Gender Differences and the Impact of Partnership and Children on Quality of Life During the COVID-19 Pandemic.

Objectives: The COVID-19 pandemic and its protective measures have changed the daily lives of families and may have affected quality of life (QoL). The aim of this study was to analyze gender differences in QoL and to examine individuals living in different partnership and family constellations. Methods: Data from the Gutenberg COVID-19 cohort study (N = 10,250) with two measurement time points during the pandemic (2020 and 2021) were used. QoL was assessed using the EUROHIS-QOL questionnaire. Descriptive analyses and autoregressive regressions were performed. Results: Women reported lower QoL than men, and QoL was significantly lower at the second measurement time point in both men and women. Older age, male gender, no migration background, and higher socioeconomic status, as well as partnership and children (especially in men), were protective factors for QoL. Women living with children under 14 and single mothers reported significantly lower QoL. Conclusion: Partnership and family were protective factors for QoL. However, women with young children and single mothers are vulnerable groups for lower QoL. Support is especially needed for women with young children.

Cardiac Function Modifies the Impact of Heart Base Dose on Survival: A Voxel-Wise Analysis of Patients With Lung Cancer From the PET-Plan Trial.

INTRODUCTION: Heart dose has emerged as an independent predictor of overall survival in patients with NSCLC treated with radiotherapy. Several studies have identified the base of the heart as a region of enhanced dose sensitivity and a potential target for cardiac sparing. We present a dosimetric analysis of overall survival in the multicenter, randomized PET-Plan trial (NCT00697333) and for the first time include left ventricular ejection fraction (EF) at baseline as a metric of cardiac function. METHODS: A total of 205 patients with inoperable stage II or III NSCLC treated with 60 to 72 Gy in 2 Gy fractions were included in this study. A voxel-wise image-based data mining methodology was used to identify anatomical regions where higher dose was significantly associated with worse overall survival. Univariable and multivariable Cox proportional hazards models tested the association of survival with dose to the identified region, established prognostic factors, and baseline cardiac function. RESULTS: A total of 172 patients remained after processing and censoring for follow-up. At 2-years posttreatment, a highly significant region was identified within the base of the heart (p < 0.005), centered on the origin of the left coronary artery and the region of the atrioventricular node. In multivariable analysis, the number of positron emission tomography-positive nodes (p = 0.02, hazard ratio = 1.13, 95% confidence interval: 1.02-1.25) and mean dose to the cardiac subregion (p = 0.02, hazard ratio = 1.11 Gy-1, 95% confidence interval: 1.02-1.21) were significantly associated with overall survival. There was a significant interaction between EF and region dose (p = 0.04) for survival, with contrast plots revealing a larger effect of region dose on survival in patients with lower EF values. CONCLUSIONS: This work validates previous image-based data mining studies by revealing a strong association between dose to the base of the heart and overall survival. For the first time, an interaction between baseline cardiac health and heart base dose was identified, potentially suggesting preexisting cardiac dysfunction exacerbates the impact of heart dose on survival.

Service provision and utilisation in German paediatric primary care practices during public health crises: Protocol of the mixed-methods COVID-19 PedCare Study.

INTRODUCTION: Public health crises such as pandemics can cause serious disruptions to the utilisation and provision of healthcare services with negative effects on morbidity and mortality. Despite the important role of paediatric primary care in maintaining high-quality healthcare services during crises, evidence about service utilisation and provision remains limited especially in Germany. This study, therefore, explores the utilisation and provision of paediatric primary care services during the ongoing COVID-19 pandemic and their barriers and facilitators. METHODS AND ANALYSIS: The study uses a convergent mixed-methods design and comprises online surveys to parents, adolescents and primary care paediatricians (PCPs) and semistructured interviews with parents and PCPs. We recruit parents and adolescents from paediatric primary care practices and PCPs via email using mailing lists of the German Professional Association of Paediatricians and the German Society of Ambulatory Primary Care Paediatrics. The parent and adolescent surveys assess, inter alia, the utilisation of paediatric primary care services and its correlates, aspects of parental and child health as well as socioeconomic characteristics. The PCP survey investigates the provision of paediatric primary care services and its correlates, aspects of PCP health as well as sociodemographic and practice characteristics. The semistructured interviews with parents and PCPs explore several aspects of the online surveys in more detail. We use descriptive statistics and generalised linear mixed models to assess service utilisation and provision and specific correlates covered in the online surveys and apply qualitative content analysis to explore barriers and facilitators of service utilisation and provision more broadly in the semistructured interviews. We will integrate findings from the quantitative and qualitative analyses at the interpretation stage. ETHICS AND DISSEMINATION: The study was approved by the Medical Ethics Review Board of the Medical Faculty Mannheim at Heidelberg University (2020-650N). Study results will be published in journals with external peer-review.

