Obesity drives adipose-derived stem cells into a senescent and dysfunctional phenotype associated with P38MAPK/NF-KB axis.

BACKGROUND: Adipose-derived stem cells (ADSC) are multipotent cells implicated in tissue homeostasis. Obesity represents a chronic inflammatory disease associated with metabolic dysfunction and age-related mechanisms, with progressive accumulation of senescent cells and compromised ADSC function. In this study, we aimed to explore mechanisms associated with the inflammatory environment present in obesity in modulating ADSC to a senescent phenotype. We evaluated phenotypic and functional alterations through 18 days of treatment. ADSC were cultivated with a conditioned medium supplemented with a pool of plasma from eutrophic individuals (PE, n = 15) or with obesity (PO, n = 14), and compared to the control. RESULTS: Our results showed that PO-treated ADSC exhibited decreased proliferative capacity with G2/M cycle arrest and CDKN1A (p21WAF1/Cip1) up-regulation. We also observed increased senescence-associated ß-galactosidase (SA-ß-gal) activity, which was positively correlated with TRF1 protein expression. After 18 days, ADSC treated with PO showed augmented CDKN2A (p16INK4A) expression, which was accompanied by a cumulative nuclear enlargement. After 10 days, ADSC treated with PO showed an increase in NF-κB phosphorylation, while PE and PO showed an increase in p38MAPK activation. PE and PO treatment also induced an increase in senescence-associated secretory phenotype (SASP) cytokines IL-6 and IL-8. PO-treated cells exhibited decreased metabolic activity, reduced oxygen consumption related to basal respiration, increased mitochondrial depolarization and biomass, and mitochondrial network remodeling, with no superoxide overproduction. Finally, we observed an accumulation of lipid droplets in PO-treated ADSC, implying an adaptive cellular mechanism induced by the obesogenic stimuli. CONCLUSIONS: Taken together, our data suggest that the inflammatory environment observed in obesity induces a senescent phenotype associated with p38MAPK/NF-κB axis, which stimulates and amplifies the SASP and is associated with impaired mitochondrial homeostasis.

Concentrations of escitalopram in blood of patients treated in a naturalistic setting: focus on patients with alcohol and benzodiazepine use disorder.

The selective serotonin reuptake inhibitor escitalopram (ESC) is indicated for the treatment of major depressive disorder (MDD) and of generalized anxiety disorder (GAD). Monitoring of blood levels (BLs) is strongly indicated due to ESC's high interindividual pharmacokinetic variability. The aim of this study was to analyse clinical efficacy and pharmacokinetic influences on ESC BLs, in patients with depressive disorder alone and with comorbid alcohol or benzodiazepine use disorder. Data were collected from patients treated under naturalistic conditions for whom Therapeutic Drug Monitoring (TDM) was requested to guide antidepressant drug therapy and analysed retrospectively. Particular emphasis was given to patients with alcohol or benzodiazepine use disorder. Responders according to the clinical global impression (CGI) scale were compared with nonresponders for their ESC blood level (BL). The patient sample included 344 patients from 16 psychiatric hospitals in Germany. Influencing factors that could explain 22% of ESC BLs were dose, sex and age. Variability was high between individuals, and doses up to 40 mg were common in real-world settings. Patients treated with ESC monotherapy who responded showed a trend towards higher BLs compared to nonresponders with a concentration of 15 ng/mL separating both groups. Pathological changes in liver function (indicated by elevated GGT in combination with an AST/ALT ratio ≥ 1) resulted in higher dose-corrected ESC concentrations. Influencing factors that could explain 22% of ESC blood levels were dose, sex, and age. Our findings confirm the currently recommended lower threshold level and support the need for standard TDM analyses in everyday clinical practice. The ICD 10 diagnosis alcohol dependence alone does not lead to pharmacokinetic changes in the metabolism of ESC, but altered liver function does.

Cost-Effectiveness of Shortening Treatment Duration Based on Interim PET Outcome in Patients With Diffuse Large B-cell Lymphoma.

