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In clinical practice, the glomerular filtration rate (GFR), a measurement of kidney functioning, is normally calculated using equations, such as the European Kidney Function Consortium (EKFC) equation. Despite being the most general equation, EKFC, just like previously proposed approaches, can still struggle to achieve satisfactory performance, limiting its clinical applicability. As a possible solution, recently machine learning (ML) has been investigated to improve GFR prediction, nonetheless the literature still lacks a general and multi-center study. Using a dataset with 19,629 patients from 13 cohorts, we investigate if ML can improve GFR prediction in comparison to EKFC. More specifically, we compare diverse ML methods, which were allowed to use age, sex, serum creatinine, cystatin C, height, weight and BMI as features, in internal and external cohorts against EKFC. The results show that the most performing ML method, random forest (RF), and EKFC are very competitive where RF and EKFC achieved respectively P10 and P30 values of 0.45 (95% CI 0.44;0.46) and 0.89 (95% CI 0.88;0.90), whereas EKFC yielded 0.44 (95% CI 0.43; 0.44) and 0.89 (95% CI 0.88; 0.90), considering the entire cohort. Small differences were, however, observed in patients younger than 12 years where RF slightly outperformed EKFC., (© 2024. The Author(s).)

Rationale & Objective: The benefits of kidney transplantation compared to treatment with dialysis, including in older adult, are primarily limited by the number of donated kidneys. We studied the potential to expand the use of older living kidney donors., Study Design: Secondary analysis of the Berlin Initiative Study, a population-based cohort., Setting: & Participants: 2069 adults aged ≥70 years in Germany., Exposures: Age and sex., Outcomes: Suitability for living donation assessed by the absence of kidney-related exclusions for donation including albuminuria and low estimated glomerular filtration rate (eGFR) as well as absence of other medical exclusions. Willingness for living and deceased kidney donation assessed by participant survey., Analytical Approach: Descriptive analysis., Results: Among the 2069 participants (median age 80 years, 53% women, median eGFR 63 ml/min/1.73m 2 ), 93% had ≥1 medical contraindication for living donation at study entry unrelated to eGFR or albuminuria. Using two published eGFR and albuminuria thresholds for donor acceptance, 38% to 54% of participants had kidney-related exclusions for donation. Among the 5% to 6% of participants with neither medical nor kidney-related exclusions for living donation at baseline, 11% to 12% remained suitable for donation during 8 years of follow-up. Willingness for living or deceased donation was high (73% and 60%, respectively)., Limitations: GFR was not measured and medical exclusions unrelated to eGFR and albuminuria were assessed using a cohort database complemented by claims data., Conclusions: One in twenty older adults were potentially suitable for living kidney donation and willingness for living donation was high. Further studies are warranted to define the feasibility of expanding living kidney donation among older adults., (Copyright © 2024. Published by Elsevier Inc.)

International consensus supports the development of standardized protocols for measured glomerular filtration rate (mGFR) to facilitate the integration of mGFR testing in both clinical and research settings. To this end, the European Kidney Function Consortium convened an international group of experts with relevant experience in mGFR. The working group performed an extensive literature search to inform the development of recommendations for mGFR determination using 1-compartment plasma clearance models and iohexol as the exogenous filtration marker. Iohexol was selected as it is non-radio labeled, inexpensive, and safe, can be assayed at a central laboratory, and the other commonly used non-radio-labeled tracers have been (inulin) or are soon to be (iothalamate) discontinued. A plasma clearance model was selected over urine clearance as it requires no urine collection. A 1 compartment was preferred to 2 compartments as it requires fewer samples. The recommendations are based on published evidence complemented by expert opinion. The consensus paper covers practical advice for patients and health professionals, preparation, administration, and safety aspects of iohexol, laboratory analysis, blood sample collection and sampling times using both multiple and single-sample protocols, description of the mGFR mathematical calculations, as well as implementation strategies. Supplementary materials include patient and provider information sheets, standard operating procedures, a study protocol template, and support for mGFR calculation., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: The development of clinical guidelines aimed at GPs is a key strategy to improving the management of chronic kidney disease (CKD). In 2019, the first CKD guideline aimed specifically at GPs practicing in Germany was published by the German College of General Practitioners and Family Physicians (DEGAM.) AIMS: The aim of this study is to identify the barriers and enablers for the implementation of this guideline. The results of this project, together with quantitative evaluation against quality indicators for CKD in primary care will inform an update to the guideline., Methods: We performed 17 semi-structured interviews with GPs practicing in Berlin and Brandenburg. Transcripts were analysed using qualitative content analysis as described by Mayring., Results: We found that the perception of low clinical priority of CKD compared to other chronic diseases, opportunity cost of using guidelines, as well as poor patient understanding were significant barriers. GPs expressed that improved graphic design or integration of guideline recommendations in clinical decision support systems were enabling factors. Clinical problems concerning CKD were mostly solved by recourse to informal communication with specialists. GPs reported that they rarely consulted CKD guidelines as an aide to clinical decision making., Conclusion: The most significant barrier to use was that guidelines were not used as step-by-step decision aide in consultations with patients. Our analysis suggests that informal contact between primary and secondary care is significant conduit for evidence-based information on CKD in German primary care. Implementation projects should support the development of these relationships., (© 2024. The Author(s).)

Approved vaccines are effective against severe COVID-19, but broader immunity is needed against new variants and transmission. Therefore, we developed genome-modified live-attenuated vaccines (LAV) by recoding the SARS-CoV-2 genome, including 'one-to-stop' (OTS) codons, disabling Nsp1 translational repression and removing ORF6, 7ab and 8 to boost host immune responses, as well as the spike polybasic cleavage site to optimize the safety profile. The resulting OTS-modified SARS-CoV-2 LAVs, designated as OTS-206 and OTS-228, are genetically stable and can be intranasally administered, while being adjustable and sustainable regarding the level of attenuation. OTS-228 exhibits an optimal safety profile in preclinical animal models, with no side effects or detectable transmission. A single-dose vaccination induces a sterilizing immunity in vivo against homologous WT SARS-CoV-2 challenge infection and a broad protection against Omicron BA.2, BA.5 and XBB.1.5, with reduced transmission. Finally, this promising LAV approach could be applicable to other emerging viruses., (© 2024. The Author(s).)

Objectives: Despite the growing evidence regarding the influence of social factors on frailty in older adults, the effect of social support remains unclear. This study aims to assess the association between social support and frailty progression (transition and incidence) in a sample of community-dwelling older adults., Methods: Using a cohort study design, 1,059 older adults from the Berlin Initiative Study were followed up for 2.1 years. Multinomial and logistic regression analyses were performed to assess the association of social support using Oslo Social Support Scale-3 with frailty transition and incidence, respectively. Gender differences were explored using stratified analyses., Results: At baseline, frailty prevalence in the study population [mean (SD) age 84.3 (5.6) years; 55.8% women] reached 33.1% with 47.0, 29.4 and 23.6% of the participants reporting moderate, strong and poor social support, respectively. Over the follow-up period, social support was not significantly associated with the frailty transition categories in the adjusted model. Conversely, the adjusted logistic regression analysis showed that participants with poor social support had twice the odds of becoming frail compared to those with strong social support (OR 2.07; 95% CI 1.08-3.95). Gender-stratified analyses showed comparable estimates to the main analysis but were statistically non-significant., Discussion: Our study results underpin the role of social factors in frailty incidence and highlight social support as a potential target for frailty-preventing interventions in older adults. Therefore, it is important to adopt a biopsychosocial model rather than a purely biomedical model to understand and holistically improve the health of community-dwelling older adults., Competing Interests: NE received honoraria as member of an EAB for Bayer AG, Leverkusen. ES receives honoraria from AstraZeneca and from the National Kidney Foundation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Barghouth, Klein, Bothe, Ebert, Schaeffner and Mielke.)

