German Cohort Research Articles

Real-world Effectiveness of Glecaprevir/Pibrentasvir (GLE/PIB) for Chronic Hepatitis C Infection: Evidence From a German Single-center Cohort Study

Background: Glecaprevir/pibrentasvir (GLE/PIB) is the latest approved pan-genotypic direct-acting antiviral agent (DAA) for the treatment of chronic hepatitis C virus (HCV) infection. However, real-world data of GLE/PIB in European patient cohorts are limited. Methods: A single-center cohort of 100 unselected HCV patients seen at the Outpatient Clinic of the University Medical Center Hamburg-Eppendorf from October 2017 until September 2019 was retrospectively analyzed by chart review with a special focus on demographic clinical and virologic aspects as well as treatment compliance outcome. Results: A total of 99 patients with chronic HCV infection (genotype (GT) 1 - 6), who started antiviral treatment with GLE/PIB, were included. Treatment duration lasted from 4 to 16 weeks. The primary endpoint was a sustained virological response at week 12 (SVR12) after the end of treatment (EoT). Only three patients (3/100; 3%) were diagnosed with liver cirrhosis by non-invasive measures. Ten patients (10/100; 10%) were pre-treated with Interferon (IFN) containing regiments. Most patients received 8 weeks of treatment (96/100; 96%). One patient discontinued treatment after four weeks due to poor compliance (1/100; 1%). A high number of patients were lost to follow-up (22/100; 22%). All patients who were regularly seen to follow-up visits (76/100; 76%) achieved SVR12 (76/76; 100%). Virological relapse occurred in none of the patients. Adverse events (AEs) were rarely reported (4 patients) (4/100; 4%), and none of these patients discontinued treatment. Conclusions: This study demonstrated that initial and re-treatment with GLE/PIB were effective and safe in a German cohort with chronic HCV infection in real-life settings, regardless of GT.

Effectiveness and Distribution of Testosterone Levels within First Year of Androgen Deprivation Therapy in a Real-World Setting: Results from the Non-Interventional German Cohort LEAN Study

Background: Observational studies generate information on real-world therapy and complement data from prospective randomized trials. LEAN is an open-label, non-interventional, multi-centre, German cohort study on leuprorelin in routine clinical practice. Objectives: To extend knowledge on the use, effectiveness, and tolerability of HEXAL/Sandoz leuprorelin (in this article, the term Leuprone® HEXAL® covers Leuprorelin Sandoz® as well) solid implant in patients with prostate cancer (PCa) in a real-world setting. Methods: 959 PCa patients scheduled for androgen deprivation therapy (ADT) received leuprorelin acetate implant. Metabolism, serum prostate-specific antigen (PSA), and testosterone data, if available, were collected at baseline and follow-up visits for ≥12 months. Results: Of 694 patients in the modified full analysis set, 26.4% received GnRH analogues ≤6 months before enrolment. Fifty-one percent of patients were treated for locally advanced or metastatic PCa. In 19.6% of patients, ADT was used in neoadjuvant or adjuvant settings and in 28.5% with rising PSA after definite therapy. Testosterone levels <0.5 ng/mL were achieved in >90% of patients. Safety profile was in line with the summary of product characteristics. Therapy was well tolerated, with patient-triggered therapy discontinuation in 3.6%. Conclusions: This interim analysis confirmed previous efficacy findings for leuprorelin implant in a real-world setting. This contemporary cohort showed a shift in the use of ADT to non-metastatic PCa stages.

A Novel SNCA A30G Mutation Causes Familial Parkinsonʼs Disease

The SNCA gene encoding α-synuclein (αSyn) is the first gene identified to cause autosomal-dominant Parkinson's disease (PD). We report the identification of a novel heterozygous A30G mutation of the SNCA gene in familial PD and describe clinical features of affected patients, genetic findings, and functional consequences. Whole exome sequencing was performed in the discovery family proband. Restriction digestion with Bbvl was used to screen SNCA A30G in two validation cohorts. The Greek cohort included 177 familial PD probands, 109 sporadic PD cases, and 377 neurologically healthy controls. The German cohort included 136 familial PD probands, 380 sporadic PD cases, and 116 neurologically healthy controls. We also conducted haplotype analysis using 13 common single nucleotide variants around A30G to determine the possibility of a founder effect for A30G. We then used biophysical methods to characterize A30G αSyn. We identified a novel SNCA A30G (GRCh37, Chr4:90756730, c.89 C>G) mutation that co-segregated with the disease in five affected individuals of three Greek families and was absent from controls. A founder effect was strongly suggested by haplotype analysis. The A30G mutation had a local effect on the intrinsically disordered structure of αSyn, slightly perturbed membrane binding, and promoted fibril formation. Based on the identification of A30G co-segregating with the disease in three families, the absence of the mutation in controls and population databases, and the observed functional effects, we propose SNCA A30G as a novel causative mutation for familial PD. © 2021 International Parkinson and Movement Disorder Society.