BACKGROUND: Guideline recommendations for diffuse large-B-cell lymphoma (DLBCL) treatment are shifting from long to short treatment duration, although it is still unclear whether shortening treatment duration does not cause any harm. As interim PET (I-PET) has high negative predictive value for progression, we evaluated the cost-effectiveness of shortening treatment duration dependent on I-PET result. MATERIALS AND METHODS: We developed a Markov cohort model using the PET Re-Analysis (PETRA) database to evaluate a long treatment duration (LTD) strategy, ie 8x R-CHOP or 6x R-CHOP plus 2 R, and a short treatment duration (STD) strategy, ie 6x R-CHOP. Strategies were evaluated separately in I-PET2 positive and I-PET2 negative patients. Outcomes included total costs and quality-adjusted life-years (QALYs) per patient (pp) from a societal perspective. Net monetary benefit (NMB) per strategy was calculated using a willingness-to-pay threshold of €50,000/QALY. Robustness of model predictions was assessed in sensitivity analyses. RESULTS: In I-PET2 positive patients, shortening treatment duration led to 50.4 additional deaths per 1000 patients. The STD strategy was less effective (-0.161 [95%CI: -0.343;0.028] QALYs pp) and less costly (-€2768 [95%CI: -€8420;€1105] pp). Shortening treatment duration was not cost-effective (incremental NMB -€5281). In I-PET2 negative patients, shortening treatment duration led to 5.0 additional deaths per 1000 patients and a minor difference in effectiveness (-0.007 [95%CI: -0.136;0.140] QALY pp). The STD strategy was less costly (-€5807 [95%CI: -€10,724;-€2685] pp) and led to an incremental NMB of €5449, indicating that it is cost-effective to shorten treatment duration. Robustness of these findings was underpinned by deterministic and probabilistic sensitivity analyses. CONCLUSION: Treatment duration should not be shortened in I-PET2 positive patients whereas it is cost-effective to shorten treatment duration in I-PET2 negative patients.

Optimal timing and criteria of interim PET in DLBCL: a comparative study of 1692 patients.

Interim 18F-fluorodeoxyglucose positron emission tomography (Interim-18F-FDG-PET, hereafter I-PET) has the potential to guide treatment of patients with diffuse large B-cell lymphoma (DLBCL) if the prognostic value is known. The aim of this study was to determine the optimal timing and response criteria for evaluating prognosis with I-PET in DLBCL. Individual patient data from 1692 patients with de novo DLBCL were combined and scans were harmonized. I-PET was performed at various time points during treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Scans were interpreted using the Deauville score (DS) and change in maximum standardized uptake value (ΔSUVmax). Multilevel Cox proportional hazards models corrected for International Prognostic Index (IPI) score were used to study the effects of timing and response criteria on 2-year progression-free survival (PFS). I-PET after 2 cycles (I-PET2) and I-PET4 significantly discriminated good responders from poor responders, with the highest hazard ratios (HRs) for I-PET4. Multivariable HRs for a PET-positive result at I-PET2 and I-PET4 were 1.71 and 2.95 using DS4-5, 4.91 and 6.20 using DS5, and 2.93 and 4.65 using ΔSUVmax, respectively. ΔSUVmax identified a larger proportion of poor responders than DS5 did. For all criteria, the negative predictive value was >80%, and positive predictive values ranged from 30% to 70% at I-PET2 and I-PET4. Unlike I-PET1, I-PET3 discriminated good responders from poor responders using DS4-5 and DS5 thresholds (HRs, 2.94 and 4.67, respectively). I-PET2 and I-PET4 predict good response equally during R-CHOP therapy in DLBCL. Optimal timing and response criteria depend on the clinical context. Good response at I-PET2 is suggested for de-escalation trials, and poor response using ΔSUVmax at I-PET4 is suggested for randomized trials that are evaluating new therapies.

In Vitro Calcification of Bioprosthetic Heart Valves: Test Fluid Validation on Prosthetic Material Samples.

