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BackgroundChronic conditions are a significant public health concern due to their rising prevalence, association with high mortality, and substantial healthcare costs. General practitioners play a crucial role in managing these conditions, and quality indicators are essential tools for assessing the quality of care. Electronic feedback reports incorporating quality indicator performance have shown promise in improving care quality. However, most studies have focused on single conditions or link feedback to financial incentives, which may not sustain long-term practice changes. This study aims to evaluate the effectiveness of a multi-condition electronic feedback reports on quality indicator performance in Swiss general practice without financial incentives.MethodsThis randomized controlled trial involves general practitioners enrolled in the FIRE project, a database of electronic medical records from Swiss primary care. Participants are randomized to receive either a plain feedback report or a comprehensive quality indicator -specific feedback report bi-monthly for 12 months. The plain feedback report contains descriptive summaries of practice activities, while the quality indicator-specific feedback report includes performance data on 14 quality indicators across cardiovascular, endocrine, pulmonary, and renal domains. The quality indicators were selected in multi-step process involving review of the literature and clinical guidelines, domain expert consultations, and a panel discussion with general practitioners. The primary study objective is to compare the effectiveness of the quality indicator-specific feedback report and of the plain feedback report with respect to the performance of the selected quality indicators.ConclusionThe study addresses a critical gap by evaluating a multi-condition feedback report without financial incentives. Its findings can inform future health policies and strategies, in line with national and international initiatives that promote or even require the implementation of quality measurement activities in general practice.Trial registrationTrial registry: ISRCTN. Registration number: ISRCTN10637092, https://www.isrctn.com/ISRCTN10637092. Registered January 9, 2024.

Background: Chronic conditions are a significant public health concern due to their rising prevalence, association with high mortality, and substantial healthcare costs. General practitioners play a crucial role in managing these conditions, and quality indicators are essential tools for assessing the quality of care. Electronic feedback reports incorporating quality indicator performance have shown promise in improving care quality. However, most studies have focused on single conditions or link feedback to financial incentives, which may not sustain long-term practice changes. This study aims to evaluate the effectiveness of a multi-condition electronic feedback reports on quality indicator performance in Swiss general practice without financial incentives. Methods: This randomized controlled trial involves general practitioners enrolled in the FIRE project, a database of electronic medical records from Swiss primary care. Participants are randomized to receive either a plain feedback report or a comprehensive quality indicator -specific feedback report bi-monthly for 12 months. The plain feedback report contains descriptive summaries of practice activities, while the quality indicator-specific feedback report includes performance data on 14 quality indicators across cardiovascular, endocrine, pulmonary, and renal domains. The quality indicators were selected in multi-step process involving review of the literature and clinical guidelines, domain expert consultations, and a panel discussion with general practitioners. The primary study objective is to compare the effectiveness of the quality indicator-specific feedback report and of the plain feedback report with respect to the performance of the selected quality indicators. Conclusion: The study addresses a critical gap by evaluating a multi-condition feedback report without financial incentives. Its findings can inform future health policies and strategies, in line with national and international initiatives that promote or even require the implementation of quality measurement activities in general practice. Trial registration: Trial registry: ISRCTN. Registration number: ISRCTN10637092, https://www.isrctn.com/ISRCTN10637092. Registered January 9, 2024. [ABSTRACT FROM AUTHOR]

Critical transitions describe a phenomenon where a system abruptly shifts from one stable state to an alternative, often detrimental, stable state. Understanding and possibly preventing the occurrence of a critical transition is thus highly relevant to many ecological, sociological, and physical systems. In this context, it has been shown that the underlying network structure of a system heavily impacts the transition behavior of that system. In this paper, we study a crucial but often overlooked aspect in critical transitions: the modularity of the system's underlying network topology. In particular, we investigate how the transition behavior of a networked system changes as we alter the local network structure of the system through controlled changes of the degree assortativity. We observe that systems with high modularity undergo cascading transitions, while systems with low modularity undergo more unified transitions. We also observe that networked systems that consist of nodes with varying degrees of connectivity tend to transition earlier in response to changes in a control parameter than one would anticipate based solely on the average degree of that network. However, in rare cases, such as when there is both low modularity and high degree disassortativity, the transition behavior aligns with what we would expected given the network's average degree. Results are confirmed for a diverse set of degree distributions including stylized two-degree networks, uniform, Poisson, and power-law degree distributions. On the basis of these results, we argue that to understand critical transitions in networked systems, they must be understood in terms of individual system components and their roles within the network structure.

[This corrects the article DOI: 10.1371/journal.pone.0277347.].

Background Mental comorbidities of physically ill patients lead to higher morbidity, mortality, health-care utilization and costs. Objective The aim of the study was to investigate the impact of mental comorbidity and physical multimorbidity on the length-of-stay in medical inpatients at a maximum-care university hospital. Design The study follows a retrospective, quantitative cross-sectional analysis approach to investigate mental comorbidity and physical multimorbidity in internal medicine patients. Patients The study comprised a total of n = 28.553 inpatients treated in 2017, 2018 and 2019 at a German Medical University Hospital. Main measures Inpatients with a mental comorbidity showed a median length-of-stay of eight days that was two days longer compared to inpatients without a mental comorbidity. Neurotic and somatoform disorders (ICD-10 F4), behavioral syndromes (F5) and organic disorders (F0) were leading with respect to length-of-stay, followed by affective disorders (F3), schizophrenia and delusional disorders (F2), and substance use (F1), all above the sample mean length-of-stay. The impact of mental comorbidity on length-of-stay was greatest for middle-aged patients. Mental comorbidity and Elixhauser score as a measure for physical multimorbidity showed a significant interaction effect indicating that the impact of mental comorbidity on length-of-stay was greater in patients with higher Elixhauser scores. Conclusions The findings provide new insights in medical inpatients how mental comorbidity and physical multimorbidity interact with respect to length-of-stay. Mental comorbidity had a large effect on length-of-stay, especially in patients with high levels of physical multimorbidity. Thus, there is an urgent need for new service models to especially care for multimorbid inpatients with mental comorbidity.

Methods to forecast critical transitions, i.e. abrupt changes in systems’ equilibrium states have relevance in scientific fields such as ecology, seismology, finance and medicine among others. So far, the bulk of investigations on forecasting methods builds on equation-based modeling methods, which consider system states as aggregates and thus do not account for the different connection strengths in each part of the system. This seems inadequate against the background of studies that insinuate that critical transitions can originate in sparsely connected parts of systems. Here we use agent-based spin-shifting models with assortative network representations to distinguish different interaction densities. Our investigations confirm that signals of imminent critical transitions can indeed be detected significantly earlier in network parts with low link degrees. We discuss the reason for this circumstance on the basis of the free energy principle.

Critical transitions can be conceptualized as abrupt shifts in the state of a system typically induced by changes in the system's critical parameter. They have been observed in a variety of systems across many scientific disciplines including physics, ecology, and social science. Because critical transitions are important to such a diverse set of systems it is crucial to understand what parts of a system drive and shape the transition. The underlying network structure plays an important role in this regard. In this paper, we investigate how changes in a network's degree sequence impact the resilience of a networked system. We find that critical transitions in degree mixed networks occur in general sooner than in their degree homogeneous counterparts of equal average degree. This relationship can be expressed with parabolic curves that describe how the tipping point changes when the nodes of an initially homogeneous degree network composed only of nodes with degree k1 are replaced by nodes of a different degree k2. These curves mark clear tipping boundaries for a given degree mixed network and thus allow the identification of possible tipping intersections and forbidden tipping regions when comparing networks with different degree sequences.

