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Association of a lifestyle risk index with visceral and subcutaneous adipose tissue in the German National Cohort (NAKO)
Full text linkOBJECTIVE: This cross-sectional study examined a Lifestyle Risk Factor Index (LSRI) in relation to adiposity measures including visceral adipose tissue (VAT) in the German National Cohort (NAKO). METHODS: Based on self-reports at baseline among 30,920 of > 205,000 NAKO eligible participants with magnetic resonance imaging (MRI) scans, one point each for not smoking, adhering to ≥ 3/7 diet recommendations, consuming ≤ 1 (women)/≤ 2 (men) alcoholic drinks/day, and ≥ 150 min/week physical activity was assigned. VAT volume, obtained from whole-body MRI at 3T, was analyzed by deep learning-based image segmentation. General linear models estimated adjusted geometric mean adiposity measures by LSRI and stratified analyses by sex and BMI. RESULTS: Of 18,508 participants aged 48.2 ± 12.2 years, the respective proportions for 0/1, 2, 3, and 4 LSRI points were 7%, 24%, 51%, and 18%. Participants with LSRI scores of 4 versus 0/1 had lower adjusted geometric mean volumes of VAT (2.3; 95% CI 2.2, 2.3 vs. 3.0; 95% CI 2.9, 3.1 L). These differences were slightly attenuated after adding BMI. This association was weaker for individuals with obesity than normal/overweight. CONCLUSION: A combination of lifestyle factors appears to be associated with lower VAT volume, but an elevated BMI may have a greater influence on VAT accumulation than lifestyle behaviors alone
Factors associated with device-based measured physical activity and sedentary behavior in a cross-sectional citizen science study of adolescents during the COVID-19 pandemic
Full text linkBACKGROUND: Insufficient physical activity (PA) and extensive sedentary behavior (SB) in adolescents has been related to adverse outcomes related to physical fitness, body weight as well as social and psychological health indicators. Furthermore, these behaviors tend to track from adolescence to adulthood, thereby affecting adult chronic disease risk. The knowledge of factors associated with PA and SB is needed particularly in adolescents, in order to plan public health strategies aiming at increasing PA and reducing SB. The aim of this Citizen Science project (conducted between February 2020 and June 2021) was to work together with young citizens on a school-based epidemiologic study assessing device-based measured PA and SB in students (grades 8 or higher) to identify associated factors based on both established as well as co-created questionnaires. METHODS: In 12 school classes from Berlin and Brandenburg, students were as Citizen Scientists involved in the co-creation of class-specific questionnaires by collecting factors that may influence their PA and SB. Students participating in the study wore thigh-worn accelerometers (activPAL) for seven consecutive days and subsequently completed established as well as the newly developed class-specific questionnaires to ascertain potential influencing factors of PA and SB. Multilevel linear regression models were used to identify factors associated with time spent in moderate-to-vigorous physical activity (MVPA) and SB. RESULTS: Accelerometry data with at least four recorded days were available for 119 students (783 recorded days). In models adjusted for age, sex and parental socioeconomic status, high traffic safety around the school (14.8 min/day, 95% CI 0.9, 28.7) and higher degree school type (10.7 min/day, 95% CI 1.7; 19.8) were associated with more time spent in MVPA. From the class-specific questionnaires developed based on input from students, the feeling of being exhausted after school and homework was associated with less time spent in MVPA, while internal motivation to be physically active, active hobbies and working out regularly at a gym were associated with more time spent in MVPA. The potential influencing factors under investigation were not associated with sedentary time (except female sex, which was related to lower sedentary time). CONCLUSIONS: Although our findings warrant confirmation in larger samples, this Citizen Science study points to potential action points that may be targeted in public health interventions aimed at increasing PA to improve health in adolescents
Number of affected lymph nodes predicts outcome in extremity rhabdomyosarcoma
No full textBACKGROUND: Rhabdomyosarcoma (RMS) of the extremity has poor outcomes due to its high potential for lymphatic and haematogenic spread. METHODS: Data were selected from the SEER17 registry 2000–2020 for non-pleomorphic extremity rhabdomyosarcoma (all ages and stages). RESULTS: 473 cases were identified, 181 at upper and 292 at lower extremity. Median age was 14years. Histology was alveolar in 250. The median tumor size was 7 cm. 144 tumors were localized, 131 regional and 178 distant (20 unknown). Median follow-up for 229 survivors was 8.17years. 5-year-DSS and OS was 49.7 % ± 4.9(95 % CI) and 46.3 % ± 4.9, respectively. A total of 169 patients underwent pathological examination of regional lymph nodes. In 51, one node was examined, in 24 two and in 63 ≥ 3 nodes were examined. Overall, 85 patients had pathologically positive nodes: 36 had one positive regional lymph node, 12 had two and 15 had ≥3. When adjusted for age, histology, size and stage, involvement of ≥3 lymph nodes was independently associated with worse survival. This observation was also applicable to the Cox regression analysis, which exclusively considered the 275 cases of localized/regional stage. CONCLUSION: The number of regional lymph nodes affected correlates with survival, suggesting the extent of lymph node involvement as a new and crucial predictive factor. Further analysis of the extent of regional lymph node involvement is advisable. This includes identifying the most effective methods for detecting affected nodes and establishing how many nodes need to be examined to obtain representative results