Epidemiology and One-Year Follow-Up of Neonates with CDH-Data from Health Insurance Claims in Germany.

Congenital diaphragmatic hernia (CDH) is a major congenital malformation with high mortality. Outcome data on larger unselected patient groups in Germany are unavailable as there is no registry for CDH. Therefore, routine data from the largest German health insurance fund were analyzed for the years 2009–2013. Main outcome measures were incidence, survival and length of hospital stay. Follow-up was 12 months. 285 patients were included. The incidence of CDH was 2.73 per 10,000 live births. Overall mortality was 30.2%. A total of 72.1% of the fatalities occurred before surgery. Highest mortality (64%) was noted in patients who were admitted to specialized care later as the first day of life. Patients receiving surgical repair had a better prognosis (mortality: 10.8%). A total of 67 patients (23.5%) were treated with ECMO with a mortality of 41.8%. The median cumulative hospital stay among one-year survivors was 40 days and differed between ECMO- and non-ECMO-treated patients (91 vs. 32.5 days, p < 0.001). This is the largest German cohort study of CDH patients with a one-year follow-up. The ECMO subgroup showed a higher mortality. Another important finding is that delayed treatment in specialized care increases mortality. Prospective clinical registries are needed to elucidate the treatment outcomes in detail.

Serum Selenium Levels in Glaucoma: a Pilot Study.

Trace elements are assumed to be involved in glaucoma pathogenesis via changes in oxidative stress. Especially serum selenium (Se) has been linked to this neurodegenerative disease. Serum Se levels differ between countries due to nutrition and ethnicity. It was the aim of the present study to investigate serum Se levels in primary open-angle glaucoma (POAG) patients and controls in Germany and to consider potential age and gender effects. The Se concentration of 39 serum samples (22 patients with POAG, 17 controls) were analyzed by inductively coupled plasma-sector field mass spectrometry (ICP-sf-MS) in high resolution mode. Covariance and percentile regression were analyzed. Age and gender were defined as confounding factors and their different trends were investigated. Moreover, age was examined across different quantiles of Se levels. Total serum least-squares means (LS-means) Se levels were 132.02 µg/L (controls) and 134.86 µg/L (POAG). Total serum Se levels did not differ between the study groups (p > 0.05). Significant age and gender effects of serum Se were observed. Quantile analysis showed that the 1st serum Se quantile decreased with increasing age in POAG patients in contrast to controls. The odds ratios of the 1st serum Se were 1.3 (with 2nd quantile) and 1.3 (with 3rd quantile), respectively. The serum Se level of the German cohort was almost half of those of the published US cohort (glaucoma 209.11 ng/mL; control 194.45 ng/mL). Age and gender effects were observed; the serum Se level increased with age in women (controls and POAG), however, Se levels decreased with age in men (controls and POAG).

Grief and loss in old age: Exploration of the association between grief and depression.

BackgroundThe proportion of older adults is increasing due to demographic changes. Depression belongs to the most common mental disorders in late life. The loss of an emotionally significant person is a risk factor for the development of depression. The aim of this study is to analyze the association between depression and grief burden resulting from loss. Based on prior evidence, we examined loneliness as a possible mediator and social support as possible moderator of this association. MethodsThe cross-sectional analyses are based on a sample (N = 863) of study participants aged 75+ (M = 81.4 years, SD = 4.4, 62.2% female) with loss experience deriving from the multicenter prospective German cohort study AgeMooDe. Regression analyses (moderated mediation) were performed. ResultsWith increasing age (β = 0.10, p = .005) and grief burden (β = 0.33, p <. 001) depression severity increased. There was an indirect mediating effect of loneliness on the correlation of grief burden and depression (b = 0.04, CI [0.03, 0.05]), but no moderating effect of social support on the correlation of grief burden and loneliness. People living alone had a significantly higher risk of depression, increased loneliness and lack of social support. LimitationsAssessments were based on self-reporting and recorded dimensionally. The cross-sectional design limits conclusions about directions and causality of associations. Sampling bias cannot be completely excluded. ConclusionThe study provides empirical evidence and a better understanding of the association between grief and depression among the very old and the mediating role of loneliness.