Background and Hypothesis: The estimation of glomerular filtration rate (GFR) is one main tool to detect renal disease. The most used biomarker remains serum creatinine and the European Kidney Function Consortium (EKFCcrea) equation is the most validated in Europe. More recently, cystatin C, has been proposed. We studied the performances of the EKFC equations in a large cohort of subjects according to their diabetic status., Methods: Four cohorts from the EKFC dataset were retrospectively considered in which the diabetic status was available. GFR was measured by plasma clearances (mGFR) (iohexol or 51Cr-EDTA). The performance of the equations was assessed by calculating bias, precision (IQR) and P30 (percentage of eGFR-values within ± 30% of mGFR)., Results: In the whole population (n = 6 158), median [IQR] age was 61 [47;72] years, with 45.8% women. Mean mGFR was 60 [39;82] mL/min/1.73m². Compared to non-diabetic individuals (n = 5 124), diabetic patients (n = 1 034) were older, more frequently male, heavier, and had lower mGFR. The performance of the EKFCcys equation was similar to EKFCcrea, but the EKFCcrea+cys had better P30 than the single-biomarker equations. P30 values were substantially lower in diabetic patients than in non-diabetic but, according to a matched analysis, this is mainly explained by the difference in GFR levels between the two populations, not by diabetic status., Conclusion: We showed that equation combining creatinine and cystatin C present a better performance. If accuracy of equations seems better in non-diabetic than in diabetic individuals, it is more due to differences in GFR levels than to the diabetic status., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Insufficient physical activity (PA) is a leading risk factor for non-communicable diseases posing a significant economic burden to healthcare systems and societies. The study aimed to examine the differences in healthcare and indirect costs between sufficient and insufficient PA and the cost differences between PA intensity groups., Methods: The cross-sectional analysis was based on data from 157,648 participants in the baseline examination of the German National Cohort (NAKO) study. Healthcare and indirect costs were calculated based on self-reported information on health-related resource use and productivity losses. PA in the domains leisure, transport, and work was assessed by the Global Physical Activity Questionnaire and categorized into sufficient/insufficient and intensity levels (very low/low/medium/high) based on PA recommendations of the World Health Organization. Two-part models adjusted for relevant covariates were used to estimate mean costs for PA groups., Results and Conclusion: Insufficiently active people had higher average annual healthcare costs (Δ €188, 95% CI [64, 311]) and healthcare plus indirect costs (Δ €482, 95% CI [262, 702]) compared to sufficiently active people. The difference was especially evident in the population aged 60 + years and when considering only leisure PA. An inverse association was observed between leisure PA and costs, whereas a direct association was found between PA at work and costs. Adjusting for the number of comorbidities reduced the differences between activity groups, but the trend persisted. The association between PA and costs differed in direction between PA domains. Future research may provide further insight into the temporal relationship between PA and costs., (© 2024. The Author(s).)

Background: Frailty and polypharmacy are common conditions in older adults, especially in those with chronic kidney disease (CKD). Therefore, we analyzed the association of polypharmacy and incident frailty and the effect modification by CKD in very old adults., Methods: In non-frail individuals within the Berlin Initiative (cohort) Study, polypharmacy (≥ 5 medications) was assessed according to multiple definitions based on the number of regular and on demand prescription and over the counter drugs, as well as vitamins and supplements. CKD was defined as an estimated glomerular filtration rate < 60 mL/min/1.73m 2 and/or an albumin-creatinine ratio ≥ 30 mg/g. Incident frailty was assessed at follow-up using Fried criteria. Logistic regression was applied to assess (1) the association of different polypharmacy definitions with incident frailty and (2) effect modification by CKD., Results: In this cohort study, out of 757 non-frail participants (mean age 82.9 years, 52% female, 74% CKD), 298 (39%) participants reported polypharmacy. Over the observation period of 2.1 years, 105 became frail. Individuals with polypharmacy had 1.96 adjusted odds (95% confidence interval (CI): 1.20-3.19) of becoming frail compared to participants without polypharmacy. The effect of polypharmacy on incident frailty was modified by CKD on the additive scale (relative excess risk due to interaction: 1.56; 95% CI 0.01-3.12)., Conclusions: This study demonstrates an association of polypharmacy and incident frailty and suggests strong evidence for an effect modification of CKD on polypharmacy and incident frailty. Revision of prescriptions could be a target strategy to prevent frailty occurrence, especially in older adults with CKD., (© 2024. The Author(s).)

Studies on severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) have highlighted the crucial role of host proteases for viral replication and the immune response. The serine proteases furin and TMPRSS2 and lysosomal cysteine proteases facilitate viral entry by limited proteolytic processing of the spike (S) protein. While neutrophils are recruited to the lungs during COVID-19 pneumonia, little is known about the role of the neutrophil serine proteases (NSPs) cathepsin G (CatG), elastase (NE), and proteinase 3 (PR3) on SARS-CoV-2 entry and replication. Furthermore, the current paradigm is that NSPs may contribute to the pathogenesis of severe COVID-19. Here, we show that these proteases cleaved the S protein at multiple sites and abrogated viral entry and replication in vitro. In mouse models, CatG significantly inhibited viral replication in the lung. Importantly, lung inflammation and pathology were increased in mice deficient in NE and/or CatG. These results reveal that NSPs contribute to innate defenses against SARS-CoV-2 infection via proteolytic inactivation of the S protein and that NE and CatG limit lung inflammation in vivo. We conclude that therapeutic interventions aiming to reduce the activity of NSPs may interfere with viral clearance and inflammation in COVID-19 patients.

Background: Chronic kidney failure (CKF) is often treated with dialysis, which is invasive and costly and carries major medical risks. The existing studies of patients with CKF requiring dialysis that are based on claims data from German statutory health insurance (SHI) carriers employ varying definitions of this entity, with unclear consequences for the resulting statistical estimates., Methods: We carried out a cohort study on four random samples, each consisting of 62 200 persons aged 70 or above, from among the insurees of the SHI AOK Nordost, with one sample for each of the years 2012, 2014, 2016, and 2018. The prevalence, incidence, mortality, and direct health care costs of CKF requiring dialysis were estimated and compared on the basis of four different definitions from literature and a new definition developed by the authors in reference to billing data., Results: The different definitions led to variation in 12-month prevalences (range: 0.33-0.61%) and 6-month incidences (0.058-0.100%). The percentage of patients with prior acute kidney injury (AKI) ranged from 27.6% to 61.8%. Among incident patients, three-month survival ranged from 70.2% to 88.1%, and six-month survival from 60.5% to 81.3%. In CKF patients without prior AKI, the survival curves differed less across definitions (80.2-91.8% at three months, 70.7-84.4% at six months). The monthly health care costs ranged from €6010 to €9606, with marked variability across definitions in the costs of inpatient and outpatient care., Conclusion: The lack of a standardized definition of CKF requiring dialysis in German SHI claims data leads to variability in the estimated case numbers, mortality, and health care costs. These differences are most probably in part due to the variable inclusion of inpatients who received short-term dialysis after AKI.

Background: Proactive screening for cognitive dysfunction (CD) and peripheral neuropathy (PNP) in elderly patients with diabetes mellitus is essential for early intervention, yet clinical examination is time-consuming and prone to bias., Objective: We aimed to investigate PNP and CD in a diabetes cohort and explore the possibility of identifying key features linked with the respective conditions by machine learning algorithms applied to data sets obtained in playful games controlled by sensor-equipped insoles., Methods: In a cohort of patients diagnosed with diabetes (n=261) aged over 50 years PNP and CD were diagnosed based on complete physical examination (neuropathy symptom and disability scores, and Montreal Cognitive Assessment). In an observational and proof-of-concept study patients performed a 15 min lasting gaming session encompassing tutorials and four video games with 5,244 predefined features. The steering of video games was solely achieved by modulating plantar pressure values, which were measured by sensor-equipped insoles in real-time. Data sets were used to identify key features indicating game performance with correlation regarding CD and PNP findings. Thereby, machine learning models (e.g. gradient boosting and lasso and elastic-net regularized generalized linear models) were set up to distinguish patients in the different groups., Results: PNP was diagnosed in 59% (n=153), CD in 34% (n=89) of participants, and 23% (n=61) suffered from both conditions. Multivariable regression analyses suggested that PNP was positively associated with CD in patients with diabetes (adjusted odds ratio = 1.95; 95% confidence interval: 1.03-3.76; P =0.04). Predictive game features were identified that significantly correlated with CD (n=59), PNP (n=40), or both (n=59). These features allowed to set up classification models that were enriched by individual risk profiles (i.e. gender, age, weight, BMI, diabetes type, and diabetes duration). The obtained models yielded good predictive performance with the area under the receiver-operating-characteristic curves reaching 0.95 for CD without PNP, 0.83 for PNP without CD, and 0.84 for CD and PNP combined., Conclusions: The video game-based assessment was able to categorize patients with CD and/or PNP with high accuracy. Future studies with larger cohorts are needed to validate these results and potentially enhance the discriminative power of video games., Competing Interests: AM and PM filed a patent on a game-based assessment of PNP. The remaining authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ming, Lorek, Wall, Schubert, Ebert, Galatzky, Baum, Glanz, Stober and Mertens.)