Background Extracellular vesicles are released into body fluids from the majority of, if not all, cell types. Because their secretion and specific cargo (e.g., proteins) varies according to pathology, extracellular vesicles may prove a rich source of biomarkers. However, their biological and pathophysiological functions are poorly understood in hematological malignancies. Objective Here, we investigated proteome changes in the exosome-rich fraction of the plasma of myelodysplastic syndrome patients and healthy donors. Methods Exosome-rich fraction of the plasma was isolated using ExoQuick™: proteomes were compared and statistically processed; proteins were identified by nanoLC-MS/MS and verified using the ExoCarta and QuickGO databases. Mann-Whitney and Spearman analyses were used to statistically analyze the data. 2D western blot was used to monitor clusterin proteoforms. Results Statistical analyses of the data highlighted clusterin alterations as the most significant. 2D western blot showed that the clusterin changes were caused by posttranslational modifications. Moreover, there was a notable increase in the clusterin proteoform in the exosome-rich fraction of plasma of patients with more severe myelodysplastic syndrome; this corresponded with a simultaneous decrease in their plasma. Conclusions This specific clusterin proteoform seems to be a promising biomarker for myelodysplastic syndrome progression.

BackgroundChronic kidney disease (CKD) is a common condition in general practice. Data about quality and physician-level variation of CKD care provided by general practitioners is scarce. In this study, we evaluated determinants and variation of achievement of 14 quality indicators for CKD care using electronic medical records data from Swiss general practice during 2013-2019.MethodsWe defined two patient cohorts from 483 general practitioners, one to address renal function assessment in patients with predisposing conditions (n = 47,201, median age 68 years, 48.7% female) and one to address care of patients with laboratory-confirmed CKD (n = 14,654, median age 80 years, 57.5% female). We investigated quality indicator achievement with mixed-effect logistic regression and expressed physician-level variation as intraclass correlation coefficients (ICCs) and range odds ratios (rORs).ResultsWe observed the highest quality indicator achievement rate for withholding non-steroidal anti-inflammatory drug prescription in patients with CKD staged G2-3b within 12 months of follow-up (82.6%), the lowest for albuminuria assessment within 18 months of follow-up (18.1%). Highest physician-level variation was found for renal function assessment during 18 months of follow-up in patients with predisposing conditions (diabetes: ICC 0.31, rOR 26.5; cardiovascular disease: ICC 0.28, rOR 17.4; hypertension: ICC 0.24, rOR 17.2).ConclusionThis study suggests potentially unwarranted variation in general practice concerning RF assessment in patients affected by conditions predisposing for CKD. We further identified potential gaps in quality of CKD monitoring as well as lower quality of CKD care for female patients and patients not affected by comorbidities.

More than 60% of the flora of the Galapagos Islands is introduced and some of these species have become invasive, severely altering ecosystems. An example of an affected ecosystem is the Scalesia forest, originally dominated by the endemic giant daisy tree Scalesia pedunculata (Asteraceae). The remnant patches of this unique forest are increasingly being invaded by introduced plants, mainly by Rubus niveus (blackberry, Rosaceae). To help large-scale restoration of this ecologically important forest, we seek to better understand the natural regeneration of S. pedunculata after invasive plant control. We monitored naturally recruited S. pedunculata saplings and young trees over five years in an area where invasive plant species are continuously being removed by manual means. We measured survival, height and growth of S. pedunculata saplings and young trees along permanent transects. Percent cover of surrounding plant species and of canopy shade directly above each S. pedunculata individual were determined, as well as distance to the next mature S. pedunculata tree. We identified potential factors influencing initial sapling survival and growth by applying generalized linear models. Results showed a rapid growth of saplings and young trees of up to 0.45 cm per day and a high mortality rate, as is typical for pioneer species like S. pedunculata. Sapling survival, growth and mortality seemed to be influenced by light availability, surrounding vegetation and distance to the next adult S. pedunculata tree. We concluded that natural regeneration of S. pedunculata was high only five months after the last herbicide application but that 95% of these recruits had died over the 5-year period. Further studies are needed to corroborate whether the number of surviving trees is sufficient to replace the aging adult trees and this way maintain remnants of the Scalesia forest. Urgent action is needed to help improve future restoration strategies to prevent further degradation of this rapidly shrinking threatened forest ecosystem.

Mixed hematopoietic chimerism enables donor-specific tolerance for solid organ grafts. This study evaluated the influence of different serological major histocompatibility complex disparities on chimerism development, graft-versus-host disease incidence and subsequently on solid organ tolerance in a rat model. For bone marrow transplantation conditioning total body irradiation was titrated using 10, 8 or 6 Gray. Bone marrow transplantation was performed across following major histocompatibility complex mismatched barriers: complete disparity, MHC class II, MHC class I or non-MHC mismatch. Recipients were clinically monitored for graft-versus-host disease and analyzed for chimerism using flow cytometry. After a reconstitution of 100 days, composition of peripheral leukocytes was determined. Mixed chimeras were challenged with heart grafts from allogeneic donor strains to define the impact of donor MHC class disparities on solid organ tolerance on the basis of stable chimerism. After myeloablation with 10 Gray of total body irradiation, chimerism after bone marrow transplantation was induced independent of MHC disparity. MHC class II disparity increased the incidence of graft-versus-host disease and reduced induction of stable chimerism upon myelosuppressive total body irradiation with 8 and 6 Gray, respectively. Stable mixed chimeras showed tolerance towards heart grafts from donors with MHC matched to either bone marrow donors or recipients. Isolated matching of MHC class II with bone marrow donors likewise led to stable tolerance as opposed to matching of MHC class I. In summary, MHC class II disparity was critically associated with the onset of graft-versus host disease and was identified as obstacle for successful development of chimerism after bone marrow transplantation and subsequent donor-specific solid organ tolerance.

Hematopoietic stem cell transplantation is successfully applied since the late 1950s; however, its efficacy still needs to be increased. A promising strategy is to transplant high numbers of pluripotent hematopoietic stem cells (HSCs). Therefore, an improved ex vivo culture system that supports proliferation and maintains HSC pluripotency would override possible limitations in cell numbers gained from donors. To model the natural HSC niche in vitro, we optimized the HSC medium composition with a panel of cytokines and valproic acid and used an artificial 3D bone marrow-like scaffold made of polydimethylsiloxane (PDMS). This 3D scaffold offered a suitable platform to amplify human HSCs in vitro and, simultaneously, to support their viability, multipotency and ability for self-renewal. Silicon oxide-covering of PDMS structures further improved amplification of CD34+ cells, although the conservation of naïve HSCs was better on non-covered 3D PDMS. Finally, we found that HSC cultivated on non-covered 3D PDMS generated most pluripotent colonies within colony forming unit assays. In conclusion, by combining biological and biotechnological approaches, we optimized in vitro HSCs culture conditions, resulting in improved amplification, multipotency maintenance and vitality of HSCs.

Many systems in various scientific fields like medicine, ecology, economics or climate science exhibit so-called critical transitions, through which a system abruptly changes from one state to a different state. Typical examples are epileptic seizures, changes in the climate system or catastrophic shifts in ecosystems. In order to predict imminent critical transitions, a mathematical apparatus called early warning signals has been developed and this method is used successfully in many scientific areas. However, not all critical transitions can be detected by this approach (false negative) and the appearance of early warning signals does not necessarily proof that a critical transition is imminent (false positive). Furthermore, there are whole classes of systems that always show early warning signals, even though they do not feature critical transitions. In this study we identify such classes in order to provide a safeguard against a misinterpretation of the results of an early warning signal analysis of such systems. Furthermore, we discuss strategies to avoid such systematic false positives and test our theoretical insights by applying them to real world data.