Everything counts - a method to determine viral suppression among people living with HIV using longitudinal data for the HIV care continuum - results of two large, German, multi-center real-life cohort studies over 20\u2009years (1999\u20132018)

BackgroundThe aim of this study was to develop a standardized method to reconstruct persons’ individual viral load (VL) courses to determine viral suppression and duration of viremia for the HIV care continuum in Germany using longitudinal cohort data.MethodsWe analyzed data from two large, multi-center German cohort studies under the direction of the Robert Koch Institute. We included data from 1999 to 2018 of all diagnosed people and of people who initiated antiretroviral treatment (ART). We developed a model generating virtual VL values and an individual VL course corresponding to real VL measurements with a maximum distance of 180 days, considering ART status and VL dynamics. If the distance between VL measurements was > 180 days, the time between was defined as gap time. Additionally, we considered blips, which we defined as a single detectable VL < 1000 copies/ml within 180 days.ResultsA total of 22,120 people (164,691 person-years, PY) after ART initiation were included in the analyses. The proportion of people with viral suppression (VL < 50 copies/ml) increased from 34% in 1999 to 93% in 2018. The proportion of people with VL < 200 copies/ml increased from 47% in 1999 to 96% in 2018. The proportion of people with viremia > 1000 copies/ml decreased from 37% in 1999 to 3% in 2018. The proportion of people with gap time fluctuated and ranged between 18 and 28%. An analysis of the first VL after gap time showed that 90% showed viral suppression, 5% VL between 50- < 1000 copies/ml and 5% VL > 1000 copies/ml.ConclusionWe provide a method for estimating viral suppression and duration of viremia using longitudinal VL data. We observed a continuous and remarkable increase of viral suppression. Furthermore, a notable proportion of those with viremia showed low-level viremia and were therefore unlikely to transmit HIV. Individual health risks and HIV drug resistance among those with low-level viremia are problematic, and viral suppression remains the goal. In 2018, 93 and 96% of people after ART initiation showed VL < 50 copies/ml and VL < 200 copies/ml, respectively. Therefore, using the threshold of VL < 200 copies/ml, Germany reached the UNAIDS 95 target of viral suppression since 2017.

Adherence to Antithrombotic Treatment and Ischemic Stroke Recurrence in Egypt and Germany: A Comparative Analysis

Background: The burden of stroke weighs heavily in developing countries where recurrence rates clearly exceed that of developed countries. The impact of nonadherence to antithrombotic treatment within this context has been poorly investigated. Objective: The objective of this study was to evaluate patients with recurrent ischemic stroke in Egypt and Germany with focus on stroke subtype distribution and adherence to antithrombotic therapy. Methods: We conducted a comparative cross-sectional retrospective cohort study enrolling consecutive patients hospitalized for recurrent ischemic stroke in 2017 in 2 academic centers. Data were collected on demographics, risk factors, stroke subtypes, and medication adherence. Nonadherence to antithrombotic agents was analyzed at the time point of index stroke (recurrent stroke). Predictors of nonadherence were analyzed using logistic regression. Results: A total of 373 Egyptian and 468 German patients with ischemic stroke were included. The proportion of recurrent ischemic stroke among all patients was higher in the Egyptian cohort compared to the German cohort (33 vs. 10%, p < 0.05). Small-vessel occlusion stroke was the most frequent subtype in Egyptians, with a significantly greater proportion than in Germans (45 vs. 26%, p < 0.05). Nonadherence to antiplatelets at the time point of the recurrent stroke was higher in Egyptians than in Germans (82 vs. 19%, p < 0.001). Low educational attainment among Egyptians (OR 0.14, 95% CI [0.00–0.19], p < 0.01) and high comorbidity scores among Germans (OR 2.45, 95% CI [1.06–5.66], p < 0.05) were found to be predictors of nonadherence to antithrombotic treatment. Conclusions: The large stroke recurrence burden in Egypt may be partly explained by differing adherence to secondary preventative antithrombotic pharmacotherapy. Predictors of medication nonadherence have to be addressed to reduce stroke recurrence disparities.