Background: Important therapeutic decisions depend on kidney function, which is why its correct assessment is of great importance. It also plays an important role for drug dose adjustments in patients with impaired kidney function., Objectives: In clinical practice, kidney function is almost always estimated using mathematical glomerular filtration rate (GFR) equations. To estimate GFR, the patient's age and gender as well as kidney-specific endogenous biomarkers are required. This work aims to provide an overview of the advantages and disadvantages of the biomarkers serum creatinine and cystatin C in assessing kidney function. Particularly in patients with significantly reduced or increased muscle mass, creatinine is not suitable for determining GFR, and cystatin C should be used. Currently recommended GFR estimating equations are described, illustrating for which patient groups they can be used., Current Data: A large number of high-ranking publications are available investigating the validity of GFR estimating equations and the optimal choice of endogenous biomarkers. However, there are still large gaps when it comes to drug approval studies in older patients and children., Conclusion: Estimated GFR (eGFR) is only a rough estimate of kidney function and should not be interpreted as an exact number. Drug dose adjustments may be necessary in patients with an eGFR of < 50 ml/min and should be verified particularly in severely impaired GFR (< 30 ml/min). There are tools available online for this purpose., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Purpose: The validity of ICD-10 diagnostic codes for chronic kidney disease (CKD) in health claims data has not been sufficiently studied in the general population and over time., Patients and Methods: We used data from the Berlin Initiative Study (BIS), a prospective longitudinal cohort of community-dwelling individuals aged ≥70 years in Berlin, Germany. With estimated glomerular filtration rate (eGFR) as reference, we assessed the diagnostic validity (sensitivity, specificity, positive [PPV], and negative predictive values [NPV]) of different claims-based ICD-10 codes for CKD stages G3-5 (eGFR <60mL/min/1.73m²: ICD-10 N18.x-N19), G3 (eGFR 30-<60mL/min/1.73m²: N18.3), and G4-5 (eGFR <30mL/min/1.73m²: N18.4-5). We analysed trends over five study visits (2009-2019)., Results: We included data of 2068 participants at baseline (2009-2011) and 870 at follow-up 4 (2018-2019), of whom 784 (38.9%) and 440 (50.6%) had CKD G3-5, respectively. At baseline, sensitivity for CKD in claims data ranged from 0.25 (95%-confidence interval [CI] 0.22-0.28) to 0.51 (95%-CI 0.48-0.55) for G3-5, depending on the included ICD-10 codes, 0.20 (95%-CI 0.18-0.24) for G3, and 0.36 (95%-CI 0.25-0.49) for G4-5. Over the course of 10 years, sensitivity increased by 0.17 to 0.29 in all groups. Specificity, PPVs, and NPVs remained mostly stable over time and ranged from 0.82-0.99, 0.47-0.89, and 0.66-0.98 across all study visits, respectively., Conclusion: German claims data showed overall agreeable performance in identifying older adults with CKD, while differentiation between stages was limited. Our results suggest increasing sensitivity over time possibly attributable to improved CKD diagnosis and awareness., Competing Interests: NE received grants by Bayer AG. ES receives honorarium from AstraZeneca for counseling and from the National Kidney Foundation for editorial work for the American Journal of Kidney Diseases. All other authors have nothing to declare for this work., (© 2024 Bothe et al.)

Feline infectious peritonitis (FIP) is a fatal feline disease, caused by a feline coronavirus (FCoV), namely feline infectious peritonitis virus (FIPV). We produced a baby hamster kidney 21 (BHK) cell line expressing a serotype I FCoV replicon RNA with a green fluorescent protein (GFP) reporter gene (BHK-F-Rep) and used it as an in vitro screening system to test different antiviral compounds. Two inhibitors of the FCoV main protease (M pro ), namely GC376 and Nirmatrelvir, as well as the nucleoside analog Remdesivir proved to be effective in inhibiting the replicon system. Different combinations of these compounds also proved to be potent inhibitors, having an additive effect when combined. Remdesivir, GC376, and Nirmatrelvir all have a 50% cytotoxic concentration (CC50) more than 200 times higher than their half-maximal inhibitory concentrations (IC50), making them important candidates for future in vivo studies as well as clinically implemented drug candidates. In addition, results were acquired with a virus infection system, where Felis catus whole fetus 4 (Fcwf-4) cells were infected with a previously described recombinant GFP-expressing FIPV (based on the laboratory-adapted serotype I FIPV strain Black) and treated with the most promising compounds. Results acquired with the replicon system were comparable to the results acquired with the virus infection system, demonstrating that we successfully implemented the FCoV replicon system for antiviral screening. We expect that this system will greatly facilitate future screens for anti-FIPV compounds and provide a non-infectious system to study and evaluate drug-resistant mutations that may emerge in the FIPV genome.IMPORTANCEFIPV is of great significance in the cat population around the world, causing 0.3%-1.4% of feline deaths in veterinary practices (2). As there are neither effective preventive measures nor approved treatment options available, there is an urgent need to identify antiviral drugs against FIPV. Our FCoV replicon system provides a valuable tool for drug discovery in vitro . Due to the lack of cell culture systems for serotype I FCoVs (the serotype most prevalent in the feline population) (2), a different system is needed to study these viruses. A viral replicon system is a valuable tool for studying FCoVs. Overall, our results demonstrate the utility of the serotype I feline coronavirus replicon system for antiviral screening as well as to study this virus in general. We propose several compounds representing promising candidates for future clinical trials and ultimately with the potential to save cats suffering from FIP., Competing Interests: The authors declare no conflict of interest.

Importance: Chronic kidney disease (low estimated glomerular filtration rate [eGFR] or albuminuria) affects approximately 14% of adults in the US., Objective: To evaluate associations of lower eGFR based on creatinine alone, lower eGFR based on creatinine combined with cystatin C, and more severe albuminuria with adverse kidney outcomes, cardiovascular outcomes, and other health outcomes., Design, Setting, and Participants: Individual-participant data meta-analysis of 27 503 140 individuals from 114 global cohorts (eGFR based on creatinine alone) and 720 736 individuals from 20 cohorts (eGFR based on creatinine and cystatin C) and 9 067 753 individuals from 114 cohorts (albuminuria) from 1980 to 2021., Exposures: The Chronic Kidney Disease Epidemiology Collaboration 2021 equations for eGFR based on creatinine alone and eGFR based on creatinine and cystatin C; and albuminuria estimated as urine albumin to creatinine ratio (UACR)., Main Outcomes and Measures: The risk of kidney failure requiring replacement therapy, all-cause mortality, cardiovascular mortality, acute kidney injury, any hospitalization, coronary heart disease, stroke, heart failure, atrial fibrillation, and peripheral artery disease. The analyses were performed within each cohort and summarized with random-effects meta-analyses., Results: Within the population using eGFR based on creatinine alone (mean age, 54 years [SD, 17 years]; 51% were women; mean follow-up time, 4.8 years [SD, 3.3 years]), the mean eGFR was 90 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 11 mg/g (IQR, 8-16 mg/g). Within the population using eGFR based on creatinine and cystatin C (mean age, 59 years [SD, 12 years]; 53% were women; mean follow-up time, 10.8 years [SD, 4.1 years]), the mean eGFR was 88 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 9 mg/g (IQR, 6-18 mg/g). Lower eGFR (whether based on creatinine alone or based on creatinine and cystatin C) and higher UACR were each significantly associated with higher risk for each of the 10 adverse outcomes, including those in the mildest categories of chronic kidney disease. For example, among people with a UACR less than 10 mg/g, an eGFR of 45 to 59 mL/min/1.73 m2 based on creatinine alone was associated with significantly higher hospitalization rates compared with an eGFR of 90 to 104 mL/min/1.73 m2 (adjusted hazard ratio, 1.3 [95% CI, 1.2-1.3]; 161 vs 79 events per 1000 person-years; excess absolute risk, 22 events per 1000 person-years [95% CI, 19-25 events per 1000 person-years])., Conclusions and Relevance: In this retrospective analysis of 114 cohorts, lower eGFR based on creatinine alone, lower eGFR based on creatinine and cystatin C, and more severe UACR were each associated with increased rates of 10 adverse outcomes, including adverse kidney outcomes, cardiovascular diseases, and hospitalizations.

Background: The Cockcroft-Gault equation (CrCl C-G ) is recommended for dose adjustment of direct oral anticoagulant drugs (DOACs) to kidney function. We aimed to assess whether defining DOAC dose appropriateness according to various kidney function estimators changed the associations between dose appropriateness and adverse events in older adults with atrial fibrillation (AF)., Methods: Participants of the Berlin Initiative Study with AF and treated with DOACs were included. We investigated CrCl C-G and estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration and European Kidney Function Consortium equations based on creatinine and/or cystatin C. Marginal structural Cox models yielded confounder-adjusted hazard ratios for the risk of mortality, thromboembolism and bleeding associated with dose status., Results: A total of 224 patients were included in the analysis (median age 87 years). Using CrCl C-G , 154 (69%) had an appropriate dose of DOACs, 52 (23%) were underdosed and 18 (8%) were overdosed. During a 39-month median follow-up period, 109 (14.9/100 person-years) participants died, 25 (3.6/100 person-years) experienced thromboembolism and 60 (9.8/100 person-years) experienced bleeding. Dose status was not associated with mortality and thromboembolism, independent of the equation. Underdose status was associated with a lower risk of bleeding with all the equations compared with the appropriate dose group. In participants with discrepancies in dose status using CrCl C-G and eGFR equations, the occurrence of endpoints did not differ between participants having an appropriate dose using CrCl C-G or eGFR., Conclusion: In older adults with AF, the association of DOAC dose status with adverse events did not differ when using CrCl C-G or eGFR. Our results suggest that eGFR equations are not inferior to CrCl C-G within this context., Competing Interests: N.E. received fees from Bayer AG Leverkusen as a member of an editorial advisory board outside the submitted work. E.S. received a research grant from Bayer unrelated to the topic of the article and receives a stipend from the National Kidney Foundation. The other authors declare no conflicts of interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Introduction: Despite recognized geographic and sex-based differences in hemoglobin in the general population, these factors are typically ignored in patients with chronic kidney disease (CKD) in whom a single therapeutic range for hemoglobin is recommended. We sought to compare the distribution of hemoglobin across international nondialysis CKD populations and evaluate predictors of hemoglobin., Methods: In this cross-sectional study, hemoglobin distribution was evaluated in each cohort overall and stratified by sex and estimated glomerular filtration rate (eGFR). Relationships between candidate predictors and hemoglobin were assessed from linear regression models in each cohort. Estimates were subsequently pooled in a random effects model., Results: A total of 58,613 participants from 21 adult cohorts (median eGFR range of 17-49 ml/min) and 3 pediatric cohorts (median eGFR range of 26-45 ml/min) were included with broad geographic representation. Hemoglobin values varied substantially among the cohorts, overall and within eGFR categories, with particularly low mean hemoglobin observed in women from Asian and African cohorts. Across the eGFR range, women had a lower hemoglobin compared to men, even at an eGFR of 15 ml/min (mean difference 5.3 g/l, 95% confidence interval [CI] 3.7-6.9). Lower eGFR, female sex, older age, lower body mass index, and diabetic kidney disease were all independent predictors of a lower hemoglobin value; however, this only explained a minority of variance (R 2 7%-44% across cohorts)., Conclusion: There are substantial regional differences in hemoglobin distribution among individuals with CKD, and the majority of variance is unexplained by demographics, eGFR, or comorbidities. These findings call for a renewed interest in improving our understanding of hemoglobin determinants in specific CKD populations., (© 2023 Published by Elsevier, Inc., on behalf of the International Society of Nephrology.)

