Mitochondrial DNA copy number (mtDNA-CN) is a biomarker for mitochondrial dysfunction associated with several diseases. Previous genome-wide association studies (GWAS) have been performed to unravel ...underlying mechanisms of mtDNA-CN regulation. However, the identified gene regions explain only a small fraction of mtDNA-CN variability. Most of this data has been estimated from microarrays based on various pipelines. In the present study we aimed to (1) identify genetic loci for qPCR-measured mtDNA-CN from three studies (16,130 participants) using GWAS, (2) identify potential systematic differences between our qPCR derived mtDNA-CN measurements compared to the published microarray intensity-based estimates, and (3) disentangle the nuclear from mitochondrial regulation of the mtDNA-CN phenotype. We identified two genome-wide significant autosomal loci associated with qPCR-measured mtDNA-CN: at HBS1L (rs4895440, p = 3.39 × 10
) and GSDMA (rs56030650, p = 4.85 × 10
) genes. Moreover, 113/115 of the previously published SNPs identified by microarray-based analyses were significantly equivalent with our findings. In our study, the mitochondrial genome itself contributed only marginally to mtDNA-CN regulation as we only detected a single rare mitochondrial variant associated with mtDNA-CN. Furthermore, we incorporated mitochondrial haplogroups into our analyses to explore their potential impact on mtDNA-CN. However, our findings indicate that they do not exert any significant influence on our results.
PurposeThe purpose of this study was to evaluate the utility of combining the Clinical Classification (CC) and the Three Continent age-related macular degeneration (AMD) Consortium Severity Scale ...(3CACSS) for classification of AMD. MethodsIn two independent cross-sectional datasets of our population-based AugUR study (Altersbezogene Untersuchungen zur Gesundheit der Universität Regensburg), we graded AMD via color fundus images applying two established classification systems (CC and 3CACSS). We calculated the genetic risk score (GRS) across 50 previously identified variants for late AMD, its association via logistic regression, and area under the curve (AUC) for each AMD stage. ResultsWe analyzed 2188 persons aged 70 to 95 years. When comparing the two classification systems, we found a distinct pattern: CC "age-related changes" and CC "early AMD" distinguished individuals with 3CACSS "no AMD"; 3CACSS "mild/moderate/severe early AMD" stages, and distinguished CC "intermediate AMD". This suggested a 7-step scale combining the 2 systems: (i) "no AMD", (ii) "age-related changes", (iii) "very early AMD", (i.e. CC "early"), (iv) "mild early AMD", (v) "moderate early AMD", (vi) "severe early AMD", and (vii) "late AMD". GRS association and diagnostic accuracy increased stepwise by increased AMD severity in the 7-step scale and by increased restriction of controls (e.g. for CC "no AMD without age-related changes": AUC = 55.1%, 95% confidence interval CI = 51.6, 58.6, AUC = 62.3%, 95% CI = 59.1, 65.6, AUC = 63.8%, 95% CI = 59.3, 68.3, AUC = 78.1%, 95% CI = 73.6, 82.5, AUC = 82.2%, 95% CI = 78.4, 86.0, and AUC = 79.2%, 95% CI = 75.4, 83.0). A stepwise increase was also observed by increased drusen size and area. ConclusionsThe utility of a 7-step scale is supported by our clinical and GRS data. This harmonization and full data integration provides an immediate simplification over using either CC or 3CACSS and helps to sharpen the control group.
The purpose of this study was to assess recovery time following photostress and its association with age-related macular degeneration (AMD) cross-sectionally and longitudinally in an elderly ...population-based cohort.
We analyzed photostress recovery time (PRT) and AMD in >1800 AugUR study participants aged 70+ years. On color fundus images from baseline and 3-year follow-up, presence of AMD was graded manually (Three Continent AMD Consortium Severity Scale). Visual acuity (VA) was assessed via Early Treatment Diabetic Retinopathy Study (ETDRS) charts. After a 30-second bleaching of the macular region via direct ophthalmoscope, PRT was measured as the seconds to regain VA.