A Pre-registered Meta-analysis Based on Three Empirical Studies Reveals No Association Between Prenatal (Amniotic) Cortisol Exposure and Fluctuating Asymmetry in Human Infants

Developmental instability (DI) reflects an organism’s inability to develop an ideal phenotype when challenged by genetic and environmental insults. DI can be estimated via the proxy measure of fluctuating asymmetry (FA), i.e., the small random deviations from perfect bilateral symmetry observed in the morphology of paired traits. The mechanisms involved in the genesis of FA in human populations are relatively unknown, though animal research indicates that hormonal processes may be involved. As maternal stress during pregnancy is detrimental to various developmental processes, elevated prenatal cortisol may represent a causal factor in the subsequent emergence of an asymmetrical phenotype. The main purpose of this pre-registered meta-analysis based on three empirical studies was to investigate whether mid-trimester amniotic cortisol levels predict subsequent FA in finger lengths of infants from Germany, Portugal, and the UK. No statistically significant relationships were observed, and meta-analytic combination of the effect size estimates yielded a null result. We did, however, detect significant positive correlations between the cortisol present in the amniotic fluid and maternal plasma in the Portuguese cohort, and observed that FA in the German cohort was significantly lower at 70-months than at either 9- or 20-months. Taken together, the current findings run contrary to animal research showing that elevated prenatal corticosterone exposure leads to increased FA. However, this may be because a single cortisol assay obtained via amniocentesis is an inadequate proxy for average gestational exposure, and/or that prenatal cortisol levels at an earlier (i.e., first rather than second trimester) stage of pregnancy is what explains variance in subsequent FA.

Genetic variability of immune‐related lncRNAs: polymorphisms in LINC‐PINT and LY86‐AS1 are associated with pemphigus foliaceus susceptibility

Pemphigus foliaceus (PF) is an autoimmune blistering disease of the skin, clinically characterized by erosions and, histopathologically, by acantholysis. PF is endemic in the Brazilian Central-Western region. Numerous single nucleotide polymorphisms (SNPs) have been shown to affect the susceptibility for PF, including SNPs at long non-coding RNA (lncRNA) genes, which are known to participate in many physiological and pathogenic processes, such as autoimmunity. Here, we investigated whether the genetic variation of immune-related lncRNA genes affects the risk for endemic and sporadic forms of PF. We analysed 692 novel SNPs for PF from 135 immune-related lncRNA genes in 227 endemic PF patients and 194 controls. The SNPs were genotyped by Illumina microarray and analysed by applying logistic regression at additive model, with correction for sex and population structure. Six associated SNPs were also evaluated in an independent German cohort of 76 sporadic PF patients and 150 controls. Further, we measured the expression levels of two associated lncRNA genes (LINC-PINT and LY86-AS1) by quantitative PCR, stratified by genotypes, in peripheral blood mononuclear cells of healthy subjects. We found 27 SNPs in 11 lncRNA genes associated with endemic PF (p<.05 without overlapping with protein-coding genes). Among them, the LINC-PINT SNP rs10228040*A (OR=1.47, p=.012) was also associated with increased susceptibility for sporadic PF (OR=2.28, p=.002). Moreover, the A+ carriers of LY86-AS1*rs12192707 mark lowest LY86-AS1 RNA levels, which might be associated with a decreasing autoimmune response. Our results suggest a critical role of lncRNA variants in immunopathogenesis of both PF endemic and sporadic forms.

Gambling disorder in the context of outpatient counselling and treatment: Background and design of a prospective German cohort study.

ObjectiveThe prospective naturalistic study ‘Katamnese‐Studie’ conducted between 2014 and 2019 gathers evidence on the course of gambling disorder in German routine outpatient addiction care. This study elucidates design and methodological advantages and caveats of the study.MethodsParticipants of the multi‐centre cohort received written questionnaires at admission and at 6‐, 12‐, 24‐ and 36‐month follow‐up to assess socio‐demographic data, gambling behaviour, gambling‐related consequences and care offers sought. Subsequently, self‐reports were linked to client‐individual routine documentation for the German Addiction Care Statistical Service. Furthermore, employees of participating outpatient addiction care facilities were surveyed regarding experiences with and attitudes towards gambling disorder. Multivariate longitudinal regression models will portray changes in the severity of gambling disorder and gambling behaviour and explore associated client‐ and care‐related factors.ConclusionThe ‘Katamnese‐Studie’ covers the whole spectrum of outpatient gambling care. Keeping the design‐related caveats in mind (reliability of self‐reports, loss‐to‐follow‐up and issues regarding causal inference), the study is anticipated to draw a comprehensive picture of routine outpatient gambling care and key factors related to sustained remission. In the medium term, this information might support the development and subpopulation‐specific adaptation of recommendations on how to structure process and content of outpatient gambling care.