Calcification is a major failure mode of bioprosthetic heart valves. So far, cost and time saving in vitro analyses of calcification potentials are unreliable, mostly due to superficial or spontaneous precipitation of the applied fluids. In this study, we developed a near-physiological non-spontaneously precipitating fluid for an accelerated in vitro calcification assessment, and validated it by analyzing the calcification potential of two prosthetic materials within two reference-tests. The first test focused on the comparison of four calcification fluids under dynamic contact with n=12 commercial bovine pericardium patches. The second one focused on the validation of the most appropriate fluid by analyzing the calcification potential of pericardium vs. polyurethane. The patches were mounted in separate test compartments and treated simultaneously with the respective fluids at an accelerated test frequency. Calcification propensity and progression were detected macroscopically and microscopically. Structural analyses of all deposits indicated hydroxyapatite by X-ray powder diffraction, which is also most commonly observed in vivo. Histological examination by von Kossa staining showed matrix internal and superficial calcifications, depending on the fluid composition. The present study reveals promising results towards the development of a meaningful, cost and time saving in vitro analysis of the calcification potential of bioprosthetic heart valves.

Air contrast of the intervillous space enables non-disruptive Micro-CT analysis of paraffin-embedded archival placental tissue.

The morphometric parameters of the villous tree are a strong indicator of deviant placentas. Methods have been established to digitally reconstruct small peripheral branches by tracing with 3D Microscopy at subcellular resolution. Micro-CT can help scale up the scanning of villous trees with resolution in the range of a few micrometers. As placental tissue samples are routinely conserved and archived by fixation and paraffin embedding, the villous structures are inaccessible to Micro-CT imaging due to poor contrast between paraffin and paraffinized tissue. We present a novel procedure for contrast enhancement by selectively replacing wax by air in the intervillous space.

In Vitro Calcification of Bioprosthetic Heart Valves: Investigation of Test Fluids.

Calcification is a major reason for the failure of bioprosthetic heart valves. Therefore, several attempts towards an accelerated in vitro model were undertaken in order to provide a cost- and time-saving method for the analysis of calcification processes. Due to the problem of superficial or spontaneous precipitation, which occurred in the fluids applied, we focused our study on the development of a near-physiological calcification fluid. The desired fluid should not precipitate spontaneously and should neither promote nor inhibit calcification. Eleven different fluid compositions were tested without contact to potentially calcifying materials. Crucial factors regarding the fluid properties were the ionic product, the ionic strength, and the degree of supersaturation concerning dicalciumphosphate-dihydrate, octacalciumphosphate, and hydroxyapatite. The fluids were kept in polyethylene bottles and exposed to a slight vibration within a durability tester at 37 °C. The precipitation propensity was monitored optically and colorimetrically. A structural analysis of the deposits was carried out by x-ray powder diffraction and IR-spectroscopy, which showed the development of the crystal phases that are relevant in vivo. Only two of the fluids did not precipitate. Resulting from the computations of the effective fluid contents, the saturation degree concerning dicalciumphosphate-dihydrate seems to be the key factor for spontaneous precipitation.

Exploring social-ecological systems in the transition from war to peace: A scenario-based approach to forecasting the post-conflict landscape in a Colombian region.

This paper describes the relationship between the landscape and the socio-economic and political characteristics of a highly biodiverse Andean region of Colombia, which is now recovering from the socio-ecological impact of protracted armed conflict. We quantify the current spatial relationship between nature and society, and we include legacy effects from the most recent period of armed conflict and its consequences of forced displacement and land use disruption. The procedure followed provides a quantitative model where a minimum number of socio-economic and political variables explain the variation in land cover. The results represent the relationship between land use intensity and the main socio-economic and political indicators, highlighting a close interaction between landscape configuration, socio-economic structure of local populations, coercive conservation and armed conflict. A simulated post-conflict landscape shows a clear transition gradient towards agrarian expansion and intensification, also in systems where naturalness is a relevant feature. The peace process in Colombia offers opportunities for new schemes of land planning and management, including natural resource governance and policy reforms to improve welfare and resilience of local communities. The results allow to define options for future planning given the possible consequences of socio-political legacy effects yet to fully play out across Colombia.

The volume of villi with γ-sm-actin positive perivascular cells correlates with placental weight and thickness.

