ≥10 indicating current depressive symptoms. We selected 12 care indicators in diabetes based on self-reported information on care processes and outcomes. Associations of depressive symptoms with those indicators were examined in multivariable logistic regression models with stepwise adjustments. RESULTS: Overall, 15.6% of adults with diagnosed diabetes reported depressive symptoms, which were higher in women than in men (18.7% vs 12.9%). Adjusted for age, sex, education, social support, health-related behaviors, and diabetes duration, adults with depressive symptoms were more likely to report acute hypoglycemia (OR 1.81, 95% CI 1.13 to 2.88) or hyperglycemia (OR 2.10, 95% CI 1.30 to 3.37) in the past 12 months, long-term diabetes complications (OR 2.30, 95% CI 1.55 to 3.39) as well as currently having a diet plan (OR 2.14, 95% CI 1.39 to 3.29) than adults without depressive symptoms. Significant associations between depressive symptoms and other care indicators were not observed. CONCLUSIONS: The present population-based study of adults with diagnosed diabetes indicates an association between depressive symptoms and adverse diabetes-specific care with respect to outcome but largely not to process indicators. Our findings underline the need for intensified care for persons with diabetes and depressive symptoms. Future research needs to identify underlying mechanisms with a focus on the inter-relationship between diabetes, depression and diabetes-related distress.

Care for the chronically ill in Germany - The challenges during the COVID-19 pandemic.

The COVID-19 pandemic is posing major challenges to the health care sector. This scoping review compiles evidence concerning changes to health care service availability and utilisation as well as possible impacts on health for selected groups of chronically ill people in Germany. The focus is on cancer, cardiovascular diseases, diabetes mellitus and mental disorders. Most empirical data available concerned inpatient care and showed a clear decline in the utilisation of inpatient treatments in March and April 2020 in the areas of oncology and cardiology as well as in mental health. For cardiovascular emergencies such as heart attack and stroke, a decline was observed especially regarding less serious cases. Although there were indications of treatment delays, there was no evidence thus far that emergency care had been generally compromised due to adjustments to inpatient care capacities. In the outpatient setting, extensive adjustments to health care services availability were observed for all disease groups considered. Overall, very limited empirical data were available. In particular, hardly any data were available on how changes in care impacted population health. There is an urgent need for continuous surveillance and evaluation based on health care and epidemiological data.

Seroepidemiological study on the spread of SARS-CoV-2 in Germany: Study protocol of the CORONA-MONITORING bundesweit' study (RKI-SOEP study).

The SARS-CoV-2 coronavirus has spread rapidly across Germany. Infections are likely to be under-recorded in the notification data from local health authorities on laboratory-confirmed cases since SARS-CoV-2 infections can proceed with few symptoms and then often remain undetected. Seroepidemiological studies allow the estimation of the proportion in the population that has been infected with SARS-CoV-2 (seroprevalence) as well as the extent of undetected infections. The 'CORONA-MONITORING bundesweit' study (RKI-SOEP study) collects biospecimens and interview data in a nationwide population sample drawn from the German Socio-Economic Panel (SOEP). Participants are sent materials to self-collect a dry blood sample of capillary blood from their finger and a swab sample from their mouth and nose, as well as a questionnaire. The samples returned are tested for SARS-CoV-2 IgG antibodies and SARS-CoV-2 RNA to identify past or present infections. The methods applied enable the identification of SARS-CoV-2 infections, including those that previously went undetected. In addition, by linking the data collected with available SOEP data, the study has the potential to investigate social and health-related differences in infection status. Thus, the study contributes to an improved understanding of the extent of the epidemic in Germany, as well as identification of target groups for infection protection.

SARS-CoV-2 Transmissibility Within Day Care Centers-Study Protocol of a Prospective Analysis of Outbreaks in Germany.