PurposeThe purpose of the current study was to compare CT-signs of portal venous confluence infiltration for actual histopathological infiltration of the vein or the tumor/vein interface (TVI) in borderline resectable pancreatic ductal adenocarcinoma (PDAC).Methods and materials101 patients with therapy-naïve, primarily resected PDAC of the pancreatic head without arterial involvement were evaluated. The portal venous confluence was assessed for contour irregularity (defined as infiltration) and degree of contact. The sensitivity and specificity of contour irregularity versus tumor to vein contact >180° as well as the combination of the signs for tumor cell infiltration of the vessel wall or TVI was calculated. Overall survival (OS) was compared between groups.ResultsSensitivity and specificity of contour irregularity for identification of tumor infiltration of the portal venous confluence or the TVI was higher compared to tumor to vessel contact >180° for tumor cell infiltration (96%/79% vs. 91%/38% respectively, p180°/ both signs had significantly worse overall survival (16.2 vs. 26.5 months/ 17.9 vs. 37.4 months/ 18.5 vs. 26.5 months respectively, all pConclusionPortal venous confluence contour irregularity is a strong predictor of actual tumor cell infiltration of the vessel wall or the TVI and should be noted as such in radiological reports.

To investigate in vivo morphological and functional correlates of oxaliplatin-induced peripheral neuropathy (OXA-PNP) by magnetic resonance neurography (MRN).Twenty patients (7 female, 13 male, 58.9±10.0 years) with mild to moderate OXA-PNP and 20 matched controls (8 female, 12 male, 55.7±15.6 years) were prospectively enrolled. All patients underwent a detailed neurophysiological examination prior to neuroimaging. A standardized imaging protocol at 3.0 Tesla included the lumbosacral plexus and both sciatic nerves and their branches using T2-weighted fat-saturated sequences and diffusion tensor imaging. Quantitative assessment included volumetry of the dorsal root ganglia (DRG), sciatic nerve normalized T2 (nT2) signal and caliber, and fractional anisotropy (FA), mean diffusivity (MD), axial (AD) and radial diffusivity (RD). Additional qualitative evaluation of sciatic, peroneal, and tibial nerves evaluated the presence, degree, and distribution of nerve lesions.DRG hypertrophy in OXA-PNP patients (207.3±47.7mm3 vs. 153.0±47.1mm3 in controls, p = 0.001) was found as significant morphological correlate of the sensory neuronopathy. In contrast, peripheral nerves only exhibited minor morphological alterations qualitatively. Quantitatively, sciatic nerve caliber (27.3±6.7mm2 vs. 27.4±7.4mm2, p = 0.80) and nT2 signal were not significantly changed in patients (1.32±0.22 vs. 1.22±0.26, p = 0.16). AD, RD, and MD showed a non-significant decrease in patients, while FA was unchanged.OXA-PNP manifests with morphological and functional correlates that can be detected in vivo by MRN. We report hypertrophy of the DRG that stands in contrast to experimental and postmortem studies. DRG volume should be further investigated as a biomarker in other sensory peripheral neuropathies and ganglionopathies.

Rat models are widely used in preclinical studies investigating fracture healing. The interfragmentary movement at a fracture site is critical to the course of healing and therefore demands definition in order to aptly interpret the experimental results. Estimation of this movement requires knowledge of the fixation stiffness and loading. The characteristic loading for the rat femur has been estimated, but the stiffness of fixation used in rat studies has yet to be fully described. This study aimed to determine the 6 degree of freedom stiffness of four commonly used implants, two external fixators (RatExFix and UlmExFix), a locking plate, and a locking intramedullary nail, in all degrees of freedom and estimate the interfragmentary movement under specific physiological loads. The external fixator systems allow the greatest movement. Mounted 45° anterolateral on the femur, the RatExFix allows an average of 0.88 mm of motion in each anatomic direction while the stiffer UlmExFix allows about 0.6 mm of motion. The nail is far stiffer than the other implants investigated while the plate allows movement of an intermediate magnitude. Both the nail and plate demonstrate higher axial than shear stiffness. The relatively large standard deviations in external fixator shear motion imply strong dependence on bone axis alignment across the gap and the precise orientation of the specimen relative to the loading. The smaller standard deviation associated with the nail and plate results from improved alignment and minimization of the influence of rotational positioning of the specimen due to the reduced implant eccentricity relative to the specimen axis. These results show that the interfragmentary movement is complex and varies significantly between fixation devices but establishes a baseline for the evaluation of the results of different studies.

As a consequence of demographic changes, hospitals are confronted with increasing numbers of elderly patients, who are at high risk of adverse events during hospitalization. Geriatric risk screening followed by comprehensive geriatric assessment (CGA) and treatment has been requested by geriatric societies and task forces to identify patients at risk. Since empirical evidence on factors predisposing to adverse hospital events is scarce, we now prospectively evaluated implications of geriatric risk screening followed by CGA in a university hospital department of orthopedics and trauma surgery.Three hundred and eighty-one patients ≥75 years admitted to the Department of Orthopedics and Trauma Surgery of the University Hospital Essen received Identification of Seniors at Risk (ISAR) Screening followed by CGA via a geriatric liaison service in case of positive screening results. Associations between ISAR, CGA, comorbid risk factors and diseases, length of hospital stay, number of nursing and physiotherapy hours, and falls during hospital stay were analyzed.Of 381 ISAR screenings, 327 (85.8%) were positive, confirming a high percentage of patients at risk of adverse events. Of these, 300 CGAs revealed 82.7% abnormal results, indicating activities of daily living impairment combined with cognitive, emotional or mobility disturbances. Abnormal CGA resulted in a longer hospital stay (14.0±10.3 days in ISAR+/CGA abnormal compared with 7.6±7.0 days in ISAR+/CGA normal and 8.1±5.4 days in ISAR-, both p

The traditional Indian medicine, Ayurveda, provides insights and practical solutions towards a healthy life style. Rasayana is a branch of Ayurveda known for preserving and promoting health, enhancing the quality of life and delaying the aging process. In the traditional knowledge, the Rasayana herb, Chlorophytum borivilianum (C. borivilanum) is regarded as a general health promoting tonic that delays aging and increases lifespan, cognitive function and physical strength. Aging is a complex and multifactorial physiological phenomenon that manifests itself over a wide range of biological systems, tissues, and functions. Longevity is an obvious marker of physiological aging. Simple model systems such as the single-cell budding yeast Saccharomyces cerevisiae (S. cerevisiae) and the nematode, Caenorhabditis elegans (C. elegans) are widely used to study the aging process and longevity. Here, we show that a polysaccharide fraction obtained from C. borivilianum increases the lifespan of S. cerevisiae and C. elegans, using an automated screening platform (ChronoscreenTM). Chemical analysis of this extract revealed a low molecular weight polysaccharide of 1000 Da, predominantly comprising Glu1→6Glu linkage. This polysaccharide showed significant dose-dependent extension of the median lifespan of S. cerevisiae by up to 41% and of the median lifespan of C. elegans by up to 10%. Taking cue from these results and the traditionally described benefits of Rasayanas on skin rejuvenation, we tested in vitro the polysaccharide for potential skin benefits. In a keratinocyte culture, we observed that this polysaccharide increased cell proliferation significantly, and induced synthesis of hyaluronic acid (HA), a well-known extracellular matrix component. Furthermore, when added to culture medium of human reconstructed epidermis, we observed an enhanced production of epidermal markers, e.g. CD44 and HA that are otherwise diminished in aged skin. Together, these results suggest that in addition to life-span extension of S. cerevisiae and C. elegans, a polysaccharide from the Rasayana herb, C. borivilianum may have beneficial effects on skin aging parameters.