First, we analyzed 1208 AugUR participants cross-sectionally (288 with early AMD, and 78 with late AMD). Prolonged PRT was associated with early and late AMD versus no AMD (median PRT = 119.5, 198.0 versus 80.0 seconds, respectively; logistic regression odds ratio OR = 1.109-1.165 per 10 seconds, P values < 0.0001). Sensitivity analyses using alternative models or restricting to participants after cataract surgery revealed similar ORs. Second, the association was confirmed in an independent cross-sectional AugUR sample (n = 486). Third, in longitudinal analysis of 233 AugUR participants without AMD, prolonged PRT was associated with incident AMD ascertained 3 years later (follow-up time = 3.2 ± 0.2 years, OR = 1.112-1.162 per 10 seconds, P < 0.05). Overall, we demonstrate a significant association of prolonged PRT with AMD cross-sectionally and longitudinally in elderly individuals.
Prolonged PRT might capture retinal function impairment after cell damage before early AMD is visible via color fundus imaging.
Our results suggest PRT as quantitative predictive biomarker for incident AMD, making it potentially worthwhile also for clinical care.
Polygenic scores (PGSs) combining genetic variants found to be associated with creatinine-based estimated glomerular filtration rate (eGFR
) have been applied in various study populations with ...different age ranges. This has shown that PGS explain less eGFR
variance in the elderly. Our aim was to understand how differences in eGFR variance and the percentage explained by PGS varies between population of general adults and elderly.
We derived a PGS for cystatin-based eGFR (eGFR
) from published genome-wide association studies. We used the 634 variants known for eGFR
and the 204 variants identified for eGFR
to calculate the PGS in two comparable studies capturing a general adult and an elderly population, KORA S4 (n = 2,900; age 24-69 years) and AugUR (n = 2,272, age ≥ 70 years). To identify potential factors determining age-dependent differences on the PGS-explained variance, we evaluated the PGS variance, the eGFR variance, and the beta estimates of PGS association on eGFR. Specifically, we compared frequencies of eGFR-lowering alleles between general adult and elderly individuals and analyzed the influence of comorbidities and medication intake. The PGS for eGFR
explained almost twice as much (R
= 9.6%) of age-/sex adjusted eGFR variance in the general adults compared to the elderly (4.6%). This difference was less pronounced for the PGS for eGFR
(4.7% or 3.6%, respectively). The beta-estimate of the PGS on eGFR
was higher in the general adults compared to the elderly, but similar for the PGS on eGFR
. The eGFR variance in the elderly was reduced by accounting for comorbidities and medication intake, but this did not explain the difference in R
-values. Allele frequencies between general adult and elderly individuals showed no significant differences except for one variant near APOE (rs429358). We found no enrichment of eGFR-protective alleles in the elderly compared to general adults.
We concluded that the difference in explained variance by PGS was due to the higher age- and sex-adjusted eGFR variance in the elderly and, for eGFR
, also by a lower PGS association beta-estimate. Our results provide little evidence for survival or selection bias.
Cancer-related immunity has been identified as playing a key role in the outcome of colorectal cancer (CRC); however, the exact mechanisms are only partially understood. In this study, we evaluated a ...total of 242 surgical specimen of CRC patients using tissue microarrays and immunohistochemistry to evaluate tumor infiltrating immune cells (CD3, CD4, CD8, CD20, CD23, CD45 and CD56) and immune checkpoint markers (CTLA-4, PD-L1, PD-1) in systematically selected tumor regions and their corresponding lymph nodes, as well as in liver metastases. Additionally, an immune panel gene expression assay was performed on 12 primary tumors and 12 consecutive liver metastases. A higher number of natural killer cells and more mature B cells along with PD-1
expressing cells were observed in the main tumor area as compared to metastases. A higher number of metastatic lymph nodes were associated with significantly lower B cell counts. With more advanced lymph node metastatic status, higher leukocyte-particularly T cell numbers-were observed. Eleven differentially expressed immune-related genes were found between primary tumors and liver metastases. Also, alterations of the innate immune response and the tumor necrosis factor superfamily pathways had been identified.
The burden of bloodstream infections remains high worldwide and cannot be confined to short-term in-hospital mortality. We aimed to develop scores to predict short-term and long-term mortality in ...patients with bloodstream infections.
The Bloodstream Infection due to Multidrug-resistant Organisms: Multicenter Study on Risk Factors and Clinical Outcomes (BLOOMY) study is a prospective, multicentre cohort study at six German tertiary care university hospitals to develop and validate two scores assessing 14-day and 6-month mortality in patients with bloodstream infections. We excluded patients younger than 18 years or who were admitted to an ophthalmology or psychiatry ward. Microbiological, clinical, laboratory, treatment, and survival data were prospectively collected on day 0 and day 3 and then from day 7 onwards, weekly. Participants were followed up for 6 months. All patients in the derivation cohort who were alive on day 3 were included in the analysis. Predictive scores were developed using logistic regression and Cox proportional hazards models with a machine-learning approach. Validation was completed using the C statistic and predictive accuracy was assessed using sensitivity, specificity, and predictive values.