Introduction: Until today, the role of children in the transmission dynamics of SARS-CoV-2 and the development of the COVID-19 pandemic seems to be dynamic and is not finally resolved. The primary aim of this study is to investigate the transmission dynamics of SARS-CoV-2 in child day care centers and connected households as well as transmission-related indicators and clinical symptoms among children and adults. Methods and Analysis: COALA ("Corona outbreak-related examinations in day care centers") is a day care center- and household-based study with a case-ascertained study design. Based on day care centers with at least one reported case of SARS-CoV-2, we include one- to six-year-old children and staff of the affected group in the day care center as well as their respective households. We visit each child's and adult's household. During the home visit we take from each household member a combined mouth and nose swab as well as a saliva sample for analysis of SARS-CoV-2-RNA by real-time reverse transcription polymerase chain reaction (real-time RT-PCR) and a capillary blood sample for a retrospective assessment of an earlier SARS-CoV-2 infection. Furthermore, information on health status, socio-demographics and COVID-19 protective measures are collected via a short telephone interview in the subsequent days. In the following 12 days, household members (or parents for their children) self-collect the same respiratory samples as described above every 3 days and a stool sample for children once. COVID-19 symptoms are documented daily in a symptom diary. Approximately 35 days after testing the index case, every participant who tested positive for SARS-CoV-2 during the study is re-visited at home for another capillary blood sample and a standardized interview. The analysis includes secondary attack rates, by age of primary case, both in the day care center and in households, as well as viral shedding dynamics, including the beginning of shedding relative to symptom onset and viral clearance. Discussion: The results contribute to a better understanding of the epidemiological and virological transmission-related indicators of SARS-CoV-2 among young children, as compared to adults and the interplay between day care and households.

Connecting the complex microstructure of LDPE to its rheology and processing properties via a combined fractionation and modelling approach.

Well-defined mini-plant low density polyethylene samples were fractionated preparatively according to their crystallizability via preparative temperature rising elution fractionation and according to molecular weight via preparative solvent gradient fractionation (pSGF). Rheology of the fractions was measured in both the small amplitude oscillatory shear (SAOS) and the non-linear extension regimes. The linear and non-linear rheology of the pTREF fractions were dominated by molecular weight effects, while the impact of the higher degree of long chain branching for the pSGF fractions with higher molecular weights was observed in van Gurp-Palmen plots and in strain hardening behavior in the extensional rheology measurements. Additionally, the experimental fractionation process was mimicked via modelling. The branching topologies of the bulk samples were obtained by coupled kinetic and Monte Carlo calculations. These topologies were fractionated computationally and the result were used to predict the rheological behavior of the individual fractions by applying the BoB algorithm with no parameter adjustment. The experimental observed trends were predicted by the model and the overall agreement was acceptable. This study demonstrates, that polymer fractionation is possible on a preparative scale and allows for the polymer flow properties characterization of the individual fractions, a method that is highly relevant during processing. Moreover, the fractionation process is followed and understood from the modelling point of view.

Sports activity patterns and cardio-metabolic health over time among adults in Germany: Results of a nationwide 12-year follow-up study.