This study focuses on interactions between nanoparticles and a pesticide. The aim was to investigate how nano-sized aluminum oxide (410 nm) can alter the toxic effects of thiacloprid, even if no sorption between particles and the insecticide takes place. Thus, our study investigated a rather unexplored interaction. We conducted our research with larvae of Chironomus riparius and used thiacloprid as test substance as its toxicity to C. riparius is well described. The used nano-Al2O3 particles where chosen due to their suitable properties. For testing the acute effects of the interaction, we exposed larvae to thiacloprid (0.5, 1.0, 2.0, and 5.0 μg/L) and nano-Al2O3 (300 and 1000 mg/L), either solely or in binary mixtures. While thiacloprid resulted in elevated mortality, nano-Al2O3 solely did not exert any effects. Moreover, we observed an aggregation of nano-Al2O3 within the lumen of the intestinal tract of the larvae. Further results showed a significantly reduced mortality of fourth instar larvae when they were exposed to mixtures of nanoparticles and the pesticide, compared to thiacloprid alone. With increasing nano-Al2O3 concentration, this effect became gradually stronger. Additionally, chemical analyses of internal thiacloprid concentrations implicate reduced uptake of thiacloprid in animals exposed to mixtures. However, as larvae exposed to thiacloprid concentrations > 0.5 μg/L showed severe convulsions, independent of the presence or concentration of nano-Al2O3, we assume that nano-Al2O3 leads to a delay of mortality and does not entirely prevent it. As sorption measurements on pristine or defecated nano-Al2O3 did not reveal any sorptive interaction with thiacloprid, we can exclude sorption-based reduction of thiacloprid bioavailability as a mechanism behind our results. Even though we used test substances which might not co-occur in the environment in the tested concentrations, our study gives evidence for an interaction besides adsorption, which is important to generally understand how nanoparticles might affect biota.

Critical transitions of complex systems can often be predicted by so-called early-warning signals (EWS). In some cases, however, such signals cannot be detected although a critical transition is imminent. Observing a relation of EWS-detectability and the network topology in which the system is implemented, we simulate and investigate scale-free networks and identify which networks show, and which do not show EWS in the framework of a two state system that exhibits critical transitions. Additionally, we adapt our approach by examining the effective state of the system, rather than its natural state, and conclude that this transformation can reveal hidden EWS in networks where those signals are otherwise obscured by a complex topology.

[This corrects the article DOI: 10.1371/journal.pone.0176356.].

Even though positive relations between children's motor ability and their academic achievement are frequently reported, the underlying mechanisms are still unclear. Executive function has indeed been proposed, but hardly tested as a potential mediator. The aim of the present study was therefore to examine the mediating role of executive function in the relationship between motor ability and academic achievement, also investigating the individual contribution of specific motor abilities to the hypothesized mediated linkage to academic achievement. At intervals of ten weeks, 236 children aged between 10 and 12 years were tested in terms of their motor ability (t1: cardiovascular endurance, muscular strength, motor coordination), core executive functions (t2: updating, inhibition, shifting), and academic achievement (t3: mathematics, reading, spelling). Structural equation modelling revealed executive function to be a mediator in the relation between motor ability and academic achievement, represented by a significant indirect effect. In separate analyses, each of the three motor abilities were positively related to children's academic achievement. However, only in the case of children's motor coordination, the mediation by executive function accounted for a significance percentage of variance of academic achievement data. The results provide evidence in support of models that conceive executive function as a mechanism explaining the relationship that links children's physical activity-related outcomes to academic achievement and strengthen the advocacy for quality physical activity not merely focused on health-related physical fitness outcomes, but also on motor skill development and learning.

Nodular hyperplasia of parathyroid glands (PG) is the most probable cause of medical treatment failure in secondary hyperparathyroidism (sHPT). This prospective cohort study is located at the interface of medical and surgical consideration of sHPT treatment options and identifies risk-factors for nodular hyperplasia of PG.One-hundred-eight resected PG of 27 patients with a broad spectrum of sHPT severity were classified according to the degree of hyperplasia by histopathology. Twenty routinely gathered parameters from medical history, ultrasound findings of PG and laboratory results were analyzed for their influence on nodular hyperplasia of PG by risk-adjusted multivariable binary regression. A prognostic model for non-invasive assessment of PG was developed and used to weight the individual impact of identified risk-factors on the probability of nodular hyperplasia of single PG.Independent risk-factors for nodular hyperplasia of single PG were duration of dialysis in years, PG volume in mm3 determined by ultrasound and serum level of parathyroid hormone in pg/mL. Multivariable analyses computed a model with an Area Under the Receiver Operative Curve of 0.857 (95%-CI:0.773-0.941) when predicting nodular hyperplasia of PG. Theoretical assessment of risk-factor interaction revealed that the duration of dialysis had the strongest influence on the probability of nodular hyperplasia of single PG.The three identified risk-factors (duration of dialysis, PG volume determined by ultrasound and serum level of parathyroid hormone) can be easily gathered in daily routine and could be used to non-invasively assess the probability of nodular hyperplasia of PG. This assessment would benefit from periodically collected data sets of PG changes during the course of sHPT, so that the choice of medical or surgical sHPT treatment could be adjusted more to the naturally changing type of histological PG lesion on an individually adopted basis in the future.

In the wobble position of tRNAs specific for Gln, Lys, and Glu a universally conserved 5-methylene-2-thiouridine derivative (xm5s2U34, x denotes any of several chemical substituents and 34 denotes the wobble position) is present, which is 5-(carboxy)methylaminomethyl-2-thiouridine ((c)mnm5s2U34) in Bacteria and 5-methylcarboxymethyl-2-thiouridine (mcm5s2U34) in Eukarya. Here we show that mutants of the bacterium Salmonella enterica Serovar Typhimurium LT2 lacking either the s2- or the (c)mnm5-group of (c)mnm5s2U34 grow poorly especially at low temperature and do not grow at all at 15°C in both rich and glucose minimal media. A double mutant of S. enterica lacking both the s2- and the (c)mnm5-groups, and that thus has an unmodified uridine as wobble nucleoside, is nonviable at different temperatures. Overexpression of [Formula: see text] lacking either the s2- or the (c)mnm5-group and of [Formula: see text] lacking the s2-group exaggerated the reduced growth induced by the modification deficiency, whereas overexpression of [Formula: see text] lacking the mnm5-group did not. From these results we suggest that the primary function of cmnm5s2U34 in bacterial [Formula: see text] and mnm5s2U34 in [Formula: see text] is to prevent missense errors, but the mnm5-group of [Formula: see text] does not. However, other translational errors causing the growth defect cannot be excluded. These results are in contrast to what is found in yeast, since overexpression of the corresponding hypomodified yeast tRNAs instead counteracts the modification deficient induced phenotypes. Accordingly, it was suggested that the primary function of mcm5s2U34 in these yeast tRNAs is to improve cognate codon reading rather than prevents missense errors. Thus, although the xm5s2U34 derivatives are universally conserved, their major functional impact on bacterial and eukaryotic tRNAs may be different.