INTRODUCTION: The classification of histologically stained villous cross sections in villous types (terminal, intermediate and stem villi) by stromal peculiarities is known to be observer predicated. Therefore, quantitative histology of villous trees has not become a routine endpoint of studies on the role of the placenta in prenatal programming, as opposed to the gross placental parameters weight and thickness. The classification of villous cross sections in central (stem) and peripheral (terminal) parts based on the presence or absence, respectively, of immunohistochemical detection of myofibroblasts in perivascular position is less observer dependent. We hypothesized that it will, possibly, identify microscopic correlates of placental weight and thickness within the villous tree. METHODS: 50 placentas from clinically normal pregnancies were processed for the present study. Thin villous cross sections, obtained in a systematic random manner, were stained immunohistochemically to detect γ-smooth muscle (sm) actin and to classify them subsequently as part of central or peripheral villous tree. The volume fractions of histological structures visible in villous cross sections (stroma, lumen, endothelium and syncytium) were estimated by design-based stereology. RESULTS: The present study reveals a significant correlation of placental weight and thickness with the volume estimate of stroma that have myofibroblasts in perivascular position. DISCUSSION: The positive linear correlation between the volume of central parts of villous trees and the placental weight and thickness is new. Surprisingly, the volume of more peripheral parts of villous trees, which is the main site of materno-fetal exchange does not correlate with placental weight and thickness.

Pathoarchitectonics of the cerebral cortex in chorea-acanthocytosis and Huntington's disease.

AIMS: Quantitative estimation of cortical neurone loss in cases with chorea-acanthocytosis (ChAc) and its impact on laminar composition. METHODS: We used unbiased stereological tools to estimate the degree of cortical pathology in serial gallocyanin-stained brain sections through the complete hemispheres of three subjects with genetically verified ChAc and a range of disease durations. We compared these results with our previous data of five Huntington's disease (HD) and five control cases. Pathoarchitectonic changes were exemplarily documented in TE1 of a 61-year-old female HD-, a 60-year-old female control case, and ChAc3. RESULTS: Macroscopically, the cortical volume of our ChAc cases (ChAc1-3) remained close to normal. However, the average number of neurones was reduced by 46% in ChAc and by 33% in HD (P = 0.03 for ChAc & HD vs. controls; P = 0.64 for ChAc vs. HD). Terminal HD cases featured selective laminar neurone loss with pallor of layers III, V and VIa, a high density of small, pale, closely packed radial fibres in deep cortical layers VI and V, shrinkage, and chromophilia of subcortical white matter. In ChAc, pronounced diffuse astrogliosis blurred the laminar borders, thus masking the complete and partial loss of pyramidal cells in layer IIIc and of neurones in layers III, V and VI. CONCLUSION: ChAc is a neurodegenerative disease with distinct cortical neurodegeneration. The hypertrophy of the peripheral neuropil space of minicolumns with coarse vertical striation was characteristic of ChAc. The role of astroglia in the pathogenesis of this disorder remains to be elucidated.

Telediagnosis of oral lesions in primary care: The EstomatoNet Program.

OBJECTIVE: The diagnosis of oral lesions is often challenging for primary healthcare providers, which explains the high number of referrals to specialist care. This favors increases in waiting lines and delays in diagnosis, contributing to high mortality rates from oral cancer. This study aimed to summarize the experience of the EstomatoNet, a telediagnosis program catering to primary care dentists and physicians from southern Brazil. STUDY DESIGN: This exploratory study included all queries received by EstomatoNet from June 2015 to December 2016. Health providers (71 dentists and 18 physicians from primary care) submitted requests including clinical information and photographs of oral lesions by means of a cloud-based platform. Specialized oral medicine teleconsultants received the data, conveyed a diagnostic hypothesis, and conveyed management recommendations. RESULTS: Actinic cheilitis (n = 41, 15.8%), squamous cell carcinoma (n = 22, 8.5%), and inflammatory hyperplasia (21, 8.1%) were the most frequent diagnoses. Teleconsultants recommended referral to specialists in 42.9% of the cases, total biopsy in 23.6%, and follow-up in 16.2%. After the EstomatoNet use, the intention to refer the patients to face-to-face consultation reduced from 96.9% to 35.1%. CONCLUSION: Telediagnosis for oral lesions is feasible and has potential to improve the quality of primary health care by bridging the gap between primary and specialized health care.

Identifying socio-ecological networks in rural-urban gradients: Diagnosis of a changing cultural landscape.