Myocarditis and pericarditis in focus: a brief report comparing the 2025 ESC guidelines and latest ACC position papers
No full textCognitive function in patients with myelin oligodendrocyte glycoprotein antibody-associated disease
Full text linkBACKGROUND: Data on cognition in adult patients with myelin oligodendrocyte glycoprotein antibody-associated disease (pwMOGAD) are scarce. OBJECTIVE: To examine cognitive function in pwMOGAD and assess relative risks (RR) for cognitive impairment (CImp) in pwMOGAD relative to healthy controls (HC), aquaporin 4-immunoglobulin G positive neuromyelitis optica spectrum disorders (pwAQP4+NMOSD), and double-seronegative NMOSD (pwdsNMOSD) compared to HC. METHODS: Data derived from a cohort with neuroimmunological disorders. Cognitive performance was assessed using Rao's brief repeatable battery of neuropsychological tests, compared to HC using confounder-adjusted linear regressions. CImp was defined as performing two standard deviations below the HC mean in any subtest. RR for CImp was calculated using generalized linear models. RESULTS: We evaluated cognitive performance of 21 pwMOGAD and 25 HC. CImp was additionally determined in 43 pwAQP4+NMOSD and 15 pwdsNMOSD. PwMOGAD performed worse on Selective Reminding Test, and the symbol digit modalities test compared to HC. Adjusted RR for CImp were 1.9 (95% CI 0.9-4.1) in pwMOGAD, 1.9 (95% CI 1.0-3.9) in pwAQP4+NMOSD and 2.1 (95% CI 0.9-4.6) in pwdsNMOSD. CONCLUSION: pwMOGAD performed worse in information processing speed, verbal learning, storage and retrieval compared to HC. RR for CImp in pwMOGAD compared to HC was similar to that estimated for pwAQP4+NMOSD and pwdsNMOSD
Refining cardiometabolic risk assessment using MRI-derived pancreas volume and fat content: insights from the NAKO and UK Biobank
No full textBACKGROUND: The pancreas is essential for metabolic homeostasis. Alterations in morphology and parenchymal integrity may impact proper function but are not routinely used for risk stratification. Here, we propose an AI-pipeline to quantify pancreas volume and fat content from MRI to identify individuals at high-risk for cardiometabolic disease in the general population. METHODS: We quantified pancreas volume (milliliters, mL) and intrapancreatic fat content (defined as fat fraction; FF, %) from MRI of UK Biobank (UKB) and German National Cohort (NAKO) participants using deep learning. We 1) analyzed differences in volume and FF across age and sex, 2) computed percentile-curves and z-scores adjusted for age and sex to identify high-risk volumes/FF, and 3) conducted Cox regression to assess associations between z-score categories (volume: reference, z=-1 to 1; low, z=1; FF: low, z1) and incident outcomes (diabetes, major adverse cardiovascular events (MACE), all-cause mortality) after adjustment for risk factors. RESULTS: Among 63,548 UKB and NAKO-participants (57.7±12.8 years; BMI: 26.3±4.4 kg/m2, 46.9% female), automated pancreas analysis revealed a positive association between both volume and FF and age. In 33,099 UKB-participants (median 4.8 years follow-up), z-score categories were associated with incident diabetes (low volume, aHR:1.59, 95%CI[1.20-2.11]; high FF, aHR:1.70, 95%CI[1.31-2.19]), MACE (high volume, aHR: 0.79, 95%CI[0.61-1.01]; high FF, aHR: 1.32, 95%CI[1.01-1.73]), and all-cause mortality (low volume, aHR: 1.48, 95%CI[1.161.90]) beyond risk factors. Adding z-score categories to a baseline model including risk factors improved discrimination of future diabetes (volume:0.781 to 0.784, p=0.004; FF:0.781 to 0.787, p<0.001) and mortality (volume:0.781 to 0.787, p<0.001). CONCLUSIONS: Deviations from normalized pancreas volume and FF predicted cardiometabolic outcomes beyond known risk factors and alcohol intake. This automated approach identifies high-risk individuals who may benefit from cardiometabolic/endocrinology referral
Community benchmarking and evaluation of human unannotated microprotein detection by mass spectrometry based proteomics
Full text linkThousands of short open reading frames (sORFs) are translated outside of annotated coding sequences. Recent studies have pioneered searching for sORF-encoded microproteins in mass spectrometry (MS)-based proteomics and peptidomics datasets. Here, we assessed literature-reported MS-based identifications of unannotated human proteins. We find that studies vary by three orders of magnitude in the number of unannotated proteins they report. Of nearly 10,000 reported sORF-encoded peptides, 96% were unique to a single study, and 12% mapped to annotated proteins or proteoforms. Manual curation of a benchmark dataset of 406 manually evaluated spectra from 204 sORF-encoded proteins revealed large variation in peptide-spectrum match (PSM) quality between studies, with immunopeptidomics studies generally reporting higher quality PSMs than conventional enzymatic digests of whole cell lysates. We estimate that 65% of predicted sORF-encoded protein detections in immunopeptidomics studies were supported by high-quality PSMs versus 7.8% in non-immunopeptidomics datasets. Our work stresses the need for standardized protocols and analysis workflows to guide future advancements in microprotein detection by MS towards uncovering how many human microproteins exist