The impact of intraocular pressure fluctuations and other factors on conversion of ocular hypertension to primary open-angle glaucoma.

PURPOSE: To evaluate the role of intraocular pressure (IOP) fluctuations and other factors on conversion of ocular hypertension to open-angle glaucoma (OAG) within a retrospective, longitudinal cohort study. PATIENTS AND METHODS: The study population included patients with ocular hypertension defined by IOP > 21 mmHg with normal appearing optic discs and no visual field defect. IOP fluctuation, mean and maximum were examined in 61 eyes over a follow-up period of 36 months (standard deviation (SD) 24). All patients underwent at least two 48-h IOP profiles including night-time IOP measurements in the supine position, visual field examinations, Heidelberg retina tomograph analyses (HRT) and optic disc photographs. Regression analyses were performed to demonstrate the impact of IOP parameters, myopia, sex, cup/disc ratio and visual field results on conversion to glaucoma. RESULTS: While IOP fluctuation and mean did not impact conversion, myopia proved to be a risk factor (HR 14.4; 95% CI: [3.9-53.0]; p ≤ 0.001). Over an average of three years, 6/61 converted to OAG. The study yielded a mean long-term IOP over all available pressure profiles of 18.1 mmHg (SD 3.2) and an IOP fluctuation of 1.9 mmHg (SD 1.1) within a mostly treated cohort. Conversion-free five-year rate was 59.8%. CONCLUSIONS: The amount of fluctuation we measured in our study sample did not result in the development of glaucoma in treated ocular hypertension patients. Myopic subjects with ocular hypertension are at a higher risk for glaucoma conversion than non-myopic ocular hypertensive subjects are.

Effects of clopidogrel vs. prasugrel vs. ticagrelor on endothelial function, inflammatory parameters, and platelet function in patients with acute coronary syndrome undergoing coronary artery stenting: a randomized, blinded, parallel study.

AIMS: In a randomized, parallel, blinded study, we investigate the impact of clopidogrel, prasugrel, or ticagrelor on peripheral endothelial function in patients undergoing stenting for an acute coronary syndrome. METHODS AND RESULTS: The primary endpoint of the study was the change in endothelium-dependent flow-mediated dilation (FMD) following stenting. A total of 90 patients (age 62 ± 9 years, 81 males, 22 diabetics, 49 non-ST elevation myocardial infarctions) were enrolled. There were no significant differences among groups in any clinical parameter. Acutely before stenting, all three drugs improved FMD without differences between groups (P = 0.73). Stenting blunted FMD in the clopidogrel and ticagrelor group (both P < 0.01), but not in the prasugrel group. During follow-up, prasugrel was superior to clopidogrel [mean difference 2.13, 95% confidence interval (CI) 0.68-3.58; P = 0.0047] and ticagrelor (mean difference 1.57, 95% CI 0.31-2.83; P = 0.0155), but this difference was limited to patients who received the study therapy 2 h before stenting. Ticagrelor was not significantly superior to clopidogrel (mean difference 0.55, 95% CI -0.73 to 1.82; P = 0.39). No significant differences were seen among groups for low-flow-mediated dilation. Plasma interleukin (IL)-6 (P = 0.02 and P = 0.01, respectively) and platelet aggregation reactivity in response to adenosine diphosphate (P = 0.002 and P = 0.035) were lower in the prasugrel compared to clopidogrel and ticagrelor group. CONCLUSION: As compared to ticagrelor and clopidogrel, therapy with prasugrel in patients undergoing stenting for an acute coronary syndrome is associated with improved endothelial function, stronger platelet inhibition, and reduced IL-6 levels, all of which may have prognostic implications. This effect was lost in patients who received the study medication immediately after stenting. EUDRACT-NO: 2011-005305-73.

Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages.