Background: In older adults, epidemiological data on incidence rates (IR) of hospital-acquired acute kidney injury (AKI) are scarce. Also, little is known about trajectories of kidney function before hospitalization with AKI., Methods: We used data from biennial face-to-face study visits from the prospective Berlin Initiative Study (BIS) including community-dwelling participants aged 70+ with repeat estimated glomerular filtration rate (eGFR) based on serum creatinine and cystatin C. Primary outcome was first incident of hospital-acquired AKI assessed through linked insurance claims data. In a nested case-control study, kidney function decline prior to hospitalization with and without AKI was investigated using eGFR trajectories estimated with mixed-effects models adjusted for traditional cardiovascular comorbidities., Results: Out of 2020 study participants (52.9% women; mean age 80.4 years) without prior AKI, 383 developed a first incident AKI, 1518 were hospitalized without AKI, and 119 were never hospitalized during a median follow-up of 8.8 years. IR per 1000 person years for hospital-acquired AKI was 26.8 (95% confidence interval (CI): 24.1-29.6); higher for men than women (33.9 (29.5-38.7) vs. 21.2 (18.1-24.6)). IR (CI) were lowest for persons aged 70-75 (13.1; 10.0-16.8) and highest for ≥ 90 years (54.6; 40.0-72.9). eGFR trajectories declined more steeply in men and women with AKI compared to men and women without AKI years before hospitalization. These differences in eGFR trajectories remained after adjustment for traditional comorbidities., Conclusion: AKI is a frequent in-hospital complication in individuals aged 70 + showing a striking increase of IR with age. eGFR decline was steeper in elderly patients with AKI compared to elderly patients without AKI years prior to hospitalization emphasising the need for long-term kidney function monitoring pre-admission to improve risk stratification., (© 2023. The Author(s).)

Porcine epidemic diarrhea virus is a swine pathogen that has been responsible for significant animal and economic losses worldwide in recent years. In this manuscript, we report the generation of a reverse genetics system C(RGS) for the highly virulent US PEDV strain Minnesota (PEDV-MN; GenBank accession number KF468752), which was based on the assembly and cloning of synthetic DNA, using vaccinia virus as a cloning vector. Viral rescue was only possible following the substitution of 2 nucleotides within the 5'UTR and 2 additional nucleotides within the spike gene, based on the sequence of the cell culture-adapted strains. Besides displaying a highly pathogenic phenotype in newborn piglets, in comparison with the parental virus, the rescued recombinant PEDV-MN was used to confirm that the PEDV spike gene has an important role in PEDV virulence and that the impact of an intact PEDV ORF3 on viral pathogenicity is modest. Moreover, a chimeric virus with a TGEV spike gene in the PEDV backbone generated with RGS was able to replicate efficiently in vivo and could be readily transmitted between piglets. Although this chimeric virus did not cause severe disease upon the initial infection of piglets, there was evidence of increasing pathogenicity upon transmission to contact piglets. The RGS described in this study constitutes a powerful tool with which to study PEDV pathogenesis and can be used to generate vaccines against porcine enteric coronaviruses. IMPORTANCE PEDV is a swine pathogen that is responsible for significant animal and economic losses worldwide. Highly pathogenic variants can lead to a mortality rate of up to 100% in newborn piglets. The generation of a reverse genetics system for a highly virulent PEDV strain originating from the United States is an important step in phenotypically characterizing PEDV. The synthetic PEDV mirrored the authentic isolate and displayed a highly pathogenic phenotype in newborn piglets. With this system, it was possible to characterize potential viral virulence factors. Our data revealed that an accessory gene (ORF3) has a limited impact on pathogenicity. However, as it is also now known for many coronaviruses, the PEDV spike gene is one of the main determinants of pathogenicity. Finally, we show that the spike gene of another porcine coronavirus, namely, TGEV, can be accommodated in the PEDV genome background, suggesting that similar viruses can emerge in the field via recombination., Competing Interests: The authors declare no conflict of interest.

Background: Chronic kidney disease (CKD) causes congestive heart failure (CHF) with systolic dysfunction and left ventricular hypertrophy (LVH), which is a major contributor to increased mortality in CKD patients. It remains unclear whether cardiovascular changes that occur during the course of CKD can be reversed when renal function is restored by transplantation., Methods: To investigate this, chronic kidney disease was established in F344 rats by subtotal nephrectomy (SNx) for 8 weeks, followed by transplantation of a functional kidney from an isogenic F344 donor. SNx rats without transplantation and sham-operated animals served as controls. Renal function was assessed before and throughout the experiment. In addition, cardiac ultrasound was performed at weeks 0, 8, 12 and 16. At the end of the experiment, intra-arterial blood pressure was measured and kidneys and hearts were histologically and molecularly examined., Results: Eight weeks after SNx, rats developed marked renal dysfunction associated with significant glomerulosclerosis and tubulointerstitial fibrosis, but also an increase in left ventricular mass. After transplantation, renal function normalized but relative heart weight and ventricular mass as assessed by ultrasound scans showed no reduction compared with SNx controls. However, left ventricular wall thickness, fractional shortening and ejection fraction was normalized by renal transplantation. At 8 weeks after kidney transplantation, cardiac expression of BNP and FGF23 was also at levels comparable to healthy controls, whereas these factors were significantly increased in SNx rats. Cardiac fibrosis, as measured by fibronectin mRNA expression, was completely normalized, whereas cardiac fibronectin protein was still slightly but not significantly increased in transplanted animals compared to controls. In addition, the myofibroblast marker collagen 1, as assessed by immunohistochemistry, was significantly increased in SNx rats and also normalized by renal transplantation. Interestingly, CD68+ macrophages were significantly reduced in the hearts of SNx rats and in transplanted animals at slightly higher levels compared to controls., Conclusion: Restoration of renal function by kidney transplantation normalized early cardiac changes at most functional and molecular levels, but did not completely reverse LVH. However, further studies are needed to determine whether restoration of renal function can also reverse LVH at a later time point., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Hagmayer, Mayer, Ebert, Amann and Daniel.)

Background: During the COVID-19 pandemic, telephone hotlines of local health authorities in Germany were overloaded due to information requests by the public., Objective: Evaluating the use of a COVID-19-specific voicebot (CovBot) in local health authorities in Germany during the COVID-19 pandemic. This study investigates the performance of the CovBot by assessing a perceptible relief of staff in the hotline service., Methods: This prospective mixed-methods study enrolled local health authorities in Germany from 01 February 2021 to 11 February 2022 to deploy the CovBot, which was mainly designed to answer frequently asked questions. To capture the user perspective and acceptance, we performed semistructured interviews and online surveys with their staff, conducted an online survey among callers, and analyzed the performance metrics of the CovBot., Results: The CovBot was implemented in 20 local health authorities serving 6.1 million German citizens and processed almost 1.2 million calls during the study period. The overall assessment was that the CovBot contributed to a perceived relief of the hotline service. In a survey among callers, 79% indicated that a voicebot could not replace a human. The analyzed anonymous metadata revealed that 15% of calls hung up immediately, 32% after hearing an FAQ answer, and 51% of calls were forwarded to the local health authority offices., Conclusions: A voicebot primarily answering FAQs can provide additional support to relieve the hotline service of local health authorities in Germany during the COVID-19 pandemic. For complex concerns, a forwarding option to a human proved to be an essential functionality., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article: T.K. reports having received research grants from the German Federal Ministry of Health and outside the submitted work to have received research grants from the German Joint Committee. He further reports personal compensation from Eli Lilly and Company, Teva Pharmaceutical TotalEnergies S.E., the BMJ, and Frontiers. N.E. has a collaborative research agreement with Bayer AG. All other authors declare no potential conflicts of interest., (© The Author(s) 2023.)