Refining visceral adipose tissue quantification: influence of sex, age, and BMI on single slice estimation in 3D MRI of the German National Cohort
Full text linkOBJECTIVES: High prevalence of visceral obesity and its associated complications underscore the importance of accurately quantifying visceral adipose tissue (VAT) depots. While whole-body MRI offers comprehensive insights into adipose tissue distribution, it is resource-intensive. Alternatively, evaluation of defined single slices provides an efficient approach for estimation of total VAT volume. This study investigates the influence of sex-, age-, and BMI on VAT distribution along the craniocaudal axis and total VAT volume obtained from single slice versus volumetric assessment in 3D MRI and aims to identify age-independent locations for accurate estimation of VAT volume from single slice assessment. MATERIALS AND METHODS: This secondary analysis of the prospective population-based German National Cohort (NAKO) included 3D VIBE Dixon MRI from 11,191 participants (screened between May 2014 and December 2016). VAT and spine segmentations were automatically generated using fat-selective images. Standardized craniocaudal VAT profiles were generated. Axial percentage of total VAT was used for identification of reference locations for volume estimation of VAT from a single slice. RESULTS: Data from 11,036 participants (mean age, 52 ± 11 years, 5681 men) were analyzed. Craniocaudal VAT distribution differed qualitatively between men/women and with respect to age/BMI. Age-independent single slice VAT estimates demonstrated strong correlations with reference VAT volumes. Anatomical locations for accurate VAT estimation varied with sex/BMI. CONCLUSIONS: The selection of reference locations should be different depending on BMI groups, with a preference for caudal shifts in location with increasing BMI. For women with obesity (BMI >30 kg/m(2)), the L1 level emerges as the optimal reference location
Design of combination therapeutics from protein response to drugs in ovarian cancer cells
Full text linkHigh-grade serous ovarian cancer (HGSOC) remains the most lethal gynecologic malignancy and novel treatment approaches are needed. Here, we used unbiased quantitative protein mass spectrometry to assess the cellular response profile to drug perturbations in ovarian cancer cells for the rational design of potential combination therapies. Analysis of the perturbation profiles revealed proteins responding across several drug perturbations (called frequently responsive below) as well as drug-specific protein responses. The frequently responsive proteins included proteins that reflected general drug resistance mechanisms such as changes in drug efflux pumps. Network analysis of drug-specific protein responses revealed known and potential novel markers of resistance, which were used to rationalize the design of anti-resistance drug pairs. We experimentally tested the anti-proliferative effects of 12 of the proposed drug combinations in 6 HGSOC cell lines. Drug combinations tested with additive or synergistic effects are plausible candidates for overcoming or preventing resistance to single agents; these include several combinations that were synergistic (with PARPi, MEKi, and SRCi). Additionally, we observed 0.05-0.11 micromolar response to GPX4 inhibitors as single agents in the OVCAR-4 cell line. We propose several drug combinations as potential therapeutic candidates in ovarian cancer, as well as GPX4 inhibitors as single agents
Mas knockout mice present altered behavioral and neuroendocrine coping responses to chronic unpredictable stress
Full text linkStress is defined as a disruption of homeostasis that elicits adaptive responses aimed at restoring physiological balance. However, when stress becomes chronic or overwhelming, maladaptive changes may occur, contributing to endocrine, behavioral, and neuropsychiatric dysfunctions. Beyond the classical neuroendocrine axes, such as the sympatho-adrenomedullary and hypothalamic-pituitary-adrenal (HPA) axes, the renin-angiotensin system has also being implicated in stress modulation. Previous studies have shown that angiotensin-(1-7), acting through its receptor Mas, exerts a modulatory effect on the stress response, attenuating anxiety- and depression-like behaviors induced by various stressors. Here we investigated the impact of genetic deletion of Mas on the consequences of chronic unpredictable stress (CUS) exposure. Over 21 consecutive days, mice were subjected to random stressors, after which endocrine, behavioral and neurochemical assessments were performed. Mas knockout (KO) mice exposed to CUS exhibited significantly elevated corticosterone and blood glucose levels compared to stressed wild-type mice. In behavioral tests, stressed Mas KO mice displayed the highest immobility times in the forced swimming test, indicating enhanced depressive-like behavior. Anxiety-like behavior was also heightened in Mas KO mice, as evidenced by a significant reduction in the percentage of time spent in the open arms of the elevated plus maze test. Neurochemical analysis revealed a marked reduction in brain-derived neurotrophic factor (BDNF) levels in key brain regions of stressed Mas KO animals. Together, these findings suggest that Mas plays a critical role in the neurobiology of stress, since its absence exacerbates HPA axis hyperactivity, depression- and anxiety-like behaviors, as well as BDNF reduction. Overall, these results highlight the potential neuroprotective role of Mas in stress-related disorders