Many tumors evolve sophisticated strategies to evade the immune system, and these represent major obstacles for efficient antitumor immune responses. Here we explored a molecular mechanism of metabolic communication deployed by highly glycolytic tumors for immunoevasion. In contrast to colon adenocarcinomas, melanomas showed comparatively high glycolytic activity, which resulted in high acidification of the tumor microenvironment. This tumor acidosis induced Gprotein-coupled receptor-dependent expression of the transcriptional repressor ICER in tumor-associated macrophages that led to their functional polarization toward a non-inflammatory phenotype and promoted tumor growth. Collectively, our findings identify a molecular mechanism of metabolic communication between non-lymphoid tissue and the immune system that was exploited by high-glycolytic-rate tumors for evasion of the immune system.

Sunitinib added to FOLFIRI versus FOLFIRI in patients with chemorefractory advanced adenocarcinoma of the stomach or lower esophagus: a randomized, placebo-controlled phase II AIO trial with serum biomarker program.

BACKGROUND: As a multi-targeted anti-angiogenic receptor tyrosine kinase (RTK) inhibitor sunitinib (SUN) has been established for renal cancer and gastrointestinal stromal tumors. In advanced refractory esophagogastric cancer patients, monotherapy with SUN was associated with good tolerability but limited tumor response. METHODS: This double-blind, placebo-controlled, multicenter, phase II clinical trial was conducted to evaluate the efficacy, safety and tolerability of SUN as an adjunct to second and third-line FOLFIRI (NCT01020630). Patients were randomized to receive 6-week cycles including FOLFIRI plus sodium folinate (Na-FOLFIRI) once every two weeks and SUN or placebo (PL) continuously for four weeks followed by a 2-week rest period. The primary study endpoint was progression-free survival (PFS). Preplanned serum analyses of VEGF-A, VEGF-D, VEGFR2 and SDF-1α were performed retrospectively. RESULTS: Overall, 91 patients were randomized, 45 in each group (one patient withdrew). The main grade ≥3 AEs were neutropenia and leucopenia, observed in 56 %/20 % and 27 %/16 % for FOLFIRI + SUN/FOLFIRI + PL, respectively. Median PFS was similar, 3.5 vs. 3.3 months (hazard ratio (HR) 1.11, 95 % CI 0.70-1.74, P = 0.66) for FOLFIRI + SUN vs. FOLFIRI + PL, respectively. For FOLFIRI + SUN, a trend towards longer median overall survival (OS) compared with placebo was observed (10.4 vs. 8.9 months, HR 0.82, 95 % CI 0.50-1.34, one-sided P = 0.21). In subgroup serum analyses, significant changes in VEGF-A (P = 0.017), VEGFR2 (P = 0.012) and VEGF-D (P < 0.001) serum levels were observed. CONCLUSIONS: Although sunitinib combined with FOLFIRI did not improve PFS and response in chemotherapy-resistant gastric cancer, a trend towards better OS was observed. Further biomarker-driven studies with other anti-angiogenic RTK inhibitors are warranted. TRIAL REGISTRATION: This study was registered prospectively in the NCT Clinical Trials Registry (ClinicalTrials.gov) under NCT01020630 on November 23, 2009 after approval by the leading ethics committee of the Medical Association of Rhineland-Palatinate, Mainz, in coordination with the participating ethics committees (see Additional file 2) on September 16, 2009.

Prevalence of diabetic retinopathy in screening-detected diabetes mellitus: results from the Gutenberg Health Study (GHS).