BACKGROUND: Physical activity is favorable for health, and vigorous sports activity is particularly beneficial. This study investigates the association between changes in sports participation patterns over time and cardio-metabolic and self-perceived health outcomes. METHODS: Data from 3752 adults (18-79 years of age) who participated in 2 national health interview and examination surveys in 1997-1999 and 2008-2011 were included, with a mean follow-up time of about 12 years. A change in self-reported sports activity was analyzed with respect to the incidence of type 2 diabetes, coronary heart disease (CHD), hypertension, obesity, dyslipidemia, metabolic syndrome, and poor self-perceived health. Participants with pre-existing disease or risk factor of interest at baseline were excluded from the analysis. Being sufficiently active in sports was specified as doing sports for at least 1-2 h per week, and 4 activity categories were defined: 1) inactive at both time points (inactive-inactive), 2) inactive at baseline and active at follow-up (inactive-active), 3) active at baseline and inactive at follow-up (active-inactive), and 4) active at both time points (active-active). Associations between sports activity engagement and health outcomes were estimated by logistic regression models with different stages of adjustments. RESULTS: Not engaging in any regular sports activity at both time points (inactive-inactive) was associated with higher rates of type 2 diabetes (odds ratio (OR) = 1.82, 95% confidence interval (95%CI): 1.08-3.08), CHD (OR = 1.82, 95%CI: 1.16-2.84), hypertension (OR = 1.36, 95%CI: 1.03-1.81), metabolic syndrome (OR = 1.58, 95%CI: 1.08-2.32), and poor self-perceived health (OR = 2.54, 95%CI: 1.83-3.53) compared to doing regular sports for a minimum of 1-2 h per week over time (active-active). In case of change from inactivity to any regular sports activity (inactive-active), the rate of risk factor occurrence was not statistically different from the active-active reference group except for poor self-perceived health, but it was higher for type 2 diabetes (OR = 2.15, 95%CI: 1.12-4.14) and CHD (OR = 1.77, 95%CI: 1.03-3.03). Being active at baseline but inactive at follow-up (active-inactive) was not associated with higher disease incidence of type 2 diabetes (OR = 0.70, 95%CI: 0.25-1.97) or CHD (OR = 1.20, 95%CI: 0.49-2.99), but was associated with higher rates of hypertension (OR = 1.61, 95%CI: 1.11-2.34), obesity (OR = 2.34, 95%CI: 1.53-3.57), metabolic syndrome (OR = 1.70, 95%CI: 1.11-2.63), and poor self-perceived health (OR = 2.16, 95%CI: 1.53-3.07) at follow-up. CONCLUSION: Even a low weekly quantity (1-2 h) of regular sports activity is partly associated with health benefits. Being formerly but not currently active was not associated with an increased disease incidence, but was associated with a higher risk-factor development compared to the reference group (active-active). Becoming active was preventive for risk-factor development but was not preventive for disease incidence, which probably means that the health benefits from sports activity are not sustainable and disease incidence is only shifted to a later period in life. For this reason, the promotion of and commitment to regular sports activity should be addressed as early as possible over the lifespan to achieve the best health benefits.

Serology- and PCR-based cumulative incidence of SARS-CoV-2 infection in adults in a successfully contained early hotspot (CoMoLo study), Germany, May to June 2020.

Three months after a coronavirus disease (COVID-19) outbreak in Kupferzell, Germany, a population-based study (n = 2,203) found no RT-PCR-positives. IgG-ELISA seropositivity with positive virus neutralisation tests was 7.7% (95% confidence interval (CI): 6.5-9.1) and 4.3% with negative neutralisation tests. We estimate 12.0% (95% CI: 10.4-14.0%) infected adults (24.5% asymptomatic), six times more than notified. Full hotspot containment confirms the effectiveness of prompt protection measures. However, 88% naïve adults are still at high COVID-19 risk.

Reappearance of effector T cells is associated with recovery from COVID-19.

BACKGROUND: Elucidating the role of T cell responses in COVID-19 is of utmost importance to understand the clearance of SARS-CoV-2 infection. METHODS: 30 hospitalized COVID-19 patients and 60 age- and gender-matched healthy controls (HC) participated in this study. We used two comprehensive 11-colour flow cytometric panels conforming to Good Laboratory Practice and approved for clinical diagnostics. FINDINGS: Absolute numbers of lymphocyte subsets were differentially decreased in COVID-19 patients according to clinical severity. In severe disease (SD) patients, all lymphocyte subsets were reduced, whilst in mild disease (MD) NK, NKT and γδ T cells were at the level of HC. Additionally, we provide evidence of T cell activation in MD but not SD, when compared to HC. Follow up samples revealed a marked increase in effector T cells and memory subsets in convalescing but not in non-convalescing patients. INTERPRETATION: Our data suggest that activation and expansion of innate and adaptive lymphocytes play a major role in COVID-19. Additionally, recovery is associated with formation of T cell memory as suggested by the missing formation of effector and central memory T cells in SD but not in MD. Understanding T cell-responses in the context of clinical severity might serve as foundation to overcome the lack of effective anti-viral immune response in severely affected COVID-19 patients and can offer prognostic value as biomarker for disease outcome and control. FUNDING: Funded by State of Lower Saxony grant 14-76,103-184CORONA-11/20 and German Research Foundation, Excellence Strategy - EXC2155"RESIST"-Project ID39087428, and DFG-SFB900/3-Project ID158989968, grants SFB900-B3, SFB900-B8.

Corrigendum to: Maintenance Immunosuppression Is Associated With Better Outcome in the 2017/2018 Influenza Epidemic.

[This corrects the article DOI: 10.1093/ofid/ofz381.].