Socio-ecological systems maintain reciprocal interactions between biophysical and socioeconomic structures. As a result of these interactions key essential services for society emerge. Urban expansion is a direct driver of land change and cause serious shifts in socio-ecological relationships and the associated lifestyles. The framework of rural-urban gradients has proved to be a powerful tool for ecological research about urban influences on ecosystems and on sociological issues related to social welfare. However, to date there has not been an attempt to achieve a classification of municipalities in rural-urban gradients based on socio-ecological interactions. In this paper, we developed a methodological approach that allows identifying and classifying a set of socio-ecological network configurations in the Region of Madrid, a highly dynamic cultural landscape considered one of the European hotspots in urban development. According to their socio-ecological links, the integrated model detects four groups of municipalities, ordered along a rural-urban gradient, characterized by their degree of biophysical and socioeconomic coupling and different indicators of landscape structure and social welfare. We propose the developed model as a useful tool to improve environmental management schemes and land planning from a socio-ecological perspective, especially in territories subject to intense urban transformations and loss of rurality.

Syncytial nuclei accumulate at the villous surface in IUGR while proliferation is unchanged.

INTRODUCTION: Placental syncytiotrophoblast is responsible for feto-maternal nutrient exchange during pregnancy. It is assumed that in IUGR, placental dysfunction is crucially bound to compromised stability and function of syncytiotrophoblast, the latter being related to altered proliferation of villous trophoblast. Cell cycle data obtained on conventional thin sections has produced inconsistent results. In the present study we investigated cell cycle markers found in the villous trophoblast using a novel 3D histological quantification method. METHODS AND FINDINGS: We analyzed 40 placentas from IUGR pregnancies and 42 placentas from clinically normal pregnancies by immunohistochemical detection of the cell cycle marker PCNA. Nuclei immuno-positive for PCNA were quantified using 3D microscopy, and the results were compared to corresponding results obtained on conventional thin histological sections. These data did not show any evidence of altered trophoblast proliferation in IUGR, while the density of post-proliferative (i.e. PCNA-negative) trophoblast nuclei was statistically significantly increased in IUGR. The latter could be revealed by 3D topological microscopy, but not by conventional histology of thin sections. DISCUSSION: The data of the present study indicate a previously unknown type of regulation of syncytial stability and function, independent of proliferation. We hypothesize that in IUGR, post-proliferative trophoblast nuclei accumulate at the villous surface of peripheral villous branches. This could possibly reflect the presence of an unknown mechanism controlling syncytial function and stability by modulation of syncytial passage time rather than by modulation of proliferative supply.

Down-regulation of the liver-derived plasma protein fetuin-B mediates reversible female infertility.