AIMS/HYPOTHESIS: Individuals with type 2 diabetes mellitus may experience an asymptomatic period of hyperglycaemia, and complications may already be present at the time of diagnosis. We aimed to determine the prevalence of diabetic retinopathy in patients with newly diagnosed (screening-detected) type 2 diabetes. METHODS: The Gutenberg Health Study is a population-based study with 15,010 participants aged between 35 and 74 years. We determined the weighted prevalence of diabetic retinopathy by assessing fundus photographs. Screening-detected type 2 diabetes was defined as an HbA1c concentration of 6.5% (47.5 mmol/mol) or more, no medical diagnosis of diabetes and no intake of insulin or oral glucose-lowering agents. RESULTS: Of 14,948 participants, 1377 (9.2%) had diabetes mellitus. Of these, 347 (25.2%) had newly diagnosed type 2 diabetes detected by the screening. Overall, the weighted prevalence of screening-detected type 2 diabetes was 2.1%. Fundus photos were evaluable for 285 (82.1%) participants with newly diagnosed diabetes. The weighted prevalence of diabetic retinopathy in screening-detected type 2 diabetes was 13.0%; 12% of participants had a mild non-proliferative diabetic retinopathy and 0.6% had a moderate non-proliferative diabetic retinopathy. Diabetic retinopathy was proliferative in 0.3%. No cases of severe non-proliferative diabetic retinopathy or diabetic maculopathy were found. Thirty (14.9%) of 202 and six (7.2%) of 83 individuals with and without concomitant arterial hypertension, respectively, had diabetic retinopathy (OR 2.54, 95% CI 1.06, 7.14). Visual acuity did not differ between individuals with and without diabetic retinopathy . CONCLUSIONS/INTERPRETATION: In this large European study, the prevalence of diabetic retinopathy in screening-detected type 2 diabetes was 13%. Only a very small proportion of participants with detected diabetic retinopathy needed treatment.

Influence of GSM signals on human peripheral lymphocytes: study of genotoxicity.

Exposure to radiofrequency (RF) electromagnetic fields (EMF) is continuously increasing worldwide. Yet, conflicting results of a possible genotoxic effect of RF EMF continue to be discussed. In the present study, a possible genotoxic effect of RF EMF (GSM, 1,800 MHz) in human lymphocytes was investigated by a collaboration of six independent institutes (institutes a, b, c, d, e, h). Peripheral blood of 20 healthy, nonsmoking volunteers of two age groups (10 volunteers 16-20 years old and 10 volunteers 50-65 years old) was taken, stimulated and intermittently exposed to three specific absorption rates (SARs) of RF EMF (0.2 W/kg, 2 W/kg, 10 W/kg) and sham for 28 h (institute a). The exposures were performed in a setup with strictly controlled conditions of temperature and dose, and randomly and automatically determined waveguide SARs, which were designed and periodically maintained by ITIS (institute h). Four genotoxicity tests with different end points were conducted (institute a): chromosome aberration test (five types of structural aberrations), micronucleus test, sister chromatid exchange test and the alkaline comet assay (Olive tail moment and % DNA). To demonstrate the validity of the study, positive controls were implemented. The genotoxicity end points were evaluated independently by three laboratories blind to SAR information (institute c = laboratory 1; institute d = laboratory 2; institute e = laboratory 3). Statistical analysis was carried out by institute b. Methods of primary statistical analysis and rules to adjust for multiple testing were specified in a statistical analysis plan based on a data review before unblinding. A linear trend test based on a linear mixed model was used for outcomes of comet assay and exact permutation test for linear trend for all other outcomes. It was ascertained that only outcomes with a significant SAR trend found by at least two of three analyzing laboratories indicated a substantiated suspicion of an exposure effect. On the basis of these specifications, none of the nine end points tested for SAR trend showed a significant and reproducible exposure effect. Highly significant differences between sham exposures and positive controls were detected by each analyzing laboratory, thus validating the study. In conclusion, the results show no evidence of a genotoxic effect induced by RF EMF (GSM, 1,800 MHz).

Genetic variations in genes encoding RANK, RANKL, and OPG in rheumatoid arthritis: a case-control study.

OBJECTIVE: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the joints, which may lead to structural damage of the cartilage and bone. The receptor activator of nuclear factor-kappaB (RANK) and the osteoprotegerin (OPG) cascade system have been reported to be essential in osteoclastogenesis. Genetic variations in the genes coding for RANK, RANK ligand (RANKL), and OPG are thought to play roles in the susceptibility to RA. METHODS: In our case-control study, genomic DNA was obtained from 534 patients with RA who fulfilled the American College of Rheumatology 1987 criteria and 516 healthy control blood donors (HC). We studied 7 single-nucleotide polymorphisms (SNP) in the genes of RANK (2 SNP: rs1805034, rs35211496), OPG (2 SNP: rs3102735, rs2073618), and RANKL (3 SNP: rs9533156, rs2277438, rs1054016) using TaqMan assay-guided polymerase chain reaction. Genotype and allelic frequencies comparing RA patients with HC were analyzed by chi-square test for 2 x 3 and 2 x 2 tables, respectively. RESULTS: Genotype distributions of the SNP rs35211496 in the RANK gene as well as the SNP rs2277438 in the RANKL gene differed significantly between patients with RA and HC. The frequency of the minor allele of rs9533156 of RANKL was significantly higher in patients with RA than in HC (OR 0.84, 95% CI 0.71-0.99, p = 0.047). Multivariate analysis adjusted to sex and investigating SNP demonstrated a significantly elevated risk for RA associated with the major allele in the RANK SNP rs35211496 (p = 0.0231) and with the minor allele in the RANKL SNP rs2277438 (p = 0.0092). No significantly increased risk was detected in the other SNP. CONCLUSION: The minor allele of the RANK SNP rs35211496 may be protective against RA, while the minor alleles of the RANKL SNP rs2277438 may increase susceptibility to RA.