Background: Chronic kidney disease (CKD) is a common condition, especially in the elderly. In order to prevent progression and complications of the disease, guideline-adherent outpatient care of patients with CKD should be prioritized. Quality indicators (QIs) can be used to measure and evaluate the quality of ambulatory care for patients with CKD. QIs specifically made for evaluating CKD care in Germany are not yet available. The goal of this work was to develop QIs for the quality assessment of outpatient care for patients over the age of 70 with CKD not requiring dialysis., Materials and Methods: QIs were operationalized from the recommendations of the German national guideline for CKD and others were proposed based on a published review of international QIs. The resulting QIs were divided into sets based on routine data (e.g., health insurance billing data) and data collection in practices (chart review). A panel of experts from various disciplines as well as a patient representative evaluated the proposed QIs in a two-stage Delphi process via online survey in October 2021 and January 2022 and a final consensus conference in March 2022. In addition, ranking lists of the most important QIs from each set were created., Results: An incidence indicator and a prevalence indicator were established; these were not subject to vote. Further, 21 QIs were voted upon by the expert panel. The seven most important QIs in each set (billing data or chart review) were selected. Only one QI was rated by the expert panel as not suitable for additional use in adults under the age of 70 years., Discussion: The QIs will enable the evaluation of the quality of outpatient care for patients with CKD with the long-term aim of optimizing guideline-adherent outpatient care., (© 2023. The Author(s).)

Purpose: To perform a preclinical trial comparing the efficacy of fractionated radiotherapy versus radiochemotherapy with cisplatin in HPV-positive and negative human head and neck squamous cell carcinoma (HNSCC) xenografts., Material and Methods: Three HPV-negative and three HPV-positive HNSCC xenografts in nude mice were randomized to radiotherapy (RT) alone or to radiochemotherapy (RCT) with weekly cisplatin. To evaluate tumour growth time, 20 Gy radiotherapy (±cisplatin) were administered in 10 fractions over 2 weeks. Dose-response curves for local tumour control were generated for RT with 30 fractions over 6 weeks to different dose levels given alone or combined with cisplatin (RCT)., Results: One of three investigated HPV-negative and two out of three HPV-positive tumour models showed a significant increase in local tumour control after RCT compared to RT alone. Pooled analysis of the HPV-positive tumour models showed a statistically significant and substantial benefit of RCT versus RT alone, with an enhancement ratio of 1.34. Although heterogeneity in response to both RT and RCT was also observed between the different HPV-positive HNSCC, these overall were more RT and RCT sensitive than HPV-negative models., Conclusion: The impact of adding chemotherapy to fractionated radiotherapy on local control was heterogenous, both in HPV-negative and in HPV-positive tumours, calling for predictive biomarkers. RCT substantially increased local tumour control in the pooled group of all HPV-positive tumours whereas this was not found in HPV-negative tumours. Omission of chemotherapy in HPV-positive HNSCC as part of a treatment de-escalation strategy is not supported by this preclinical trial., (Copyright © 2023. Published by Elsevier B.V.)

Background and Objectives: Studies analysing the association of albuminuria and prevalent frailty in community-dwelling very old adults are scarce and lack information on incident frailty. We investigated the association of kidney function decline and increase of albuminuria with frailty worsening or death in very old adults., Design: Longitudinal analyses with biennial visits of the Berlin Initiative (cohort) Study and a frailty follow-up of 2.1 years., Setting/subjects: 1,076 participants with a mean age of 84.3 (5.6) years of whom 54% were female., Methods: Partial proportional odds models were used to assess the association of estimated glomerular filtration rate (eGFR) decline and/or albuminuria (albumin creatinine ratio, ACR) with frailty worsening or death., Results: At frailty baseline, 1,076 participants with an eGFR of 50 (13) ml/min/1.73 m2, 48% being prefrail and 31% frail were included. After median 2.1 years, 960 (90%) participants had valid information on frailty transition: 187 (17.5%) worsened and 111 (10.3%) died. In the multivariable model, the odds of frailty worsening for participants with albuminuria in combination with eGFR <60 ml/min/1.73 m2 were elevated [OR (95% CI): 2.47 (1.41-4.31)] compared to participants without albuminuria and eGFR ≥60 ml/min/1.73 m2 as there was a rapid eGFR decline of ≥3 ml/min/1.73 m2 per year [1.55 (1.04-2.33)] and albuminuria trajectories six years prior [1.53 (1.11-2.10)] to frailty baseline. The odds of death for each exposure were even higher., Conclusions: In older adults, advanced stages of CKD and albuminuria alone were associated with 2-fold odds of frailty worsening independent of death., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The SARS-CoV-2 main protease (3CLpro) is one of the promising therapeutic targets for the treatment of COVID-19. Nirmatrelvir is the first 3CLpro inhibitor authorized for treatment of COVID-19 patients at high risk of hospitalization. We recently reported on the in vitro selection of SARS-CoV-2 3CLpro resistant virus (L50F-E166A-L167F; 3CLpro res ) that is cross-resistant with nirmatrelvir and other 3CLpro inhibitors. Here, we demonstrate that the 3CLpro res virus replicates efficiently in the lungs of intranasally infected female Syrian hamsters and causes lung pathology comparable to that caused by the WT virus. Moreover, hamsters infected with 3CLpro res virus transmit the virus efficiently to co-housed non-infected contact hamsters. Importantly, at a dose of 200 mg/kg (BID) of nirmatrelvir, the compound was still able to reduce the lung infectious virus titers of 3CLpro res -infected hamsters by 1.4 log 10 with a modest improvement in the lung histopathology as compared to the vehicle control. Fortunately, resistance to Nirmatrelvir does not readily develop in clinical setting. Yet, as we demonstrate, in case drug-resistant viruses emerge, they may spread easily which may thus impact therapeutic options. Therefore, the use of 3CLpro inhibitors in combination with other drugs may be considered, especially in immunodeficient patients, to avoid the development of drug-resistant viruses., (© 2023. The Author(s).)

Recently, transformer architectures have shown superior performance compared to their CNN counterparts in many computer vision tasks. The self-attention mechanism enables transformer networks to connect visual dependencies over short as well as long distances, thus generating a large, sometimes even a global receptive field. In this paper, we propose our Parallel Local-Global Vision Transformer (PLG-ViT), a general backbone model that fuses local window self-attention with global self-attention. By merging these local and global features, short- and long-range spatial interactions can be effectively and efficiently represented without the need for costly computational operations such as shifted windows. In a comprehensive evaluation, we demonstrate that our PLG-ViT outperforms CNN-based as well as state-of-the-art transformer-based architectures in image classification and in complex downstream tasks such as object detection, instance segmentation, and semantic segmentation. In particular, our PLG-ViT models outperformed similarly sized networks like ConvNeXt and Swin Transformer, achieving Top-1 accuracy values of 83.4%, 84.0%, and 84.5% on ImageNet-1K with 27M, 52M, and 91M parameters, respectively.

Rationale & Objective: Serum creatinine and cystatin C are used to estimate glomerular filtration rate, but creatinine-based estimated glomerular filtration rate (eGFRcr), cystatin C-based estimated glomerular filtration rate (eGFRcys), and combined creatinine- and cystatin C-based estimated glomerular filtration rate (eGFRcr-cys) are often divergent, particularly in older adults. We investigated which estimated glomerular filtration rate (eGFR) was more accurate and less biased compared with measured glomerular filtration rate (mGFR)., Study Design: A diagnostic test study from the Berlin Initiative Study., Setting & Participants: The study population included 657 individuals aged 70 years or older with iohexol plasma clearance (mGFR) and serum creatinine and cystatin C measurements: 567 community-dwelling participants and 90 with a serum creatinine of ≥1.5 mg/dL., Tests Compared: We defined 3 groups on the basis of the difference eGFRcys - eGFRcr: whether < -5 mL/min/1.73 m 2 (lower eGFRcys), within 5 mL/min/1.73 m 2 (reference), or  ≥ 5 mL/min/1.73 m 2 (lower eGFRcr). eGFRcr, eGFRcys, and eGFRcr-cys were compared to mGFR to assess bias and accuracy., Outcome: Median bias (eGFR minus mGFR) with 95% CIs and accuracy (percentage of eGFR values within ±30% of mGFR)., Results: The mean ± standard deviation age was 78 ± 6 years; the mean eGFRcys, eGFRcr, and eGFRcr-cys were 59 ± 23, 64 ± 20, and 61 ± 22 mL/min/1.73 m 2 , respectively, and the mean mGFR was 56 ± 19 mL/min. Half of the participants were in the lower eGFRcys group (n=337, 51%). Among them, the median bias for eGFRcys was the lowest (median bias, -2.7; 95% CI, -3.8 to -1.9) compared with the other eGFR equations. Conversely, in the lower eGFRcr group (n=121, 18%), the median bias for eGFRcr was the lowest compared with those for eGFRcys and eGFRcr-cys (2.9; [95% CI, 0.9-4.8] vs 13.8 [95% CI, 11.4-15.6] and 9.5 [95% CI, 7.7-11.0], respectively). Accuracy (percentage of eGFR values within ±30% of mGFR) was 93% for eGFRcr in the lower eGFRcr group and 92% for eGFRcys and 94% for eGFRcr-cys in the lower eGFRcys group., Limitations: Untested generalizability in younger populations., Conclusions: Among older adults, the lower eGFR between eGFRcys and eGFRcr was a more accurate and less biased estimate of mGFR when comparing the groups., (© 2023 The Authors.)