Alien species, one of the biggest threats to natural ecosystems worldwide, are of particular concern for oceanic archipelagos such as Galápagos. To enable more effective management of alien species, we reviewed, collated and analysed all available records of alien species for Galápagos. We also assembled a comprehensive dataset on pathways to and among the Galápagos Islands, including tourist and resident numbers, tourist vessels, their itineraries and visitation sites, aircraft capacity and occupancy, air and sea cargo and biosecurity interceptions. So far, 1,579 alien terrestrial and marine species have been introduced to Galápagos by humans. Of these, 1,476 have become established. Almost half of these were intentional introductions, mostly of plants. Most unintentional introductions arrived on plants and plant associated material, followed by transport vehicles, and commodities (in particular fruit and vegetables). The number, frequency and geographic origin of pathways for the arrival and dispersal of alien species to and within Galápagos have increased over time, tracking closely the increase in human population (residents and tourists) on the islands. Intentional introductions of alien species should decline as biosecurity is strengthened but there is a danger that unintentional introductions will increase further as tourism on Galápagos expands. This unique world heritage site will only retain its biodiversity values if the pathways for invasion are managed effectively.

INTRODUCTION:Correct risk assessment of disease recurrence in patients with early breast cancer is critically important to detect patients who may be spared adjuvant chemotherapy. In clinical practice this is increasingly done based on the results of gene expression assays. In the present study we compared the concordance of the 70-gene signature MammaPrint (MP) with the 12 gene assay EndoPredict (EP). METHODS:Representative tissue of 48 primary tumours was analysed with the MP during routine diagnostic purposes. Corresponding formalin-fixed, paraffin-embedded tissue was thereafter analysed by the EP test. Risk categories of both tests were compared. RESULTS:41 of 48 tumours could be directly compared by both tests. Of the 17 MP low risk cases, only 9 were considered low risk by EP (53% agreement) and of the 24 MP high risk cases, 18 were high risk by EP (75% agreement). Discrepancies occurred in 14 of 41 cases (34.1%). There was only a weak and non-significant correlation between the MP and EP test with an overall concordance of only 66%. The original therapeutic recommendation was based on the MP and would have been changed in 38% of the patients following EP test results. 4 patients developed distant metastases. The respective tumours of these patients were all classified as high risk by the EP, but only 3 were classified as high risk by the MP. CONCLUSION:Both tests resulted in different treatment recommendations for a significant proportion of patients and cannot be used interchangeably. The results underscore the urgent need for further comparative analyses of multi-genomic tests to avoid misclassification of disease recurrence risk in breast cancer patients.

Background: Mental comorbidities of physically ill patients lead to higher morbidity, mortality, health-care utilization and costs. Objective: The aim of the study was to investigate the impact of mental comorbidity and physical multimorbidity on the length-of-stay in medical inpatients at a maximum-care university hospital. Design: The study follows a retrospective, quantitative cross-sectional analysis approach to investigate mental comorbidity and physical multimorbidity in internal medicine patients. Patients: The study comprised a total of n = 28.553 inpatients treated in 2017, 2018 and 2019 at a German Medical University Hospital. Main measures: Inpatients with a mental comorbidity showed a median length-of-stay of eight days that was two days longer compared to inpatients without a mental comorbidity. Neurotic and somatoform disorders (ICD-10 F4), behavioral syndromes (F5) and organic disorders (F0) were leading with respect to length-of-stay, followed by affective disorders (F3), schizophrenia and delusional disorders (F2), and substance use (F1), all above the sample mean length-of-stay. The impact of mental comorbidity on length-of-stay was greatest for middle-aged patients. Mental comorbidity and Elixhauser score as a measure for physical multimorbidity showed a significant interaction effect indicating that the impact of mental comorbidity on length-of-stay was greater in patients with higher Elixhauser scores. Conclusions: The findings provide new insights in medical inpatients how mental comorbidity and physical multimorbidity interact with respect to length-of-stay. Mental comorbidity had a large effect on length-of-stay, especially in patients with high levels of physical multimorbidity. Thus, there is an urgent need for new service models to especially care for multimorbid inpatients with mental comorbidity. [ABSTRACT FROM AUTHOR]

OBJECTIVE:A monoclonal antibody (mAb) against the leukocyte common antigen CD45 (RT7 in rats) could facilitate bone marrow transplantation (BMT). This study in rats evaluates a depletive rat anti-RT7a mAb as isolated tool for BMT conditioning without using irradiation or any chemotherapeutic / immunosuppressive agent. METHODS:The model used a CD45 di-allelic polymorphism (RT7a/RT7b). The anti-RT7a mAb was intravenously administered to LEW.1W rats (RT1uRT7a) at 5, 10 and 15 mg/kg. 1x10(8) BM cells of MHC syngeneic (RT1u), MHC disparate (RT1l) or MHC haploidentical (RT1u/l) donors were transplanted. All BM donor strains carried the RT7b allele so that their CD45+ cells were not affected by the anti-RT7a mAb. Recipients were monitored for reconstitution and donor-chimerism in blood leukocytes. RESULTS:mAb dosages of 5 or 10 mg/kg were myelosuppressive, whereas 15 mg/kg was myeloablative. Multi-lineage donor-chimerism at day 100 indicated engraftment of MHC syngeneic BM after any used mAb dosage (5 mg/kg: 46+/-7%; 10 mg/kg: 62+/-5%; 15 mg/kg: 80+/-4%). MHC disparate BM resulted in autologous reconstitution after conditioning by 10 mg/kg of the mAb and caused transient chimerism ending up in death associated with aplasia after conditioning by 15 mg/kg of the mAb. MHC haploidentical BM (F1 to parental) engrafted only after conditioning by 15 mg/kg (chimerism at day 100: 78+/-7%). Abandonment of α/β TCR+ cell depletion from BM grafts impaired the engraftment process after conditioning using 15 mg/kg of the mAb in the MHC syngeneic setting (2 of 6 recipients failed to engraft) and the MHC haploidentical setting (3 of 6 recipients failed). CONCLUSION:This depletive anti-RT7a mAb is myelosuppressive and conditions for engraftment of MHC syngeneic BM. The mAb also facilitates engraftment of MHC haploidentical BM, if a myeloablative dose is used. RT7b expressing, BM-seeded α/β TCR+ cells seem to impair the engraftment process after myeloablative mAb conditioning.

Protein fibrillation is the pathological hallmark of several neurodegenerative diseases and also complicates the manufacturing and use of protein drugs. As a case study, the inhibitory activity of the natural compound aloin against insulin fibrillation was investigated. Based on Thioflavin T assays, high-performance liquid chromatography and transmission electron microscopy it was found that a degradation product of aloin, formed over weeks of storage, was able to significantly inhibit insulin fibrillation. The activity of the stored aloin was significantly reduced in the presence of small amounts of sodium azide or ascorbic acid, suggesting the active compound to be an oxidation product. A high-performance liquid chromatography method and a liquid chromatography-mass spectrometry method were developed to investigate the degradation products in the aged aloin solution. We found that the major compounds in the solution were aloin A and aloin B. In addition, 10-hydroxy aloin and elgonica dimers were detected in smaller amounts. The identified compounds were isolated and tested for activity by means of Thioflavin T assays, but no activity was observed. Thus, the actual fibrillation inhibitor is an as yet unidentified and potentially metastable degradation product of aloin. These results suggest that degradation products, and in particular oxidation products, are to be considered thoroughly when natural products are investigated for activity against protein fibrillation.