Comparison of early onset breast cancer patients to older premenopausal breast cancer patients.

BACKGROUND: The objective of this study was to show differences between breast cancer patients < or =35 and >35 years with regard to tumor characteristics and to present the patient-relevant outcomes overall survival (OAS) and recurrence-free survival (RFS). METHODS: We analyzed data from 119 women aged 35 years or younger with breast cancer and compared multiple parameters against breast cancer patients between 36 and 55 (n = 1,097), all pre-menopausal. Data were adjusted for tumor characteristics and therapy. RESULTS: There was no statistically significant difference in tumor size, axillary lymph node involvement, and histological subtypes. On the contrary, grading lymphovascular invasion and receptor negativity showed statistically significant differences. Unadjusted hazard ratio are 2.11 (1.32-3.39) (OAS) and 1.92 (1.35-2.73) (RFS). Multi-adjusted hazard ratio are 2.97 (1.70-5.18) (OAS) and 2.11 (1.42-3.13) (RFS). CONCLUSIONS: In conclusion, young breast cancer patients still have a poor prognosis. Even after adjustment of the data, OAS and RFS showed a worse prognosis. Normal prognostic factors like tumor size, axillary lymph node involvement, and grading can therefore be not the explanation for the more aggressive disease progress within early onset breast cancer patients.

TP53 codon 72 polymorphism and cervical cancer: a pooled analysis of individual data from 49 studies.

BACKGROUND: Cervical cancer is caused primarily by human papillomaviruses (HPV). The polymorphism rs1042522 at codon 72 of the TP53 tumour-suppressor gene has been investigated as a genetic cofactor. More than 80 studies were done between 1998 and 2006, after it was initially reported that women who are homozygous for the arginine allele had a risk for cervical cancer seven times higher than women who were heterozygous for the allele. However, results have been inconsistent. Here we analyse pooled data from 49 studies to determine whether there is an association between TP53 codon 72 polymorphism and cervical cancer. METHODS: Individual data on 7946 cases and 7888 controls from 49 different studies worldwide were reanalysed. Odds ratios (OR) were estimated using logistic regression, stratifying by study and ethnic origin. Subgroup analyses were done for infection with HPV, ethnic origin, Hardy-Weinberg equilibrium, study quality, and the material used to determine TP53 genotype. FINDINGS: The pooled estimates (OR) for invasive cervical cancer were 1.22 (95% CI 1.08-1.39) for arginine homozygotes compared with heterozygotes, and 1.13 (0.94-1.35) for arginine homozygotes versus proline homozygotes. Subgroup analyses showed significant excess risks only in studies where controls were not in Hardy-Weinberg equilibrium (1.71 [1.21-2.42] for arginine homozygotes compared with heterozygotes), in non-epidemiological studies (1.35 [1.15-1.58] for arginine homozygotes compared with heterozygotes), and in studies where TP53 genotype was determined from tumour tissue (1.39 [1.13-1.73] for arginine homozygotes compared with heterozygotes). Null results were noted in studies with sound epidemiological design and conduct (1.06 [0.87-1.29] for arginine homozygotes compared with heterozygotes), and studies in which TP53 genotype was determined from white blood cells (1.06 [0.87-1.29] for arginine homozygotes compared with heterozygotes). INTERPRETATION: Subgroup analyses indicated that excess risks were most likely not due to clinical or biological factors, but to errors in study methods. No association was found between cervical cancer and TP53 codon 72 polymorphism when the analysis was restricted to methodologically sound studies. FUNDING: German Research Foundation (DFG).