Stage and Grade Migration in Prostate Cancer Treated With Radical Prostatectomy in a Large German Multicenter Cohort.

Overdiagnosis and overtherapy in prostate cancer (PCa) treatment should be avoided, which has led to an awareness of the need to decrease treatment in cases of low-risk PCa with radical prostatectomy (RP). Simultaneously, prostate-specific antigen testing has become less popular in the last few years, which has resulted in higher cancer grade and stage at diagnosis. We evaluated stage and grade migration in the disease of patients treated with RP in a large German cohort. Overall, 4842 patients undergoing RP between 2000 and 2019 were included. Age, prostate-specific antigen level, biopsy, and pathologic Gleason score as well as clinical and pathologic stage were collected. D'Amico risk groups and Gleason score were evaluated over different time points. We detected a significant grade migration toward higher grade. The proportion of biopsy Gleason sum≤ 6 dropped from 45.8% to 20.6% between≤ 2010 and 2017-2019. Further, the proportion of patients with low D'Amico risk scores also decreased by almost 50% (20.8% vs 12.2%). Finally, the proportion of non-organ-confined PCa increased over time, and the proportion of postoperative Gleason sum≤ 6 decreased from 20% to 10% over time. Taken together, data indicate a significant preoperative grade and stage migration toward disease of higher grade in RP-treated PCa. Between the years 2000 and 2019, the proportion of biopsy Gleason sum≤ 6 and the proportions of D'Amico low risk disease decreased by approximately 50% (respectively, 45% to 20% and 20.8% to 12.2%). This might indicate better patient selection for RP, but might also be a telltale sign of the rising mortality and morbidity of PCa.

Modern NCDR and ACTION risk models outperform the GRACE model for prediction of in-hospital mortality in acute coronary syndrome in a German cohort

Background and purposeRisk prediction with the Global Registry of Acute Coronary Events (GRACE) risk model is guideline-recommended in acute coronary syndrome (ACS) patients. However, the performance of more contemporary scores derived from ACTION (Acute Coronary Treatment and Intervention Outcomes Network) and National Cardiovascular Data (NCDR) registries remains incompletely understood. We aimed to compare these models in German ACS patients. Methods and resultsA total of 1567 patients with (Non-)ST-segment elevation myocardial infarction (NSTEMI: 1002 patients, STEMI: 565 patients) undergoing invasive management at University Hospital Düsseldorf (Germany) from 2014 to 2018 were included. Overall in-hospital mortality was 7.5% (NSTEMI 3.7%, STEMI 14.5%). Parameters for calculation of GRACE 1.0, GRACE 2.0, ACTION and NCDR risk models and in-hospital mortality were assessed and risk model performance was compared. The GRACE 1.0 risk model for prediction of in-hospital mortality discriminated risk superior (c-index 0.84) to its successor GRACE 2.0 (c-index 0.79, pGRACE1.0vsGRACE2.0 = 0.0008). The NCDR model performed best in discrimination of risk in ACS overall (c-index 0.89; pACTIONvsNCDR < 0.0001; pGRACEvsNCDR < 0.0001) and showed superior performance compared to GRACE in NSTEMI and STEMI subgroups (pGRACEvsNCDR both < 0.02). ACTION and GRACE risk models performed comparable to each other (both c-index 0.84, pGRACEvsACTION = 0.68), with advantages for ACTION in NSTEMI patients (c-index 0.87 vs. 0.84 (GRACE); pGRACEvsACTION = 0.02). ACTION and GRACE 2.0 showed the most accurate calibration of all models. ConclusionsIn a contemporary German patient population with ACS, modern NCDR and ACTION risk models showed superior performance in prediction of in-hospital mortality compared to the gold-standard GRACE model.

Humoral immune response and lymphocyte levels after complete vaccination against COVID-19 in a cohort of multiple sclerosis patients treated with cladribine tablets.