The SARS-CoV-2 main protease (3CLpro) has an indispensable role in the viral life cycle and is a therapeutic target for the treatment of COVID-19. The potential of 3CLpro-inhibitors to select for drug-resistant variants needs to be established. Therefore, SARS-CoV-2 was passaged in vitro in the presence of increasing concentrations of ALG-097161, a probe compound designed in the context of a 3CLpro drug discovery program. We identified a combination of amino acid substitutions in 3CLpro (L50F E166A L167F) that is associated with a >20× increase in 50% effective concentration (EC 50 ) values for ALG-097161, nirmatrelvir (PF-07321332), PF-00835231, and ensitrelvir. While two of the single substitutions (E166A and L167F) provide low-level resistance to the inhibitors in a biochemical assay, the triple mutant results in the highest levels of resistance (6× to 72×). All substitutions are associated with a significant loss of enzymatic 3CLpro activity, suggesting a reduction in viral fitness. Structural biology analysis indicates that the different substitutions reduce the number of inhibitor/enzyme interactions while the binding of the substrate is maintained. These observations will be important for the interpretation of resistance development to 3CLpro inhibitors in the clinical setting. IMPORTANCE Paxlovid is the first oral antiviral approved for treatment of SARS-CoV-2 infection. Antiviral treatments are often associated with the development of drug-resistant viruses. In order to guide the use of novel antivirals, it is essential to understand the risk of resistance development and to characterize the associated changes in the viral genes and proteins. In this work, we describe for the first time a pathway that allows SARS-CoV-2 to develop resistance against Paxlovid in vitro . The characteristics of in vitro antiviral resistance development may be predictive for the clinical situation. Therefore, our work will be important for the management of COVID-19 with Paxlovid and next-generation SARS-CoV-2 3CLpro inhibitors.

Polypharmacy is associated with poorer self-rated health (SRH). However, whether polypharmacy has an impact on the SRH progression is unknown. This study investigates the association of polypharmacy with SRH change in 1428 participants of the Berlin Initiative Study aged 70 years and older over four years. Polypharmacy was defined as the intake of ≥5 medications. Descriptive statistics of SRH-change categories stratified by polypharmacy status were reported. The association of polypharmacy with being in SRH change categories was assessed using multinomial regression analysis. At baseline, mean age was 79.1 (6.1) years, 54.0% were females, and prevalence of polypharmacy was 47.1%. Participants with polypharmacy were older and had more comorbidities compared to those without polypharmacy. Over four years, five SRH-change categories were identified. After covariate adjustment, individuals with polypharmacy had higher odds of being in the stable moderate category (OR 3.55; 95% CI [2.43-5.20]), stable low category (OR 3.32; 95% CI [1.65-6.70]), decline category (OR 1.87; 95% CI [1.34-2.62]), and improvement category (OR 2.01; [1.33-3.05]) compared to being in the stable high category independent of the number of comorbidities. Reducing polypharmacy could be an impactful strategy to foster favorable SRH progression in old age.

Effective public health measures against SARS-CoV-2 require granular knowledge of population-level immune responses. We developed a Tripartite Automated Blood Immunoassay (TRABI) to assess the IgG response against three SARS-CoV-2 proteins. We used TRABI for continuous seromonitoring of hospital patients and blood donors (n = 72'250) in the canton of Zurich from December 2019 to December 2020 (pre-vaccine period). We found that antibodies waned with a half-life of 75 days, whereas the cumulative incidence rose from 2.3% in June 2020 to 12.2% in mid-December 2020. A follow-up health survey indicated that about 10% of patients infected with wildtype SARS-CoV-2 sustained some symptoms at least twelve months post COVID-19. Crucially, we found no evidence of a difference in long-term complications between those whose infection was symptomatic and those with asymptomatic acute infection. The cohort of asymptomatic SARS-CoV-2-infected subjects represents a resource for the study of chronic and possibly unexpected sequelae., Competing Interests: TPJK is a member of the board of directors of Fluidic Analytics. AA is a member of the board of directors of Mabylon AG which has funded antibody-related work in the Aguzzi lab in the past. All other authors declare no competing interests., (© 2023 The Authors.)