Between Feb 1, 2017, and Jan 31, 2019, 2568 (61·5%) of 4179 eligible patients were recruited into the derivation cohort. The in-hospital mortality rate was 23·75% (95% CI 22·15–25·44; 610 of 2568 patients) and the 6-month mortality rate was 41·55% (39·54–43·59; 949 of 2284). The model predictors for 14-day mortality (C statistic 0·873, 95% CI 0·849–0·896) and 6-month mortality (0·807, 0·784–0·831) included age, body-mass index, platelet and leukocyte counts, C-reactive protein concentrations, malignancy (ie, comorbidity), in-hospital acquisition, and pathogen. Additional predictors were, for 14-day mortality, mental status, hypotension, and the need for mechanical ventilation on day 3 and, for 6-month mortality, focus of infection, in-hospital complications, and glomerular filtration rate at the end of treatment. The scores were validated in a cohort of 1023 patients with bloodstream infections, recruited between Oct 9, 2019, and Dec 31, 2020. The BLOOMY 14-day score showed a sensitivity of 61·32% (95% CI 51·81–70·04), a specificity of 86·36% (83·80–88·58), a positive predictive value (PPV) of 37·57% (30·70–44·99), and a negative predictive value (NPV) of 94·35% (92·42–95·80). The BLOOMY 6-month score showed a sensitivity of 69·93% (61·97–76·84), a specificity of 66·44% (61·86–70·73), a PPV of 40·82% (34·85–47·07), and a NPV of 86·97% (82·91–90·18).
The BLOOMY scores showed good discrimination and predictive values and could support the development of protocols to manage bloodstream infections and also help to estimate the short-term and long-term burdens of bloodstream infections.
DZIF German Center for Infection Research.
For the German translation of the abstract see Supplementary Materials section.
Despite the pandemic status of COVID-19, there is limited information about host risk factors and treatment beyond supportive care. Immunoglobulin G (IgG) could be a potential treatment target. Our ...aim was to determine the incidence of IgG deficiency and associated risk factors in a cohort of 62 critically ill patients with COVID-19 admitted to two German ICUs (72.6% male, median age: 61 yr). Thirteen (21.0%) of the patients displayed IgG deficiency (IgG < 7 g/L) at baseline (predominant for the IgG1, IgG2, and IgG4 subclasses). Patients who were IgG-deficient had worse measures of clinical disease severity than those with normal IgG levels (shorter duration from disease onset to ICU admission, lower ratio of Formula: see text to Formula: see text, higher Sequential Organ Failure Assessment score, and higher levels of ferritin, neutrophil-to-lymphocyte ratio, and serum creatinine). Patients who were IgG-deficient were also more likely to have sustained lower levels of lymphocyte counts and higher levels of ferritin throughout the hospital stay. Furthermore, patients who were IgG-deficient compared with those with normal IgG levels displayed higher rates of acute kidney injury (76.9% vs. 26.5%;
= 0.001) and death (46.2% vs. 14.3%;
= 0.012), longer ICU 28 (6-48) vs. 12 (3-18) days;
= 0.012 and hospital length of stay 30 (22-50) vs. 18 (9-24) days;
= 0.004. Univariable logistic regression showed increasing odds of 90-day overall mortality associated with IgG-deficiency (odds ratio 5.14, 95% confidence interval 1.3-19.9;
= 0.018). IgG deficiency might be common in patients with COVID-19 who are critically ill, and warrants investigation as both a marker of disease severity as well as a potential therapeutic target.
For Clostridioides difficile infections (CDI) in Germany no longitudinal multicentre studies with standardized protocols for diagnosing CDI are available. Recent evaluations of general surveillance ...databases in Germany indicate a downward trend in CDI rates. We aimed to describe the actual burden and trends of CDI in German university hospitals from 2016 to 2020.
Our study is a prospective multicentre study covering six German university hospitals. We report the data in total, stratified by year, by medical specialty as well as by CDI severity. Multivariable regression analyses were performed to assess risk factors for severe CDI.