Changes in the ecology of macrofungi are poorly understood, not only because much of their life cycle is hidden belowground, but also because experiments often miss real-world complexity and most fruitbody inventories are limited in space and time. The National Poisons Information Centre 'Tox Info Suisse' provides countrywide 24hours/7days medical advice in case of poisonings since 1966. Here, we introduce a total of 12,126 mushroom-related phone calls that were received by Tox Info Suisse between 1966 and 2014. This indirect source of mycological information is dominated by the families of Boletaceae (11%), Agaricaceae (10%) and Amanitaceae (8%), which account for ~30% of all cases. Mushroom fruiting patterns revealed by the Poisons Centre inventory statistically resemble changes in fungal phenology, productivity and diversity as reflected by the Swiss National Data Centre 'SwissFungi'. Although the newly developed Tox Info Suisse dataset provides an innovative basis for timely environmental research, caution is advised when interpreting some of the observed long-term changes and autumnal extremes. Uncertainty of the new record relates to possible data incompleteness, imprecise species description and/or identification, as well as the inclusion of cultivated and non-indigenous mushrooms. Nevertheless, we hope that the Tox Info Suisse inventory will stimulate and enable a variety of ecological-oriented follow-up studies.

Ewing sarcoma is the second most common bone cancer in children and adolescents, with poor prognosis and outcome in ~70% of initial diagnoses and 10-15% of relapses. Hydrophobic triterpene acids and hydrophilic lectins and viscotoxins from European mistletoe (Viscum album L.) demonstrate anticancer properties, but have not yet been investigated for Ewing sarcoma. Commercial Viscum album L. extracts are aqueous, excluding the insoluble triterpenes. We recreated a total mistletoe effect by combining an aqueous extract (viscum) and a triterpene extract (TT) solubilized with cyclodextrins. Ewing sarcoma cells were treated with viscum, TT and viscumTT in vitro, ex vivo and in vivo. In vitro and ex vivo treatment of Ewing sarcoma cells with viscum inhibited proliferation and induced apoptosis in a dose-dependent fashion, while viscumTT combination treatment generated a synergistic effect. Apoptosis occurred via intrinsic and extrinsic apoptotic pathways, evidenced by activation of both CASP8 and CASP9. We show that viscumTT treatment shifts the balance of apoptotic regulatory proteins towards apoptosis, mainly via CLSPN, MCL1, BIRC5 and XIAP downregulation. ViscumTT also demonstrated strong antitumor activity in a cell line- and patient-derived mouse model, and may be considered an adjuvant therapy option for pediatric patients with Ewing sarcoma.

INTRODUCTION:The occurrence of skeletal metastases in cancer, e.g. breast cancer (BC), deteriorates patient life expectancy and quality-of-life. Current treatment options against tumor-associated bone disease are limited to anti-resorptive therapies and aimed towards palliation. There remains a lack of therapeutic approaches, which reverse or even prevent the development of bone metastases. Recent studies demonstrate that not only osteoclasts (OCs), but also osteoblasts (OBs) play a central role in the pathogenesis of skeletal metastases, partly by producing hepatocyte growth factor (HGF), which promotes tumor cell migration and seeding into the bone. OBs consist of a heterogeneous cell pool with respect to their maturation stage and function. Recent studies highlight the critical role of pre-OBs in hematopoiesis. Whether the development of bone metastases can be attributed to a particular OB maturation stage is currently unknown. METHODS AND RESULTS:Pre-OBs were generated from healthy donor (HD)-derived bone marrow stromal cells (BMSC) as well as the BMSC line KM105 and defined as ALPlow OPNlow RUNX2high OSX high CD166high. Conditioned media (CM) of pre-OBs, but not of undifferentiated cells or mature OBs, enhanced migration of metastatic BC cells. Importantly, HGF mRNA was significantly up-regulated in pre-OBs versus mature OBs, and CM of pre-OBs activated the MET signaling pathway. Highlighting a key role for HGF, CM from HGF-negative pre-OBs derived from the BMSC line HS27A did not support migration of BC cells. Genetically (siMET) or pharmacologically (INCB28060) targeting MET inhibited both HGF- and pre-OB CM- mediated BC cell migration. CONCLUSIONS:Our data demonstrate for the first time a role for pre-OBs in mediating HGF/MET- dependent migration of BC cells and strongly support the clinical evaluation of INCB28060 and other MET inhibitors to limit and/or prevent BC-associated bone metastases.

Aseptic loosening is a major cause of revision surgery of total hip arthroplasty (THA). Only few host factors affecting aseptic loosening have been identified until now, although they are urgently needed to identify and possibly treat those patients at higher risk for aseptic loosening. To determine whether the functional single nucleotide polymorphism (SNP) c.-938C>A (rs2279115), located in the promoter region of the BCL2 gene has an impact on aseptic loosening of THA we genotyped and analyzed 234 patients suffering from aseptic loosening and 231 patients after primary THA. The polymorphism is associated with risk for aseptic loosening with the CC genotype at highest risk for aseptic loosening, Odds Ratio CC vs. AA 1.93, 95%CI 1.15-3.25, p = 0.013. In contrast, low risk AA genotype carriers that still developed aseptic loosening showed a significantly shorter time to aseptic loosening than patients carrying the C allele (p = 0.004). These results indicate that the BCL2 -938C>A polymorphism influences the occurrence and course of aseptic loosening and suggests this polymorphism as an interesting candidate for prospective studies and analyses in THA registers.

The cannabinoid receptors 1 and 2 (CNR1&2) are overexpressed in a variety of malignant diseases and cannabinoids can have noteworthy impact on tumor cell viability and tumor growth. Patients diagnosed with chronic lymphocytic leukemia (CLL) present with very heterogeneous disease characteristics translating into highly differential risk properties. To meet the urgent need for refinement in risk stratification at diagnosis and the search for novel therapies we studied CNR expression and response to cannabinoid treatment in CLL. Expression levels of CNR1&2 were determined in 107 CLL patients by real-time PCR and analyzed with regard to prognostic markers and survival. Cell viability of primary CLL cells was determined in suspension and co-culture after incubation in increasing cannabinoid concentrations under normal and reduced serum conditions and in combination with fludarabine. Impact of cannabinoids on migration of CLL cells towards CXCL12 was determined in transwell plates. We found CNR1&2 to be overexpressed in CLL compared to healthy B-cells. Discriminating between high and low expressing subgroups, only high CNR1 expression was associated with two established high risk markers and conferred significantly shorter overall and treatment free survival. Viability of CLL primary cells was reduced in a dose dependent fashion upon incubation with cannabinoids, however, healthy cells were similarly affected. Under serum reduced conditions, no significant differences were observed within suspension and co-culture, respectively, however, the feeder layer contributed significantly to the survival of CLL cells compared to suspension culture conditions. No significant differences were observed when treating CLL cells with cannabinoids in combination with fludarabine. Interestingly, biologic activity of cannabinoids was independent of both CNR1&2 expression. Finally, we did not observe an inhibition of CXCL12-induced migration by cannabinoids. In contrast to other tumor entities, our data suggest a limited usability of cannabinoids for CLL therapy. Nonetheless, we could define CNR1 mRNA expression as novel prognostic marker.