BackgroundPatients with multiple sclerosis (MS) receiving immunomodulatory drugs were excluded from clinical trials on COVID-19 vaccines. Therefore, data regarding the efficacy of COVID-19 vaccines to induce humoral immunity in MS patients treated with B- and T-cell depleting agents is urgently warranted. Cladribine tablets are a high-efficacy disease-modifying treatment that exerts its therapeutic effect via sustained but transient lymphocyte depletion.AimWe report humoral responses in a German cohort of MS patients treated with cladribine tablets.MethodsThis retrospective analysis included patients ≥18 years who were treated with cladribine tablets for relapsing MS in the first or second year and were fully vaccinated against COVID-19. Two weeks after the second vaccination at the earliest, blood samples were obtained for the assessment of anti-SARS-CoV-2 IgG antibodies, lymphocyte counts, B-cells, CD4+ T-cells, and CD8+ T-cells. Anti-SARS-CoV-2 IgG antibodies were quantified with the LIAISON® SARS-CoV-2 TrimericS IgG assay. Positivity was defined at a cutoff value of 33.8 BAU/mL.ResultsIn total, 38 patients (73.7% female, aged 23–66 years) were included in the analysis. Ten patients (26.3%) were treatment-naïve before initiating treatment with cladribine tablets. Most patients (84.2%) received mRNA vaccines. The time between the last dose of cladribine tablets and vaccination ranged between 2 and 96 weeks. Six patients (15.8%) were vaccinated within 4 weeks of their last cladribine dose. All patients achieved positive anti-SARS-CoV-2 IgG antibody levels. Humoral immune response was independent of age, time of vaccination in relation to the last cladribine dose, lymphocyte counts as well as B- and T-cell counts.ConclusionsTreatment with cladribine tablets did not impair humoral response to COVID-19 vaccination. Time since last cladribine dose, age, prior therapy, lymphocyte count as well as B- and T-cell counts had no effect on seropositivity of anti-SARS-CoV-2 IgG antibodies.

Coronary calcium scoring assessed on native screening chest CT imaging as predictor for outcome in COVID-19: An analysis of a hospitalized German cohort.

Since the outbreak of the COVID-19 pandemic, a number of risk factors for a poor outcome have been identified. Thereby, cardiovascular comorbidity has a major impact on mortality. We investigated whether coronary calcification as a marker for coronary artery disease (CAD) is appropriate for risk prediction in COVID-19. Hospitalized patients with COVID-19 (n = 109) were analyzed regarding clinical outcome after native computed tomography (CT) imaging for COVID-19 screening. CAC (coronary calcium score) and clinical outcome (need for intensive care treatment or death) data were calculated following a standardized protocol. We defined three endpoints: critical COVID-19 and transfer to ICU, fatal COVID-19 and death, composite endpoint critical and fatal COVID-19, a composite of ICU treatment and death. We evaluated the association of clinical outcome with the CAC. Patients were dichotomized by the median of CAC. Hazard ratios and odds ratios were calculated for the events death or ICU or a composite of death and ICU. We observed significantly more events for patients with CAC above the group's median of 31 for critical outcome (HR: 1.97[1.09,3.57], p = 0.026), for fatal outcome (HR: 4.95[1.07,22.9], p = 0.041) and the composite endpoint (HR: 2.31[1.28,4.17], p = 0.0056. Also, odds ratio was significantly increased for critical outcome (OR: 3.01 [1.37, 6.61], p = 0.01) and for fatal outcome (OR: 5.3 [1.09, 25.8], p = 0.02). The results indicate a significant association between CAC and clinical outcome in COVID-19. Our data therefore suggest that CAC might be useful in risk prediction in patients with COVID-19.

Conversations and Reactions Around Severe Hypoglycaemia (CRASH): Results from the German Cohort of a Global Survey of People with Type 1 Diabetes or Insulin-Treated Type 2 Diabetes and Caregivers.

A global cross-sectional survey (CRASH) was designed to provide information about the experiences of people with diabetes (PWD) and their caregivers in relation to severe hypoglycaemic events. Adults with type 1 diabetes or insulin-treated type 2 diabetes who had experienced one or more severe hypoglycaemic events within the past 3 years, and adult caregivers for such people, were recruited from medical research panels using purposive sampling. We present here results from Germany. Approximately 100 individuals in each of the four participant groups completed a 30-minute online survey. Survey results indicated that the most recent severe hypoglycaemic event made many participants feel scared (80.4%), unprepared (70.4%), and/or helpless (66.5%). Severe hypoglycaemia was discussed by healthcare professionals at every visit with only 20.2% of participants who had ever had this conversation, and 53.5% of participants indicated that their insulin regimen had not changed following their most recent event. 37.1% of PWD/people with diabetes cared for by caregivers owned a glucagon kit at the time of survey completion. The survey identified areas for improvement in the prevention and management of severe hypoglycaemic events. For healthcare professionals, these include enquiring more frequently about severe hypoglycaemia and adjusting blood glucose-lowering medication after a severe hypoglycaemic event. For individuals with diabetes and their caregivers, potential improvements include ensuring availability of glucagon at all times. Changes in these areas could lead not only to improved patient wellbeing but also to reduced use of emergency services/hospitalisation and, consequently, lower healthcare costs.