STUDY QUESTION: Does antisense oligonucleotide (ASO)-mediated down-regulation of serum fetuin-B cause infertility like fetuin-B gene deficiency in female mice? SUMMARY ANSWER: Pharmacological fetuin-B down-regulation by ASO therapy results in reversible infertility in female mice. WHAT IS KNOWN ALREADY: Female fetuin-B deficient (Fetub-/-) mice are infertile owing to premature zona pellucida (ZP) hardening. Enzyme activity studies demonstrated that fetuin-B is a potent and highly specific inhibitor of the zona proteinase ovastacin, which cleaves ZP protein 2 (ZP2) and thus mediates definitive ZP hardening. STUDY DESIGN, SIZE, DURATION: Ten fetuin-B ASO boli (100 mg/kg) were injected s.c. over 20 days in 12 female mice, and 10 phosphate-buffered saline (PBS)-treated mice were used as control. At day 20 females were mated to evaluate fetuin-B as a potential molecular target for contraception. ASO and PBS treatment was continued for ten injections. After treatment cessation at day 50, mating was continued to investigate if infertility was reversible. PARTICIPANTS/MATERIALS, SETTING, METHODS: We generated fetuin-B/ovastacin double deficient (Fetub-/-, Astl-/-) mice by conventional breeding to test if fertility of Fetub-/- female mice was restored when the target proteinase would likewise be deleted. At least five matings with each female genotype (Fetub-/- single deficient, Astl-/- single deficient, Fetub-/-, Astl-/- double deficient) were performed. To test the contraceptive effect of fetuin-B down-regulation, 22 female mice (6-13 weeks old) were treated with repetitive boli of 100 mg/kg fetuin-B ASO (n = 12) or PBS (n = 10) and mated continuously. Serum fetuin-B was determined by immunoblot before, during and after the ASO treatment. After 3 weeks of ASO treatment, in 6 females Fetub mRNA in liver was analyzed by PCR, and six PBS-treated females were used as control. Aspartate (AST) and alanine aminotransferase (ALT) were also measured in serum of six mice in each group. To determine the minimum permissive serum fetuin-B concentration required for successful fertilization IVF was performed in five fetuin-B ASO-treated mice. As a control, six females were injected with control oligonucleotides and six females were left untreated. MAIN RESULTS AND THE ROLE OF CHANCE: Fertility of Fetub-/- female mice was restored by additional ovastacin deficiency (Astl-/-). Unlike Fetub-/- mice, female Fetub-/-, Astl-/- mice were fertile, confirming ovastacin as a primary molecular target of fetuin-B. At day 20, after receiving 10 fetuin-B ASO boli, serum fetuin-B was down-regulated to 8 ± 6% (mean ± SD) of baseline level. Fetuin-B down-regulation was confirmed at the mRNA level. Fetuin-B ASO-treated females had 12.1 ± 3.1% of the liver Fetub mRNA level seen in PBS-treated females. In the following mating study, 11 out of 12 mated females failed to become pregnant during 50 days of ASO treatment and continuous mating from day 20 onwards. IVF of oocytes derived from ASO-treated females suggested that a serum fetuin-B level of less than 10 µg/ml was required to prevent pregnancy. Withdrawal of ASO treatment normalized serum fetuin-B and restored fertility; all female mice became pregnant and had litters within 60.3 ± 35.9 days after cessation of ASO treatment. The first litter was significantly smaller than that of control mice (4.6 ± 2.3 versus 6.7 ± 1.8 pups, n = 20, P = 0.04) but the smaller litter size was only temporary. The size of the second litter was similar to the first litter of control mice (7.6 ± 1.3 versus 6.7 ± 1.8 pups, n = 18, P = 0.25). LIMITATIONS, REASONS FOR CAUTION: The repeated dose of 100 mg/kg fetuin-B ASO boli caused an increased serum ALT and AST activity, suggesting hepatotoxicity. Daily vaginal plug checks indicated successful mating, but mating plugs in ASO-treated mice were less stable (vaginal tract not closed) than in control mice. WIDER IMPLICATIONS OF THE FINDINGS: Pharmacological fetuin-B down-regulation in mice caused reversible infertility. Control of ovastacin proteinase activity by fetuin-B is a necessary determinant of female fertility that can serve as a target for female contraception. Although promising in terms of human contraception, further studies analyzing the balance between sufficient fetuin-B down-regulation and tolerable side effects are required to improve safety before transfer into human reproductive biology can be considered. LARGE SCALE DATA: None. STUDY FUNDING AND COMPETING INTERESTS: The research was supported by a grant from Deutsche Forschungsgemeinschaft and by the START program of the Medical Faculty of RWTH Aachen University. The authors E.D., J.F. and W.J.-D. are named inventors on a patent application of RWTH Aachen University covering the use of fetuin-B in ovary and oocyte culture. No conflict of interest is declared by C.S. and A.C.

Verification of redox-processes as switching and retention failure mechanisms in Nb:SrTiO3/metal devices.

Nanoscale redox reactions in transition metal oxides are believed to be the physical foundation of memristive devices, which present a highly scalable, low-power alternative for future non-volatile memory devices. The interface between noble metal top electrodes and Nb-doped SrTiO3 single crystals may serve as a prominent but not yet well-understood example of such memristive devices. In this report, we will present experimental evidence that nanoscale redox reactions and the associated valence change mechanism are indeed responsible for the resistance change in noble metal/Nb-doped SrTiO3 junctions with dimensions ranging from the micrometer scale down to the nanometer regime. Direct verification of the valence change mechanism is given by spectromicroscopic characterization of switching filaments. Furthermore, it is found that the resistance change over time is driven by the reoxidation of a previously oxygen-deficient region. The retention times of the low resistance states, accordingly, can be dramatically improved under vacuum conditions as well as through the insertion of a thin Al2O3 layer which prevents this reoxidation. These insights finally confirm the resistive switching mechanism at these interfaces and are therefore of significant importance for the study and application of memristive devices based on Nb-doped SrTiO3 as well as systems with similar switching mechanisms.

