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Background: Misconceptions about ADHD stigmatize affected people, reduce credibility of providers, and prevent/delay treatment. To challenge misconceptions, we curated findings with strong evidence base. Methods: We reviewed studies with more than 2000 participants or meta-analyses from five or more studies or 2000 or more participants. We excluded meta-analyses that did not assess publication bias, except for meta-analyses of prevalence. For network meta-analyses we required comparison adjusted funnel plots. We excluded treatment studies with waiting-list or treatment as usual controls. From this literature, we extracted evidence-based assertions about the disorder. Results: We generated 208 empirically supported statements about ADHD. The status of the included statements as empirically supported is approved by 80 authors from 27 countries and 6 continents. The contents of the manuscript are endorsed by 366 people who have read this document and agree with its contents. Conclusions: Many findings in ADHD are supported by meta-analysis. These allow for firm statements about the nature, course, outcome causes, and treatments for disorders that are useful for reducing misconceptions and stigma.
The tyrosine kinase inhibitor sunitinib is used as first‐line therapy in patients with metastasized renal cell carcinoma (mRCC), given in fixed‐dose regimens despite its high variability in pharmacokinetics (PKs). Interindividual variability of drug exposure may be responsible for differences in response. Therefore, dosing strategies based on pharmacokinetic/pharmacodynamic (PK/PD) models may be useful to optimize treatment. Plasma concentrations of sunitinib, its active metabolite SU12662, and the soluble vascular endothelial growth factor receptors sVEGFR‐2 and sVEGFR‐3, were measured in 26 patients with mRCC within the EuroTARGET project and 21 patients with metastasized colorectal cancer (mCRC) from the C‐II‐005 study. Based on these observations, PK/PD models with potential influence of genetic predictors were developed and linked to time‐to‐event (TTE) models. Baseline sVEGFR‐2 levels were associated with clinical outcome in patients with mRCC, whereas active drug PKs seemed to be more predictive in patients with mCRC. The models provide the basis of PK/PD‐guided strategies for the individualization of anti‐angiogenic therapies.
The highly infectious disease COVID-19 caused by the Betacoronavirus SARS-CoV-2 poses a severe threat to humanity and demands the redirection of scientific efforts and criteria to organized research projects. The international COVID19-NMR consortium seeks to provide such new approaches by gathering scientific expertise worldwide. In particular, making available viral proteins and RNAs will pave the way to understanding the SARS-CoV-2 molecular components in detail. The research in COVID19-NMR and the resources provided through the consortium are fully disclosed to accelerate access and exploitation. NMR investigations of the viral molecular components are designated to provide the essential basis for further work, including macromolecular interaction studies and high-throughput drug screening. Here, we present the extensive catalog of a holistic SARS-CoV-2 protein preparation approach based on the consortium’s collective efforts. We provide protocols for the large-scale production of more than 80% of all SARS-CoV-2 proteins or essential parts of them. Several of the proteins were produced in more than one laboratory, demonstrating the high interoperability between NMR groups worldwide. For the majority of proteins, we can produce isotope-labeled samples of HSQC-grade. Together with several NMR chemical shift assignments made publicly available on covid19-nmr.com, we here provide highly valuable resources for the production of SARS-CoV-2 proteins in isotope-labeled form.
A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard.
We present the first measurement of fluctuations from event to event in the production of strange particles in collisions of heavy nuclei. The ratio of charged kaons to charged pions is determined for individual central Pb+Pb collisions. After accounting for the fluctuations due to detector resolution and finite number statistics we derive an upper limit on genuine non-statistical fluctuations, perhaps related to a first or second order QCD phase transition. Such fluctuations are shown to be very small.
The large acceptance and high momentum resolution as well as the significant particle identification capabilities of the NA49 experiment at the CERN SPS allow for a broad study of fluctuations and correlations in hadronic interactions. In the first part recent results on event-by-event charge and p_t fluctuations are presented. Charge fluctuations in central Pb+Pb reactions are investigated at three different beam energies (40, 80, and 158 AGeV), while for the p_t fluctuations the focus is put on the system size dependence at 158 AGeV. In the second part recent results on Bose Einstein correlations of h-h- pairs in minimum bias Pb+Pb reactions at 40 and 158 AGeV, as well as of K+K+ and K-K- pairs in central Pb+Pb collisions at 158 AGeV are shown. Additionally, other types of two particle correlations, namely pi p, Lambda p, and Lambda Lambda correlations, have been measured by the NA49 experiment. Finally, results on the energy and system size dependence of deuteron coalescence are discussed.
The COVID-19 pandemic is affecting countries across the globe. Only a globally coordinated response, however, will enable the containment of the virus. Responding to a request from policy makers for ethics input for a global resource pledging event as a starting point, this paper outlines normative and procedural principles to inform a coordinated global coronavirus response. Highlighting global connections and specific vulnerabilities from the pandemic, and proposing standards for reasonable and accountable decision-making, the ambition of the paper is two-fold: to raise awareness for the justice dimensions in the global response, and to argue for moving health from the periphery to the centre of philosophical debates about social and global justice.