Background: The accuracy of estimation of kidney function with the use of routine metabolic tests, such as measurement of the serum creatinine level, has been controversial. The European Kidney Function Consortium (EKFC) developed a creatinine-based equation (EKFC eGFRcr) to estimate the glomerular filtration rate (GFR) with a rescaled serum creatinine level (i.e., the serum creatinine level is divided by the median serum creatinine level among healthy persons to control for variation related to differences in age, sex, or race). Whether a cystatin C-based EKFC equation would increase the accuracy of estimated GFR is unknown., Methods: We used data from patients in Sweden to estimate the rescaling factor for the cystatin C level in adults. We then replaced rescaled serum creatinine in the EKFC eGFRcr equation with rescaled cystatin C, and we validated the resulting EKFC eGFRcys equation in cohorts of White patients and Black patients in Europe, the United States, and Africa, according to measured GFR, levels of serum creatinine and cystatin C, age, and sex., Results: On the basis of data from 227,643 patients in Sweden, the rescaling factor for cystatin C was estimated at 0.83 for men and women younger than 50 years of age and 0.83 + 0.005 × (age - 50) for those 50 years of age or older. The EKFC eGFRcys equation was unbiased, had accuracy that was similar to that of the EKFC eGFRcr equation in both White patients and Black patients (11,231 patients from Europe, 1093 from the United States, and 508 from Africa), and was more accurate than the Chronic Kidney Disease Epidemiology Collaboration eGFRcys equation recommended by Kidney Disease: Improving Global Outcomes. The arithmetic mean of EKFC eGFRcr and EKFC eGFRcys further improved the accuracy of estimated GFR over estimates from either biomarker equation alone., Conclusions: The EKFC eGFRcys equation had the same mathematical form as the EKFC eGFRcr equation, but it had a scaling factor for cystatin C that did not differ according to race or sex. In cohorts from Europe, the United States, and Africa, this equation improved the accuracy of GFR assessment over that of commonly used equations. (Funded by the Swedish Research Council.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: A new Chronic Kidney Disease Epidemiology Collaboration equation without the race variable has been recently proposed (CKD-EPIAS). This equation has neither been validated outside USA nor compared with the new European Kidney Function Consortium (EKFC) and Lund-Malmö Revised (LMREV) equations, developed in European cohorts., Methods: Standardized creatinine and measured glomerular filtration rate (GFR) from the European EKFC cohorts (n = 13 856 including 6031 individuals in the external validation cohort), from France (n = 4429, including 964 Black Europeans), from Brazil (n = 100) and from Africa (n = 508) were used to test the performances of the equations. A matched analysis between White Europeans and Black Africans or Black Europeans was performed., Results: In White Europeans (n = 9496), both the EKFC and LMREV equations outperformed CKD-EPIAS (bias of -0.6 and -3.2, respectively versus 5.0 mL/min/1.73 m², and accuracy within 30% of 86.9 and 87.4, respectively, versus 80.9%). In Black Europeans and Black Africans, the best performance was observed with the EKFC equation using a specific Q-value (= concentration of serum creatinine in healthy males and females). These results were confirmed in matched analyses, which showed that serum creatinine concentrations were different in White Europeans, Black Europeans and Black Africans for the same measured GFR, age, sex and body mass index. Creatinine differences were more relevant in males., Conclusion: In a European and African cohort, the performances of CKD-EPIAS remain suboptimal. The EKFC equation, using usual or dedicated population-specific Q-values, presents the best performance in the whole age range in the European and African populations included in this study., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Aims: The 2021 European Society of Cardiology (ESC) guideline on cardiovascular disease (CVD) prevention categorizes moderate and severe chronic kidney disease (CKD) as high and very-high CVD risk status regardless of other factors like age and does not include estimated glomerular filtration rate (eGFR) and albuminuria in its algorithms, systemic coronary risk estimation 2 (SCORE2) and systemic coronary risk estimation 2 in older persons (SCORE2-OP), to predict CVD risk. We developed and validated an 'Add-on' to incorporate CKD measures into these algorithms, using a validated approach., Methods: In 3,054 840 participants from 34 datasets, we developed three Add-ons [eGFR only, eGFR + urinary albumin-to-creatinine ratio (ACR) (the primary Add-on), and eGFR + dipstick proteinuria] for SCORE2 and SCORE2-OP. We validated C-statistics and net reclassification improvement (NRI), accounting for competing risk of non-CVD death, in 5,997 719 participants from 34 different datasets., Results: In the target population of SCORE2 and SCORE2-OP without diabetes, the CKD Add-on (eGFR only) and CKD Add-on (eGFR + ACR) improved C-statistic by 0.006 (95%CI 0.004-0.008) and 0.016 (0.010-0.023), respectively, for SCORE2 and 0.012 (0.009-0.015) and 0.024 (0.014-0.035), respectively, for SCORE2-OP. Similar results were seen when we included individuals with diabetes and tested the CKD Add-on (eGFR + dipstick). In 57 485 European participants with CKD, SCORE2 or SCORE2-OP with a CKD Add-on showed a significant NRI [e.g. 0.100 (0.062-0.138) for SCORE2] compared to the qualitative approach in the ESC guideline., Conclusion: Our Add-ons with CKD measures improved CVD risk prediction beyond SCORE2 and SCORE2-OP. This approach will help clinicians and patients with CKD refine risk prediction and further personalize preventive therapies for CVD., Competing Interests: Conflict of interest: Ku.M. reports grants from NIDDK; grants and personal fees from Kyowa Kirin, personal fees from Akebia outside the submitted work. M.G. reports grants from NIH and National Kidney Foundation outside the submitted work. J.A. reports personal fees from AstraZeneca, Novartis, and Boerhinger Ingelheim outside the submitted work. A.R.C. reports personal fees from Novartis, Reata, and Amgen; grants from Novo Nordisk outside the submitted work. N.E. reports personal fees from Bayer and AG Leverkusen outside the submitted work. K.E. reports grants from Amgen, Astra Zenceca, Bayer, Evotec, and Vifor; personal fees from Akebia, Astra Zeneca, Bayer, Otsuka, and Retrophin outside the submitted work. S.K.J reports salary support from US Government and Department of Veterans Affairs during the conduct of the study. C.K. reports personal fees from Bayer, Abbott, Astra-Zeneca, Takeda, Tricida, Akebia, Cara Therapeutics, Vifor, Rockwell, CSL Behring, Reata, Boehringer Ingelheim, and GSK outside the submitted work. A.S.L. reports grants and contracts from NIH and NKF for studies in CKD and a contract from AstraZeneca for DSMB for clinical trials of dapagliflozin. Ka.M. reports grants from Ministry of Health, Labor, and Welfare, Japan. G.N.N reports personal fees from Renalytix, Daiichi Sankyo, Menarini Medical, Qiming Capital, and Variant Bio; other fees from Pensieve Health, Nexus I Connect outside the submitted work; patent KidneyIntelX pending to Renalytix. M.G.S. reports grants from NIH- NIA/NIDDK/NHLBI during the conduct of the study; personal fees from Cricket Health, Intercept Pharmaceuticals, Bayer Pharmaceuticals, AztraZeneca, Boeringer Ingelheim; grants from Bayer Pharmaceuticals outside the submitted work. M.D.S reports a honoraria from AstraZeneca outside the submitted work. N.S. is a current employee of GSK and employed at AMGA. M.W. reports personal fees from Amgen and Freeline outside the submitted work. J.C. reports grants from National Institute of Health and National Kidney Foundation, during the conduct of the study; personal fees from Healthy.io and SomaLogic outside the submitted work. No other potential conflicts of interest relevant to this article were reported. All other authors report no potential conflicts., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The European Working Group on Sarcopenia in Older People (EWGSOP) updated in 2018 the cut-off points for low grip strength to assess sarcopenia based on pooled data from 12 British studies., Objective: Comparison of the EWGSOP2 cut-off points for low grip strength to those derived from a large German sample., Methods: We assessed the grip strength distribution across age and derived low grip strength cut-off points for men and women (peak mean -2.5 × SD) based on 200,389 German National Cohort (NAKO) participants aged 19-75 years. In 1,012 Cooperative Health Research in the Region of Augsburg (KORA)-Age participants aged 65-93 years, we calculated the age-standardised prevalence of low grip strength and time-dependent sensitivity and specificity for all-cause mortality., Results: Grip strength increased in the third and fourth decade of life and declined afterwards. Calculated cut-off points for low grip strength were 29 kg for men and 18 kg for women. In KORA-Age, the age-standardised prevalence of low grip strength was 1.5× higher for NAKO-derived (17.7%) compared to EWGSOP2 (11.7%) cut-off points. NAKO-derived cut-off points yielded a higher sensitivity and lower specificity for all-cause mortality., Conclusions: Cut-off points for low grip strength from German population-based data were 2 kg higher than the EWGSOP2 cut-off points. Higher cut-off points increase the sensitivity, thereby suggesting an intervention for more patients at risk, while other individuals might receive additional diagnostics/treatment without the urgent need. Research on the effectiveness of intervention in patients with low grip strength defined by different cut-off points is needed., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Severity of COVID-19 shows an extraordinary correlation with increasing age. We generated a mouse model for severe COVID-19 and show that the age-dependent disease severity is caused by the disruption of a timely and well-coordinated innate and adaptive immune response due to impaired interferon (IFN) immunity. Aggravated disease in aged mice was characterized by a diminished IFN-γ response and excessive virus replication. Accordingly, adult IFN-γ receptor-deficient mice phenocopied the age-related disease severity, and supplementation of IFN-γ reversed the increased disease susceptibility of aged mice. Further, we show that therapeutic treatment with IFN-λ in adults and a combinatorial treatment with IFN-γ and IFN-λ in aged Ifnar1-/- mice was highly efficient in protecting against severe disease. Our findings provide an explanation for the age-dependent disease severity and clarify the nonredundant antiviral functions of type I, II, and III IFNs during SARS-CoV-2 infection in an age-dependent manner. Our data suggest that highly vulnerable individuals could benefit from immunotherapy combining IFN-γ and IFN-λ., (© 2022 Beer et al.)

Prior research on how to improve the effectiveness of information security warnings has predominantly focused on either the informational content of warnings or their visual saliency. In an online experiment ( N  = 1'486), we disentangle the effect of both manipulations and demonstrate that both factors simultaneously influence decision making. Our data indicate that the proportion of people who engage in protection behavior can be increased by roughly 65% by making a particular warning message more visually salient (i.e. a more conspicuous visual design is used). We also show that varying the message's saliency can make people behave very differently when confronted with the same threat or behave very similarly when confronted with threats that differ widely in terms of severity of outcomes. Our results suggest that the visual design of a warning may warrant at least as much attention as the informational content that the warning message conveys., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Variant of concern (VOC) Omicron-BA.1 has achieved global predominance in early 2022. Therefore, surveillance and comprehensive characterization of Omicron-BA.1 in advanced primary cell culture systems and animal models are urgently needed. Here, we characterize Omicron-BA.1 and recombinant Omicron-BA.1 spike gene mutants in comparison with VOC Delta in well-differentiated primary human nasal and bronchial epithelial cells in vitro, followed by in vivo fitness characterization in hamsters, ferrets and hACE2-expressing mice, and immunized hACE2-mice. We demonstrate a spike-mediated enhancement of early replication of Omicron-BA.1 in nasal epithelial cultures, but limited replication in bronchial epithelial cultures. In hamsters, Delta shows dominance over Omicron-BA.1, and in ferrets Omicron-BA.1 infection is abortive. In hACE2-knock-in mice, Delta and a Delta spike clone also show dominance over Omicron-BA.1 and an Omicron-BA.1 spike clone, respectively. Interestingly, in naïve K18-hACE2 mice, we observe Delta spike-mediated increased replication and pathogenicity and Omicron-BA.1 spike-mediated reduced replication and pathogenicity, suggesting that the spike gene is a major determinant of replication and pathogenicity. Finally, the Omicron-BA.1 spike clone is less well-controlled by mRNA-vaccination in K18-hACE2-mice and becomes more competitive compared to the progenitor and Delta spike clones, suggesting that spike gene-mediated immune evasion is another important factor that led to Omicron-BA.1 dominance., (© 2022. The Author(s).)