Multicenter Validation of the max-ICH Score in Intracerebral Hemorrhage.

Outcome prognostication unbiased by early care limitations (ECL) is essential for guiding treatment in patients presenting with intracerebral hemorrhage (ICH). The aim of this study was to determine whether the max-ICH (maximally treated ICH) Score provides improved and clinically useful prognostic estimation of functional long-term outcomes after ICH. This multicenter validation study compared the prognostication of the max-ICH Score versus the ICH Score regarding diagnostic accuracy (discrimination and calibration) and clinical utility using decision curve analysis. We performed a joint investigation of individual participant data of consecutive spontaneous ICH patients (n = 4,677) from 2 retrospective German-wide studies (RETRACE I + II; anticoagulation-associated ICH only) conducted at 22 participating centers, one German prospective single-center study (UKER-ICH; nonanticoagulation-associated ICH only), and 1 US-based prospective longitudinal single-center study (MGH; both anticoagulation- and nonanticoagulation-associated ICH), treated between January 2006 and December 2015. Of 4,677 included ICH patients, 1,017 (21.7%) were affected by ECL (German cohort: 15.6% [440 of 2,377]; MGH: 31.0% [577 of 1,283]). Validation of long-term functional outcome prognostication by the max-ICH Score provided good and superior discrimination in patients without ECL compared with the ICH Score (area under the receiver operating curve [AUROC], German cohort: 0.81 [0.78-0.83] vs 0.74 [0.72-0.77], p < 0.01; MGH: 0.85 [0.81-0.89] vs 0.78 [0.74-0.82], p < 0.01), and for the entire cohort (AUROC, German cohort: 0.84 [0.82-0.86] vs 0.80 [0.77-0.82], p < 0.01; MGH: 0.83 [0.81-0.85] vs 0.77 [0.75-0.79], p < 0.01). Both scores showed no evidence of poor calibration. The clinical utility investigated by decision curve analysis showed, at high threshold probabilities (0.8, aiming to avoid false-positive poor outcome attribution), that the max-ICH Score provided a clinical net benefit compared with the ICH Score (14.1 vs 2.1 net predicted poor outcomes per 100 patients). The max-ICH Score provides valid and improved prognostication of functional outcome after ICH. The associated clinical net benefit in minimizing false poor outcome attribution might potentially prevent unwarranted care limitations in patients with ICH. ANN NEUROL 2021;89:474-484.

CT Features of COVID-19 Pneumonia Differ Depending on the Severity and Duration of Disease.

CT is important in the care of patients with COVID-19 pneumonia. However, CT morphology can change significantly over the course of the disease. To evaluate the CT morphology of RT-PCR-proven COVID-19 pneumonia in a German cohort with special emphasis on identification of potential differences of CT features depending on duration and severity of disease. All patients with RT-PCR-proven COVID-19 pneumonia and chest CT performed between March 1 and April 15, 2020 were retrospectively identified. The CT scans were evaluated regarding the presence of different CT features (e. g. ground glass opacity, consolidation, crazy paving, vessel enlargement, shape, and margin of opacifications), distribution of lesions in the lung and extent of parenchymal involvement. For subgroup analyses the patients were divided according to the percentage of parenchymal opacification (0-33 %, 34-66 %, 67-100 %) and according to time interval between symptom onset and CT date (0-5 d, 6-10 d, 11-15 d, > 15 d). Differences in CT features and distribution between subgroups were tested using the Mantel-Haenszel Chi Squared for trend. The frequency of CT features (ground glass opacity, consolidation, crazy paving, bronchial dilatation, vessel enlargement, lymphadenopathy, pleural effusion) as well as pattern of parenchymal involvement differed significantly depending on the duration of disease and extent of parenchymal involvement. The early phase of disease was characterized by GGO and to a lesser extent consolidation. The opacifications tended to be round and to some extent with sharp margins and a geographic configuration. The vessels within/around the opacifications were frequently dilated. Later on, the frequency of consolidation and especially crazy paving increased, and the round/geographic shape faded. After day 15, bronchial dilatation occurred, and lymphadenopathy and pleural effusion were seen more frequently than before. The prevalence of CT features varied considerably during the course of disease and depending on the severity of parenchymal involvement. Radiologists should take into account the time interval between symptom onset and date of CT and the severity of disease when discussing the likelihood of COVID-19 pneumonia based on CT morphology. · The frequency of CT features and pattern of parenchymal involvement vary depending on the duration and extent of COVID-19 pneumonia.. · The early phase is characterized by GGO and consolidation which demonstrate a round shape and at least to some extent have sharp margins and a geographic configuration.. · The frequency of consolidation and especially crazy paving increases during the course of disease.. · Beyond day 15 after symptom onset, bronchial dilatation occurs.. · Radiologists should take into account the duration and severity of disease when considering COVID-19 pneumonia.. · Schaible J, Meiler S, Poschenrieder F et al. CT Features of COVID-19 Pneumonia Differ Depending on the Severity and Duration of Disease. Fortschr Röntgenstr 2021; 193: 672 - 682.