We registered 3,780 CDI cases among 1,436,352 patients. The median length of stay (LOS) of CDI cases was 20 days (IQR 11-37) compared with a general LOS of 4.2 days. In-hospital all-cause mortality in CDI patients was 11.7% (n=444/3780), while mortality attributed to CDI was 0.4% (n=16/3761). CDI recurrence rate was comparatively low at 7.2%. The incidence density of severe healthcare-associated healthcare onset (HAHO)-CDI showed a significant decrease from 2.25/10,000 patient days (pd) in 2016 to 1.49/10,000 pd in 2020 (trend calculation p = 0.032).
Compared with a European point-prevalence study in 2013/2014, where overall CDI incidence density was 11.2 cases/10,000 pd in Germany (EUCLID), we see in our study halved overall CDI rates of 5.6 cases/10,000 pd in 2020. Our study shows current data on the distribution of CDI cases in German university hospitals and thus provides international comparative data on the key indicators of CDI.
Assessment of vancomycin-resistant Enterococcus faecium (VREfm) prevalence upon hospital admission and analysis of risk factors for colonization.
From 2014 to 2018, patients were recruited within ...72 hours of admission to seven participating German university hospitals, screened for VREfm and questioned for potential risk factors (prior multidrug-resistant organism detection, current/prior antibiotic consumption, prior hospital, rehabilitation or long-term care facility stay, international travel, animal contact and proton pump inhibitor PPI/antacid therapy). Genotype analysis was done using cgMLST typing. Multivariable analysis was performed.
In 5 years, 265 of 17,349 included patients were colonized with VREfm (a prevalence of 1.5%). Risk factors for VREfm colonization were age (adjusted OR aOR, 1.02; 95% CI, 1.01–1.03), previous (aOR, 2.71; 95% CI, 1.87–3.92) or current (aOR, 2.91; 95% CI, 2.60–3.24) antibiotic treatment, prior multidrug-resistant organism detection (aOR, 2.83; 95% CI, 2.21–3.63), prior stay in a long-term care facility (aOR, 2.19; 95% CI, 1.62–2.97), prior stay in a hospital (aOR, 2.91; 95% CI, 2.05–4.13) and prior consumption of PPI/antacids (aOR, 1.29; 95% CI, 1.18–1.41). Overall, the VREfm admission prevalence increased by 33% each year and 2% each year of life. 250 of 265 isolates were genotyped and 141 (53.2%) of the VREfm were the emerging ST117. Multivariable analysis showed that ST117 and non-ST117 VREfm colonized patients differed with respect to admission year and prior multidrug-resistant organism detection.
Age, healthcare contacts and antibiotic and PPI/antacid consumption increase the individual risk of VREfm colonization. The VREfm admission prevalence increase in Germany is mainly driven by the emergence of ST117.
Abstract
Objectives
To analyse the influence of antibiotic consumption on healthcare-associated healthcare onset (HAHO) Clostridioides difficile infection (CDI) in a German university hospital ...setting.
Methods
Monthly ward-level antibiotic consumption measured in DDD/100 patient days (pd) and CDI surveillance data from five university hospitals in the period 2017 through 2019 were analysed. Uni- and multivariable analyses were performed with generalized estimating equation models.
Results
A total of 225 wards with 7347 surveillance months and 4 036 602 pd participated. With 1184 HAHO-CDI cases, there was a median incidence density of 0.17/1000 pd (IQR 0.03–0.43) across all specialties, with substantial differences among specialties. Haematology-oncology wards showed the highest median incidence density (0.67/1000 pd, IQR 0.44–1.01), followed by medical ICUs (0.45/1000 pd, IQR 0.27–0.73) and medical general wards (0.32/1000 pd, IQR 0.18–0.53). Multivariable analysis revealed carbapenem (mostly meropenem) consumption to be the only antibiotic class associated with increased HAHO-CDI incidence density. Each carbapenem DDD/100 pd administered increased the HAHO-CDI incidence density by 1.3% incidence rate ratio (IRR) 1.013; 95% CI 1.006–1.019. Specialty-specific analyses showed this influence only to be valid for haematological-oncological wards. Overall, factors like ward specialty (e.g. haematology-oncology ward IRR 2.961, 95% CI 2.203–3.980) or other CDI cases on ward had a stronger influence on HAHO-CDI incidence density (e.g. community-associated CDI or unknown association case in same month IRR 1.476, 95% CI 1.242–1.755) than antibiotic consumption.
Conclusions
In the German university hospital setting, monthly ward-level carbapenem consumption seems to increase the HAHO-CDI incidence density predominantly on haematological-oncological wards. Furthermore, other patient-specific factors seem to be equally important to control HAHO-CDI.
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