Importance: Kidney function is usually estimated from serum creatinine level, whereas an alternative glomerular filtration marker (cystatin C level) associates more closely with future risk of cardiovascular disease (CVD) and mortality., Objectives: To evaluate whether testing concordance between estimated glomerular filtration rates based on cystatin C (eGFRcys) and creatinine (eGFRcr) levels would improve risk stratification for future outcomes and whether estimations differ by age., Design, Setting, and Participants: A prospective population-based cohort study (UK Biobank), with participants recruited between 2006-2010 with median follow-up of 11.5 (IQR, 10.8-12.2) years; data were collected until August 31, 2020. Participants had eGFRcr greater than or equal to 45 mL/min/1.73 m2, albuminuria (albumin <30 mg/g), and no preexisting CVD or kidney failure., Exposures: Chronic kidney disease status was categorized by concordance between eGFRcr and eGFRcys across the threshold for hronic kidney disease (CKD) diagnosis (60 mL/min/1.73 m2)., Main Outcomes and Measures: Ten-year probabilities of CVD, mortality, and kidney failure were assessed according to CKD status. Multivariable-adjusted Cox proportional hazards models tested associations between CVD and mortality. Area under the receiving operating curve tested discrimination of eGFRcr and eGFRcys for CVD and mortality. The Net Reclassification Index assessed the usefulness of eGFRcr and eGFRcys for CVD risk stratification. Analyses were stratified by older (age 65-73 years) and younger (age <65 years) age., Results: There were 428 402 participants: median age was 57 (IQR, 50-63) years and 237 173 (55.4%) were women. Among 76 629 older participants, there were 9335 deaths and 5205 CVD events. Among 351 773 younger participants, there were 14 776 deaths and 9328 CVD events. The 10-year probability of kidney failure was less than 0.1%. Regardless of the eGFRcr, the 10-year probabilities of CVD and mortality were low when eGFRcys was greater than or equal to 60 mL/min/1.73 m2; conversely, with eGFRcys less than 60 mL/min/1.73 m2, 10-year risks were nearly doubled in older adults and more than doubled in younger adults. Use of eGFRcys better discriminated CVD and mortality risk than eGFRcr. Across a 7.5% 10-year risk threshold for CVD, eGFRcys improved case Net Reclassification Index by 0.7% (95% CI, 0.6%-0.8%) in older people and 0.7% (95% CI, 0.7%-0.8%) in younger people; eGFRcr did not add to CVD risk estimation., Conclusions and Relevance: The findings of this study suggest that eGFRcr 45 to 59 mL/min/1.73 m2 includes a proportion of individuals at low risk and fails to capture a substantial proportion of individuals at high-risk for CVD and mortality. The eGFRcys appears to be more sensitive and specific for CVD and mortality risks in mild CKD.

The German National Cohort (NAKO) is a multidisciplinary, population-based prospective cohort study that aims to investigate the causes of widespread diseases, identify risk factors and improve early detection and prevention of disease. Specifically, NAKO is designed to identify novel and better characterize established risk and protection factors for the development of cardiovascular diseases, cancer, diabetes, neurodegenerative and psychiatric diseases, musculoskeletal diseases, respiratory and infectious diseases in a random sample of the general population. Between 2014 and 2019, a total of 205,415 men and women aged 19-74 years were recruited and examined in 18 study centres in Germany. The baseline assessment included a face-to-face interview, self-administered questionnaires and a wide range of biomedical examinations. Biomaterials were collected from all participants including serum, EDTA plasma, buffy coats, RNA and erythrocytes, urine, saliva, nasal swabs and stool. In 56,971 participants, an intensified examination programme was implemented. Whole-body 3T magnetic resonance imaging was performed in 30,861 participants on dedicated scanners. NAKO collects follow-up information on incident diseases through a combination of active follow-up using self-report via written questionnaires at 2-3 year intervals and passive follow-up via record linkages. All study participants are invited for re-examinations at the study centres in 4-5 year intervals. Thereby, longitudinal information on changes in risk factor profiles and in vascular, cardiac, metabolic, neurocognitive, pulmonary and sensory function is collected. NAKO is a major resource for population-based epidemiology to identify new and tailored strategies for early detection, prediction, prevention and treatment of major diseases for the next 30 years., (© 2022. The Author(s).)

An accurate estimated glomerular filtration rate (eGFR) is essential in drug dosing. This study demonstrates the limitations of indexed (ml/min/1.73 m 2 ) and de-indexed (ml/min) eGFR based drug dosing in patients with obesity or underweight. This systematic study aimed to determine the most appropriate approach to estimate the GFR for standardized eGFR based drug dosing in these patients. (Raw) data of 12 studies were selected to investigate the accuracy and bias of both the indexed and de-indexed estimations of the Modification of Diet in Renal Disease (MDRD) study equation and the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI), and of the Cockcroft-Gault (CG) in patients with obesity or underweight. Accuracy was calculated as the proportion of eGFR values within 30% of the measured GFR (P30) using an inert tracer (e.g., iohexol, inulin, 51 Cr-EDTA, or iothalamate clearance). An accuracy of at least 80% was considered acceptable. GFR values estimated with the CG, MDRD, and CKD-EPI differ significantly within a patient with obesity or underweight regardless of whether it is indexed or de-indexed. All studies, with two exceptions, show that all three equations are inaccurate for patients with underweight or class II obesity (P30: 55%-94%). De-indexing eGFR improves not or modestly the accuracy, and mostly remains below the 80% (P30: 62%-100%). CG was highly inaccurate in obese and underweight patients (P30: 7%-82%). Although these results show that CG is obsolete, the accuracy of MDRD and CKD-EPI is low in patients with obesity or underweight and de-indexing is not the solution. Better education and more accurate methods for appropriate drug dosing (e.g., measured GFR with inert tracer, therapeutic drug monitoring, or 24-h creatinine clearance) are recommended., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Differences in the performance of estimated glomerular filtration rate (eGFR) equations have been attributed to the mathematical form of the equations and to differences between patient demographics and measurement methods. We evaluated differences in serum creatinine (SCr) and eGFR in cohorts matched for age, sex, body mass index (BMI) and measured GFR (mGFR)., Methods: White North Americans from Minnesota ( n  = 1093) and the Chronic Renal Insufficiency Cohort (CRIC) ( n  = 1548) and White subjects from the European Kidney Function Consortium (EKFC) cohort ( n  = 7727) were matched for demographic patient characteristics (sex, age ± 3 years, BMI ± 2.5 kg/m 2 ) and renal function (mGFR ± 3 ml/min/1.73 m 2 ). SCr was measured with isotope dilution mass spectrometry (IDMS)-traceable assays in the Minnesota and EKFC cohorts and with non-standardized SCr assays recalculated to IDMS in the CRIC. The Minnesota cohort and CRIC shared a common method to measure GFR (renal clearance of iothalamate), while the EKFC cohort used a variety of exogenous markers and methods, all with recognized sufficient accuracy. We compared the SCr levels and eGFR predictions [for Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and EKFC equations] of patients fulfilling these matching criteria., Results: For 305 matched individuals, mean SCr (mg/dL) was not different between the Minnesota and EKFC cohorts (females 0.83 ± 0.20 versus 0.86 ± 0.23, males 1.06 ± 0.23 versus 1.12 ± 0.37; P  > .05) but significantly different from the CRIC [females 1.13 ± 0.23 ( P  < .0001), males 1.42 ± 0.31 ( P  < .0001)]. The CKD-EPI equations performed better than the EKFC equation in the CRIC, while the opposite was true in the Minnesota and EKFC cohorts., Conclusion: Significant differences in SCr concentrations between the Minnesota and EKFC cohorts versus CRIC were observed in subjects with the same level of mGFR and equal demographic characteristics and can be explained by the difference in SCr calibration., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Background and Objectives: In older adults, data on the age-related course of GFR are scarce, which might lead to misjudgment of the clinical relevance of reduced GFR in old age., Design, Setting, Participants, & Measurements: To describe the course of eGFR in older adults and derive reference values in population-based individuals, we used the longitudinal design of the Berlin Initiative Study (BIS) with a repeated estimation of GFR over a median of 6.1 years of follow-up. In 2069 community-dwelling older individuals (mean inclusion age 80 years, range 70-99), GFR was estimated biennially with the BIS-2 equation, including standardized creatinine and cystatin C levels, sex, and age. We described the crude and adjusted course using a mixed-effects model and analyzed the influence of death on the GFR course applying joint models. GFR slopes were compared using GFR equations on the basis of creatinine and/or cystatin C., Results: We observed a decreasing, thus nonlinear, eGFR decline with increasing age in a population of old adults. The estimated 1-year slope for ages 75 and 90 diminished for men from -1.67 to -0.99 and for women from -1.52 to -0.97. The modeled mean eGFR for men aged ≥79 and women ≥78 was below 60 ml/min per 1.73 m 2 . Multivariable adjustment attenuated slopes only minimally. Taking death into account by applying joint models did not alter the nonlinear eGFR decline. Using eGFR equations on the basis of creatinine only showed linear slope patterns in contrast to nonlinear patterns for equations including cystatin C., Conclusions: The eGFR decline depended on sex and age and changed only marginally after multivariable adjustment but decelerated with increasing age. Equations including cystatin C demonstrated a nonlinear slope challenging the previously assumed linearity of the decline of eGFR in old age., (Copyright © 2022 by the American Society of Nephrology.)

To provide insights into the biology of the attenuated canine distemper virus (CDV) Onderstepoort (OP) strain (large plaque forming variant), design next-generation multivalent vaccines, or further investigate its promising potential as an oncolytic vector, we employed contemporary modifications to establish an efficient OP-CDV-based reverse genetics platform. Successful viral rescue was obtained however only upon recovery of a completely conserved charged residue (V13E) residing at the N-terminal region of the large protein (L). Although L-V13 and L-V13E did not display drastic differences in cellular localization and physical interaction with P, efficient polymerase complex (P+ L) activity was recorded only with L-V13E. Interestingly, grafting mNeonGreen to the viral N protein via a P2A ribosomal skipping sequence (OP neon ) and its derivative V-protein-knockout variant (OP neon -V ko ) exhibited delayed replication kinetics in cultured cells. Collectively, we established an efficient OP-CDV-based reverse genetics system that enables the design of various strategies potentially contributing to veterinary medicine and research., (Copyright © 2022. Published by Elsevier B.V.)