Genetic Variants in the Regulatory T cell-Related Pathway and Colorectal Cancer Prognosis.

High numbers of lymphocytes in tumor tissue, including T regulatory cells (Treg), have been associated with better colorectal cancer survival. Tregs, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and therefore variants in genes related to Treg differentiation and function could be associated with colorectal cancer prognosis. In a prospective German cohort of 3,593 colorectal cancer patients, we assessed the association of 771 single-nucleotide polymorphisms (SNP) in 58 Treg-related genes with overall and colorectal cancer-specific survival using Cox regression models. Effect modification by microsatellite instability (MSI) status was also investigated because tumors with MSI show greater lymphocytic infiltration and have been associated with better prognosis. Replication of significant results was attempted in 2,047 colorectal cancer patients of the International Survival Analysis in Colorectal Cancer Consortium (ISACC). A significant association of the TGFBR3 SNP rs7524066 with more favorable colorectal cancer-specific survival [hazard ratio (HR) per minor allele: 0.83; 95% confidence interval (CI), 0.74-0.94; P value: 0.0033] was replicated in ISACC (HR: 0.82; 95% CI, 0.68-0.98; P value: 0.03). Suggestive evidence for association was found with two IL7 SNPs, rs16906568 and rs7845577. Thirteen SNPs with differential associations with overall survival according to MSI in the discovery analysis were not confirmed. Common genetic variation in the Treg pathway implicating genes such as TGFBR3 and IL7 was shown to be associated with prognosis of colorectal cancer patients. The implicated genes warrant further investigation.

Antimicrobial Susceptibility and Phylogenetic Relations in a German Cohort Infected with Mycobacterium abscessus

Mycobacterium abscessus is a highly antibiotic-resistant opportunistic pathogen causing clinically challenging infections in patients with preexisting lung diseases or under immunosuppression. Hence, reliable antibiotic susceptibility data are required for effective treatment. Aims of this study were to investigate (i) the congruence of genotypic and phenotypic antimicrobial susceptibility testing, (ii) the relationship between resistance profile and clinical course, and (iii) the phylogenetic relations of M. abscessus in a German patient cohort. A total of 39 isolates from 29 patients infected or colonized with M. abscessus underwent genotypic and phenotypic drug susceptibility testing. Clinical data were correlated with susceptibility data. Phylogenetic analysis was performed by means of whole-genome sequencing (WGS) and single-nucleotide polymorphism (SNP) analysis. Macrolide resistance was mainly mediated by functional Erm(41) methyltransferases (T28 sequevars) in M. abscessus subsp. abscessus (n = 25) and M. abscessus subsp. bolletii (n = 2). It was significantly associated with impaired culture conversion (P = 0.02). According to the core SNP phylogeny, we identified three clusters of closely related isolates with SNP distances below 25. Representatives of all circulating global clones (Absc. 1, Absc. 2, and Mass. 1) were identified in our cohort. However, we could not determine evidence for in-hospital interhuman transmission from clinical data. In our patient cohort, we identified three M. abscessus clusters with closely related isolates and representatives of the previously described international clusters but no human-to-human in-hospital transmission. Macrolide and aminoglycoside susceptibility data are critical for therapeutic decision-making in M. abscessus infections.