ABSTRACT
Although there is strong evidence that SARS-CoV-2 infection is associated with adverse outcomes in certain ethnic groups, the association of disease severity and risk factors such as comorbidities and biomarkers with racial disparities remains undefined. This retrospective study between March 2020 and February 2021 explores COVID-19 risk factors as predictors for patients' disease progression through country comparison. Disease severity predictors in Germany and Japan were cardiovascular-associated comorbidities, dementia, and age. We adjusted age, sex, body mass index, and history of cardiovascular disease comorbidity in the country cohorts using a propensity score matching (PSM) technique to reduce the influence of differences in sample size and the surprisingly young, lean Japanese cohort. Analysis of the 170 PSM pairs confirmed that 65.29% of German and 85.29% of Japanese patients were in the uncomplicated phase. More German than Japanese patients were admitted in the complicated and critical phase. Ethnic differences were identified in patients without cardiovascular comorbidities. Japanese patients in the uncomplicated phase presented a suppressed inflammatory response and coagulopathy with hypocoagulation. In contrast, German patients exhibited a hyperactive inflammatory response and coagulopathy with hypercoagulation. These differences were less pronounced in patients in the complicated phase or with cardiovascular diseases. Coagulation/fibrinolysis-associated biomarkers rather than inflammatory-related biomarkers predicted disease severity in patients with cardiovascular comorbidities: platelet counts were associated with severe illness in German patients. In contrast, high D-dimer and fibrinogen levels predicted disease severity in Japanese patients. Our comparative study indicates that ethnicity influences COVID-19-associated biomarker expression linked to the inflammatory and coagulation (thrombo-inflammatory) response. Future studies will be necessary to determine whether these differences contributed to the less severe disease progression observed in Japanese COVID-19 patients compared with those in Germany.
ABSTRACT
Using HIV sequence data to characterize clusters of HIV transmission may provide insight into the epidemic. Phylogenetic and network analyses were performed to infer putative relationships between HIV-1 partial pol sequences from 2,774 individuals receiving care in three German regions between 1999-2016. The regions have in common that they host some of the largest annual festivals in Europe (Carnival and Oktoberfest). Putative links with sequences (n = 150,396) from the Los Alamos HIV Sequence database were evaluated. A total of 595/2,774 (21.4%) sequences linked with at least one other sequence, forming 184 transmission clusters. Clustering individuals were significantly more likely to be younger, male, and report sex with men as their main risk factor (p < 0.001 each). Most clusters (77.2%) consisted exclusively of men; 41 (28.9%) of these included men reporting sex with women. Thirty-two clusters (17.4%) contained sequences from more than one region; clustering men were significantly more likely to be in a position bridging regional HIV epidemics than clustering women (p = 0.027). We found 236 clusters linking 547 sequences from our sample with sequences from the Los Alamos database (n = 1407; 31% from other German centres). These results highlight the pitfalls of focusing HIV prevention efforts on specific risk groups or specific locales.
Subject(s)
Epidemics , HIV Infections/epidemiology , HIV Infections/transmission , HIV-1/classification , Homosexuality, Male/statistics & numerical data , Adult , Cluster Analysis , Female , Germany/epidemiology , HIV Infections/virology , HIV-1/genetics , HIV-1/isolation & purification , Heterosexuality/statistics & numerical data , Holidays , Humans , Incidence , Male , Middle Aged , Molecular Epidemiology , Risk Factors , Sex FactorsABSTRACT
PURPOSE: Caspofungin (CAS) is an antifungal agent for intravenous application in adults and children. Our aim was the development and validation of a physiology-based pharmacokinetic (PBPK) model in order to predict the pharmacokinetics in different patient populations, particularly in paediatrics. METHODS: A PBPK model for adults was built and validated with raw data of the two clinical trials CASLAMB and CASMTD. Afterwards, the model was scaled for paediatric patients under the consideration of known biochemical differences between adults and paediatrics. RESULTS: The simulated results of the PBPK model were in good agreement with the observed values of the CASLAMB and CASMTD trial. Patients of the CASLAMB trial received CAS in combination with cyclosporine A (CsA), which leads to an increased AUC0-24h of CAS hypothetically due to an inhibition of the hepatic transport protein OATP1B1 by CsA. However, there was no difference in the transport rate of OATP1B1 between CASLAMB and CASMTD patients in the PBPK model, suggesting that CsA might not influence OATP1B1. Furthermore, the model was able to sufficiently predict the pharmacokinetics of paediatric patients compared to published data. CONCLUSION: The final PBPK model of CAS without individualized parameter is able to predict the pharmacokinetics in different patient populations correctly. Thus, the model provides a basis for investigators to choose doses and sampling times for special populations such as infants and small children.
Subject(s)
Antifungal Agents/pharmacokinetics , Echinocandins/pharmacokinetics , Models, Biological , Adolescent , Adult , Age Factors , Antifungal Agents/administration & dosage , Area Under Curve , Caspofungin , Child , Child, Preschool , Computer Simulation , Cyclosporine/administration & dosage , Drug Administration Schedule , Drug Dosage Calculations , Drug Interactions , Echinocandins/administration & dosage , Female , Humans , Infant , Infant, Newborn , Infusions, Intravenous , Linear Models , Lipopeptides , Liver-Specific Organic Anion Transporter 1 , Male , Metabolic Clearance Rate , Middle Aged , Organic Anion Transporters/antagonists & inhibitors , Organic Anion Transporters/metabolism , Polypharmacy , Prospective Studies , Protein Binding , Reproducibility of Results , Young AdultABSTRACT
Candida spp. are the fourth most common cause of nosocomial bloodstream infections in the United States, as well as the single most important cause of opportunistic fungal infections worldwide. A delayed diagnosis of invasive candidiasis and/or inadequate treatment choice is associated with high mortality rates and prolonged hospital stays. Even though the antifungal armamentarium has been broadened significantly over the last years, the best options for diagnosing and treating invasive candidiasis still remain a matter of discussion. In this article we present and analyze current evidence on the epidemiology, diagnostic methods and treatment options of invasive candidiasis, with a focus on results from randomized clinical trials. Finally, the reader is provided with a brief overview on promising clinical trial designs and antifungals that might shape the treatment of invasive candidiasis in the years to come.