Progression of fibrosis in usual interstitial pneumonia: serial evaluation of the native lung after single lung transplantation.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a poor prognosis. Usual interstitial pneumonia (UIP) is the histopathological pattern identifying patients with the clinical entity of IPF. Despite aggressive immunosuppressive therapy the clinical course is usually dismal. For selected patients only lung transplantation improves prognosis and quality of life. After lung transplantation patients often receive a potent cyclosporine-based immunosuppressive therapy. Some reports suggest that cyclosporine has the potential to prevent progression of fibrosis. OBJECTIVE: In patients with single lung transplantation (sLTx) for UIP we evaluated the effect of cyclosporine-based immunosuppressive therapy on progression of fibrosis using a high-resolution computed tomography (HRCT) scoring system. METHODS: This retrospective observational study included 13 patients (24-64 years old) with histologically confirmed UIP who had HRCT scans preceding and following sLTx and who survived at least 6 months after sLTx. All patients were initially treated with cyclosporin A, prednisone and azathioprine. Three radiologists analyzed HRCT scans by setting a score regarding fibrosis [fibrosis score (FS); range 0-5 for each lobe] and ground-glass opacity [ground-glass score (GGS); range 0-5 for each lobe]. A comparison of serial changes (interval: 12-96 months posttransplant, 2-4 HRCT examinations/patient) was performed with the sign test. RESULTS: Mean pretransplant FS and GGS of the nontransplanted lung were 1.80 and 1.61, respectively. Comparing pre- and posttransplant HRCT scans, mean lung FS significantly increased (0.35 +/- 0.15/year; p = 0.00024), while GGS tended to decrease (0.06 +/- 0.26/year; p = 0.5). CONCLUSION: A cyclosporin A based triple immunosuppressive regimen following sLTx does not seem to prevent progression of the fibrotic changes of the native lung in patients with IPF.

Prognostic value of SSEP in early aneurysm surgery after SAH in poor-grade patients.

We evaluate the prognostic value of somatosensory evoked potentials (SSEP) in poor-grade patients after early surgery for aneurysmal subarachnoid hemorrhage compared to the Hunt and Hess (H&H) and WFNS scales. Ninety patients with angiographically proven aneurysms graded H&H IV or V were evaluated retrospectively. The aneurysms of 72 patients were clipped. In 53 out of 72 patients 147 SSEP examinations were recorded. The SSEP were classified according to the central conduction time (CCT) and the number of cortical potentials. Outcome was determined according to the Glasgow Outcome Scale. To evaluate the predictability of the SSEP to clinical grading scales receiver operating characteristic (ROC) analysis was done. The H&H scale did not demonstrate statistically significant predictability for poor-grade patients. The WFNS scale predicted the outcome for only one group (survival/death) (p = 0.035). Predictability of outcome by the SSEP was statistically confirmed. Normal CCT indicated a potential for a good recovery, but not consistently so. Bilaterally enhanced CCT was predictive of a poor outcome. Bilateral lack of cortical responses was always related to fatal outcome. ROC analysis confirmed that SSEP are superior to clinical grading scales in determining prognosis in poor-grade patients. In doubt, whether early aneurysm surgery or conservative treatment in a poor-grade patient should be done, SSEP will be helpful.

Is there a differential impact of fatigue and physical disability on quality of life in multiple sclerosis?

To investigate the quantitative impact of fatigue on health-related quality of life (HRQoL) in multiple sclerosis (MS) and to determine whether fatigue was related to HRQoL independently from bodily disability, data on HRQoL were ascertained for 87 patients with definite MS by using the SF-36. HRQoL scores and subscores were related to the basic MS disability score (EDSS) and further MS parameters, and to fatigue, which was assessed by using different fatigue scales. Factors related to predominantly physical but not mental HRQoL aspects were identified as related to EDSS, duration of disease, and age. Different fatigue scores did impact significantly on both physical and especially mental HRQoL. The influence of fatigue on physical HRQoL was independent from EDSS. Fatigue experience reduces HRQoL markedly and independently from EDSS. Therefore, fatigue assessment provides additional information to disability-derived scales such as the EDSS with relevant implications for therapeutic decisions.