The wobble nucleoside 5-methylaminomethyl-2-thio-uridine (mnm5s2U) is present in bacterial tRNAs specific for Lys and Glu and 5-carboxymethylaminomethyl-2-thio-uridine (cmnm5s2U) in tRNA specific for Gln. The sulfur of (c)mnm5s2U may be exchanged by selenium (Se)-a reaction catalyzed by the selenophosphate-dependent tRNA 2-selenouridine synthase encoded by the mnmH (ybbB, selU, sufY) gene. The MnmH protein has a rhodanese domain containing one catalytic Cys (C97) and a P-loop domain containing a Walker A motif, which is a potential nucleotide binding site. We have earlier isolated a mutant of Salmonella enterica, serovar Typhimurium with an alteration in the rhodanese domain of the MnmH protein (G67E) mediating the formation of modified nucleosides having a geranyl (ge)-group (C10H17-fragment) attached to the s2 group of mnm5s2U and of cmnm5s2U in tRNA. To further characterize the structural requirements to increase the geranylation activity, we here report the analysis of 39 independently isolated mutants catalyzing the formation of mnm5ges2U. All these mutants have amino acid substitutions in the rhodanese domain demonstrating that this domain is pivotal to increase the geranylation activity. The wild type form of MnmH+ also possesses geranyltransferase activity in vitro although only a small amount of the geranyl derivatives of (c)mnm5s2U is detected in vivo. The selenation activity in vivo has an absolute requirement for the catalytic Cys97 in the rhodanese domain whereas the geranylation activity does not. Clearly, MnmH has two distinct enzymatic activities for which the rhodanese domain is pivotal. An intact Walker motif in the P-loop domain is required for the geranylation activity implying that it is the binding site for geranylpyrophosphate (GePP), which is the donor molecule in vitro in the geranyltransfer reaction. Purified MnmH from wild type and from the MnmH(G67E) mutant have bound tRNA, which is enriched with geranylated tRNA. This in conjunction with earlier published data, suggests that this bound geranylated tRNA may be an intermediate in the selenation of the tRNA.

Immunoresponsive gene 1 (IRG1) is one of the highest induced genes in macrophages under pro-inflammatory conditions. Its function has been recently described: it codes for immune-responsive gene 1 protein/cis-aconitic acid decarboxylase (IRG1/CAD), an enzyme catalysing the production of itaconic acid from cis-aconitic acid, a tricarboxylic acid (TCA) cycle intermediate. Itaconic acid possesses specific antimicrobial properties inhibiting isocitrate lyase, the first enzyme of the glyoxylate shunt, an anaplerotic pathway that bypasses the TCA cycle and enables bacteria to survive on limited carbon conditions. To elucidate the mechanisms underlying itaconic acid production through IRG1 induction in macrophages, we examined the transcriptional regulation of IRG1. To this end, we studied IRG1 expression in human immune cells under different inflammatory stimuli, such as TNFα and IFNγ, in addition to lipopolysaccharides. Under these conditions, as previously shown in mouse macrophages, IRG1/CAD accumulates in mitochondria. Furthermore, using literature information and transcription factor prediction models, we re-constructed raw gene regulatory networks (GRNs) for IRG1 in mouse and human macrophages. We further implemented a contextualization algorithm that relies on genome-wide gene expression data to infer putative cell type-specific gene regulatory interactions in mouse and human macrophages, which allowed us to predict potential transcriptional regulators of IRG1. Among the computationally identified regulators, siRNA-mediated gene silencing of interferon regulatory factor 1 (IRF1) in macrophages significantly decreased the expression of IRG1/CAD at the gene and protein level, which correlated with a reduced production of itaconic acid. Using a synergistic approach of both computational and experimental methods, we here shed more light on the transcriptional machinery of IRG1 expression and could pave the way to therapeutic approaches targeting itaconic acid levels.

The aim of this study was to assess the role of European ambulatory pediatricians in caring for asthmatic children, especially in terms of their therapeutic education. We developed a survey that was observational, declarative, retrospective and anonymous in nature. 436 ambulatory pediatricians in Belgium, France, Germany, Italy, Luxembourg and Slovenia were asked to participate in the survey providing information on three children over 6 years old suffering from persistent asthma, who had been followed for at least 6 months. We considered the pediatricians' profile, and their role in the therapeutic education of children. 277 pediatricians (64%) responded: 81% were primary care pediatricians; 46% participated in networks; 4% had specific training in Therapeutic Patient Education; 69% followed more than 5 asthmatic children per month, and over long periods (7 ± 4 years). The profiles of 684 children were assessed. Answers diverged concerning the provision of a Personalized Action Plan (60-88%), training the child to measure and interpret his Peak Expiratory Flow (31-99%), and the prescription of pulmonary function tests during the follow-up programme of consultations (62-97%). Answers converged on pediatricians' perception of their role in teaching children about their condition and its treatment (99%), about inhalation techniques (96%), and in improving the children's ability to take preventive measures when faced with risk situations (97%). This study highlights the role of European pediatricians in caring for asthmatic children, and their lack of training in Therapeutic Patient Education. Programmes and tools are required in order to train ambulatory pediatricians in Therapeutic Patient Education, and such resources should be integrated into primary health care, and harmonized at the European level.

BackgroundBiomarker fatty acids (FAs) reflecting de novo lipogenesis (DNL) are strongly linked to the risk of cardiometabolic diseases. Liver fat accumulation could mediate this relation. There is very limited data from human population-based studies that have examined this relation.ObjectiveThe aim of this study was to investigate the relation between specific FAs in the DNL pathway and liver fat accumulation in a large population-based study.MethodsWe conducted a cross-sectional analysis of a subsample (n = 1,562) of the EPIC-Potsdam study, which involves 27,548 middle-aged men and women. Baseline blood samples have been analyzed for proportions of 32 FAs in erythrocyte membranes (determined by gas chromatography) and biomarker concentrations in plasma. As indicators for DNL, the DNL-index (16:0 / 18:2n-6) and proportions of individual blood FAs in the DNL pathway were used. Plasma parameters associated with liver fat content (fetuin-A, ALT, and GGT) and the algorithm-based fatty liver index (FLI) were used to reflect liver fat accumulation.ResultsThe DNL-index tended to be positively associated with the FLI and was positively associated with GGT activity in men (p for trend: 0.12 and 0.003). Proportions of 14:0 and 16:0 in erythrocytes were positively associated with fetuin-A, whereas 16:1n-7 were positively associated with the FLI and GGT activity (all p for trends in both sexes at least 0.004). Furthermore, the proportion of 16:1n-7 was positively related to fetuin-A in women and ALT activity in men (all p for trend at least 0.03). The proportion of 16:1n-9 showed positive associations with the FLI and GGT activity in men and fetuin-A in both sexes, whereas 18:1n-7 was positively associated with GGT activity in men (all p for trend at least 0.048).ConclusionFindings from this large epidemiological study suggest that liver fat accumulation could link erythrocyte FAs in the DNL pathway to the risk of cardiometabolic diseases.