The HADDOCK2.2 Web Server: User-Friendly Integrative Modeling of Biomolecular Complexes.

The prediction of the quaternary structure of biomolecular macromolecules is of paramount importance for fundamental understanding of cellular processes and drug design. In the era of integrative structural biology, one way of increasing the accuracy of modeling methods used to predict the structure of biomolecular complexes is to include as much experimental or predictive information as possible in the process. This has been at the core of our information-driven docking approach HADDOCK. We present here the updated version 2.2 of the HADDOCK portal, which offers new features such as support for mixed molecule types, additional experimental restraints and improved protocols, all of this in a user-friendly interface. With well over 6000 registered users and 108,000 jobs served, an increasing fraction of which on grid resources, we hope that this timely upgrade will help the community to solve important biological questions and further advance the field. The HADDOCK2.2 Web server is freely accessible to non-profit users at http://haddock.science.uu.nl/services/HADDOCK2.2.

[Establishment of a Neonatal ECMO Programme on the Basis of a Special Training Programme--A 6-year Analysis]. / Etablierung neonataler ECMO bei Lungenversagen auf der Grundlage eines speziellen Trainingsprogramms--Eine 6-Jahres-Analyse.

BACKGROUND: Internationally the need for neonatal ECMO is decreasing and the Extracorporeal Life Support Organization (ELSO) recommends that centres providing neonatal ECMO should treat at least 6 children per year. METHOD: After a one-year training programme and preparation of the clinical application, neonatal ECMO was established and subsequently 41 infants [median age 1 day (1-172 days), median weight 3.25 kg (1.27-5.79 kg)] with severe respiratory failure have been treated within a 6-year period (fall 2008-fall 2014). For rescue therapy we provide inhaled nitric oxide, high-frequency oscillation and other differentiated ventilator strategies. Parallel to the clinical use of ECMO all employees have been trained in a special programme at 3-monthly intervals. RESULTS: By establishing an elaborate training programme and concentrating the treatment of critically ill newborns in one centre, the expertise of both running and preventing of neonatal ECMO due to pulmonary failure can be achieved. The diagnoses correlate to those of other centres which perform neonatal ECMO. 13 infants needed ECMO. The resulting overall survival rate was 11/12 (91.7%) infants treated with ECMO with a curative approach. All patients could be weaned from ECMO. CONCLUSION: In the context of a specialised university hospital with all treatment options for critically ill newborns and with the establishment of a specialised training programme, neonatal ECMO for pulmonary failure can achieve equally good results in comparison to those of national and international ECMO centres.

Psychosocial Information Requirements for Multimorbid Breast Cancer Patients in Breast Centres in North Rhine Westphalia.

Introduction: The importance of breast cancer patients (BPs) being supplied with sufficient information is well known. This study investigated the unfulfilled psychosocial information requirements of multimorbid BPs. Methods: This study records the unfulfilled psychosocial information requirements of 4166 patients, who were treated at one of the fifty breast centres in North Rhine Westphalia. The Cologne patient questionnaire for breast cancer 2.0 included in the postal survey following hospital stays records the information requirements using an adapted version of the "Cancer patient information needs" scale. Through a univariate analysis using the χ2 test, it was investigated whether multimorbid BPs had significantly different psychosocial information requirements than BPs without further concomitant illnesses. Results: In general, it transpired that BPs had relatively low unfulfilled information requirements regarding work (20.7 %), everyday life (26.8 %), illness (27.4 %) and treatment (35.7 %), though such requirements were higher when it came to health-related behaviour (54.2 %). Multimorbid BPs had significantly lower unfulfilled information requirements regarding work and significantly larger ones regarding treatment in comparison to BPs without concomitant illnesses. Renal diseases and concomitant mental illnesses were associated with particularly high information requirements (p < 0.05). Conclusion: The results of our study should clarify the complexity and heterogeneity of information requirements of breast cancer patients in oncological care and should help to design the supply of information to be more patient-oriented.