The fatty liver index (FLI) predicts fatty liver by using BMI, waist circumference, γ-glutamyltransferase and triglycerides. We investigated the association between the FLI and the risk of type 2 diabetes and evaluated to what extent single FLI components contribute to the diabetes risk. We analysed a case-cohort study (random sub-cohort: 1922; incident cases: 563) nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study. The proportion of exposure effect (PEE) explained by single FLI components was evaluated and effect decomposition using inverse probability weighting (IPW) was applied. Women and men with a FLI ≥ 60 compared to those with a FLI < 30 had a multivariable-adjusted Hazard Ratio (HR) of 17.6; 95% confidence interval (CI) 11.1-28.0 and HR: 10.9; 95% CI 6.22-19.2, respectively. Adjustment for BMI or waist circumference attenuated this association in men [PEE BMI (95% CI) = 53.8% (43.9%-65.8%); PEE waist (95% CI) = 54.8% (44.2%-68.8%)]. In women, adjustment for waist circumference attenuated the association to a lesser degree than in men [PEE waist (95% CI) = 31.1%; (21.9%-43.1%)] while BMI had no appreciable effect [PEE BMI (95% CI) = 11.0% (2.68%-21.0%)]. γ-glutamyltransferase and triglycerides showed only a small attenuation in women [PEE GGT(95% CI) = 3.11% (-0.72%-4.48%); PEE TG (95% CI) = 6.36% (3.81%-9.92%)] and in men [PEE GGT = 0%; PEE TG (95% CI) = 6.23% (2.03%-11.8%)]. In women, the total effect was decomposed into a direct effect and 4 indirect effects (HR BMI = 1.10; HR waist = 1.28; HR GGT = 0.97 and HR TG = 1.03). In men, the 4 indirect effects were HR BMI = 1.25; HR waist = 1.29; HR GGT = 0.97 and HR TG = 0.99. These data suggest that the FLI, as a proxy for fatty liver, is associated with risk of type 2 diabetes. This association is only partly explained by standard estimates of overall and abdominal body fatness, particularly among women.

Application of bone marrow cells (BMC) is a promising strategy for tolerance induction, but usually requires strong depletion of the host immune system. This study evaluates the ability of immunosuppressants to evolve tolerogenic properties of BMC in view of residual alloreactivity.The rat model used a major histocompatibility complex (MHC) class II disparate bone marrow transplantation (BMT) setting (LEW.1AR1 (RT1auu) → LEW.1AR2 (RT1aau)). Heart grafts (LEW.1WR1 (RT1uua)) were disparate for the complete MHC to recipients and for MHC class I to BMC donors. Limited conditioning was performed by total body irradiation of 6 Gy. Cyclosporine (CsA) or Sirolimus (Srl) were administered for 14 or 28 days. Transplantation of heart grafts (HTx) was performed at day 16 or at day 100 after BMT. Chimerism and changes in the T cell pool were detected by flow cytometry.Mixed chimeras accepted HTx indefinitely, although the composition of the regenerated T cell pool was not changed to a basically donor MHC class II haplotype. Non-chimeric animals rejected HTx spontaneously. BMC recipients, who received HTx during T cell recovery at day 16, accepted HTx only after pre-treatment with Srl, although chimerism was lost. CsA pre-treatment led to accelerated HTx rejection as did isolated application of BMC.Srl evolves tolerogenic properties of allogeneic BMC to achieve indefinite acceptance of partly MHC disparate HTx despite residual alloreactivity and in particular loss of chimerism.

Defects in intracellular transport are implicated in the pathogenesis of Alzheimer's disease (AD). Hook proteins are a family of cytoplasmic linker proteins that participate in endosomal transport. In this study we show that Hook1 and Hook3 are expressed in neurons while Hook2 is predominantly expressed in astrocytes. Furthermore, Hook proteins are associated with pathological hallmarks in AD; Hook1 and Hook3 are localized to tau aggregates and Hook2 to glial components within amyloid plaques. Additionally, the expression of Hook3 is reduced in AD. Modelling of Hook3 deficiency in cultured cells leads to slowing of endosomal transport and increases β-amyloid production. We propose that Hook3 plays a role in pathogenic events exacerbating AD.

This study investigated whether formal complexity, as described by the Chomsky Hierarchy, corresponds to cognitive complexity during language learning. According to the Chomsky Hierarchy, nested dependencies (context-free) are less complex than cross-serial dependencies (mildly context-sensitive). In two artificial grammar learning (AGL) experiments participants were presented with a language containing either nested or cross-serial dependencies. A learning effect for both types of dependencies could be observed, but no difference between dependency types emerged. These behavioral findings do not seem to reflect complexity differences as described in the Chomsky Hierarchy. This study extends previous findings in demonstrating learning effects for nested and cross-serial dependencies with more natural stimulus materials in a classical AGL paradigm after only one hour of exposure. The current findings can be taken as a starting point for further exploring the degree to which the Chomsky Hierarchy reflects cognitive processes.

For most crops, like Capsicum, their diversity remains under-researched for traits of interest for food, nutrition and other purposes. A small investment in screening this diversity for a wide range of traits is likely to reveal many traditional varieties with distinguished values. One objective of this study was to demonstrate, with Capsicum as model crop, the application of indicators of phenotypic and geographic diversity as effective criteria for selecting promising genebank accessions for multiple uses from crop centers of diversity. A second objective was to evaluate the expression of biochemical and agromorphological properties of the selected Capsicum accessions in different conditions. Four steps were involved: 1) Develop the necessary diversity by expanding genebank collections in Bolivia and Peru; 2) Establish representative subsets of ~100 accessions for biochemical screening of Capsicum fruits; 3) Select promising accessions for different uses after screening; and 4) Examine how these promising accessions express biochemical and agromorphological properties when grown in different environmental conditions. The Peruvian Capsicum collection now contains 712 accessions encompassing all five domesticated species (C. annuum, C. chinense, C. frutescens, C. baccatum, and C. pubescens). The collection in Bolivia now contains 487 accessions, representing all five domesticates plus four wild taxa (C. baccatum var. baccatum, C. caballeroi, C. cardenasii, and C. eximium). Following the biochemical screening, 44 Bolivian and 39 Peruvian accessions were selected as promising, representing wide variation in levels of antioxidant capacity, capsaicinoids, fat, flavonoids, polyphenols, quercetins, tocopherols, and color. In Peru, 23 promising accessions performed well in different environments, while each of the promising Bolivian accessions only performed well in a certain environment. Differences in Capsicum diversity and local contexts led to distinct outcomes in each country. In Peru, mild landraces with high values in health-related attributes were of interest to entrepreneurs. In Bolivia, wild Capsicum have high commercial demand.

Aqueous Viscum album L. extracts are widely used in complementary cancer medicine. Hydrophobic triterpene acids also possess anti-cancer properties, but due to their low solubility they do not occur in significant amounts in aqueous extracts. Using cyclodextrins we solubilised mistletoe triterpenes (mainly oleanolic acid) and investigated the effect of a mistletoe whole plant extract on human acute myeloid leukaemia cells in vitro, ex vivo and in vivo. Single Viscum album L. extracts containing only solubilised triterpene acids (TT) or lectins (viscum) inhibited cell proliferation and induced apoptosis in a dose-dependent manner in vitro and ex vivo. The combination of viscum and TT extracts (viscumTT) enhanced the induction of apoptosis synergistically. The experiments demonstrated that all three extracts are able to induce apoptosis via caspase-8 and -9 dependent pathways with down-regulation of members of the inhibitor of apoptosis and Bcl-2 families of proteins. Finally, the acute myeloid leukaemia mouse model experiment confirmed the therapeutic effectiveness of viscumTT-treatment resulting in significant tumour weight reduction, comparable to the effect in cytarabine-treated mice. These results suggest that the combination viscumTT may have a potential therapeutic value for the treatment AML.