Background: 15-20% of all patients initially diagnosed with colorectal cancer develop metastatic disease and surgical resection remains the only potentially curative treatment available. Current 5-year survival following R0-resection of liver metastases is 28-39%, but recurrence eventually occurs in up to 70%. To date, adjuvant chemotherapy has not improved clinical outcomes significantly. The primary objective of the ongoing LICC trial (L-BLP25 In Colorectal Cancer) is to determine whether L-BLP25, an active cancer immunotherapy, extends recurrence-free survival (RFS) time over placebo in colorectal cancer patients following R0/R1 resection of hepatic metastases. L-BLP25 targets MUC1 glycoprotein, which is highly expressed in hepatic metastases from colorectal cancer. In a phase IIB trial, L-BLP25 has shown acceptable tolerability and a trend towards longer survival in patients with stage IIIB locoregional NSCLC.
Methods: This is a multinational, phase II, multicenter, randomized, double-blind, placebo-controlled trial with a sample size of 159 patients from 20 centers in 3 countries. Patients with stage IV colorectal adenocarcinoma limited to liver metastases are included. Following curative-intent complete resection of the primary tumor and of all synchronous/metachronous metastases, eligible patients are randomized 2:1 to receive either L-BLP25 or placebo. Those allocated to L-BLP25 receive a single dose of 300 mg/m2 cyclophosphamide (CP) 3 days before first L-BLP25 dose, then primary treatment with s.c. L-BLP25 930 mug once weekly for 8 weeks, followed by s.c. L-BLP25 930 mug maintenance doses at 6-week (years 1&2) and 12-week (year 3) intervals unless recurrence occurs. In the control arm, CP is replaced by saline solution and L-BLP25 by placebo. Primary endpoint is the comparison of recurrence-free survival (RFS) time between groups. Secondary endpoints are overall survival (OS) time, safety, tolerability, RFS/OS in MUC-1 positive cancers. Exploratory immune response analyses are planned. The primary endpoint will be assessed in Q3 2016. Follow-up will end Q3 2017. Interim analyses are not planned.
Discussion: The design and implementation of such a vaccination study in colorectal cancer is feasible. The study will provide recurrence-free and overall survival rates of groups in an unbiased fashion. Trial Registration EudraCT Number 2011-000218-20
Hypersecretion and chronic phlegm are major symptoms of chronic obstructive pulmonary disease (COPD) but animal models of COPD with a defined functional hypersecretion have not been established so far. To identify an animal model of combined morphological signs of airway inflammation and functional hypersecretion, rats were continuously exposed to different levels of sulfur dioxide (SO2, 5 ppm, 10 ppm, 20 ppm, 40 ppm, 80 ppm) for 3 (short-term) or 20–25 (long-term) days. Histology revealed a dose-dependent increase in edema formation and inflammatory cell infiltration in short-term-exposed animals. The submucosal edema was replaced by fibrosis after long-term-exposure. The basal secretory activity was only significantly increased in the 20 ppm group. Also, stimulated secretion was significantly increased only after exposure to 20 ppm. BrdU-assays and AgNOR-analysis demonstrated cellular metaplasia and glandular hypertrophy rather than hyperplasia as the underlying morphological correlate of the hypersecretion.
In summary, SO2-exposure can lead to characteristic airway remodeling and changes in mucus secretion in rats. As only long-term exposure to 20 ppm leads to a combination of hypersecretion and airway inflammation, only this mode of exposure should be used to mimic human COPD. Concentrations less or higher than 20 ppm or short term exposure do not induce the respiratory symptom of hypersecretion. The present model may be used to characterize the effects of new compounds on mucus secretion in the background of experimental COPD.
Background: There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group.
Methods: The study comprised 802 women (median age 40 years, range 19–76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation.
Results: A total of 127 women with TNBC (15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1.1%). The mutation prevalence was 32.9% in the age group 20–29 years compared to 6.9% in the age group 60–69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95%CI 1.50–2.32, p < 0.001). gBRCA mutation risk was predicted to be > 10% for women diagnosed below approximately 50 years.
Conclusions: Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation.
Regeneration of large bone defects is a major objective in trauma surgery. Bone marrow mononuclear cell (BMC)-supported bone healing was shown to be efficient after immobilization on a scaffold. We hypothesized that fibrous demineralized bone matrix (DBM) in various forms with BMCs is superior to granular DBM. A total of 65 male SD rats were assigned to five treatment groups: syngenic cancellous bone (SCB), fibrous demineralized bone matrix (f-DBM), fibrous demineralized bone matrix densely packed (f-DBM 120%), DBM granules (GDBM) and DBM granules 5% calcium phosphate (GDBM5%Ca2+). BMCs from donor rats were combined with different scaffolds and placed into 5 mm femoral bone defects. After 8 weeks, bone mineral density (BMD), biomechanical stability and histology were assessed. Similar biomechanical properties of f-DBM and SCB defects were observed. Similar bone and cartilage formation was found in all groups, but a significantly bigger residual defect size was found in GDBM. High bone healing scores were found in f-DBM (25) and SCB (25). The application of DBM in fiber form combined with the application of BMCs shows promising results comparable to the gold standard, syngenic cancellous bone. Denser packing of fibers or higher amount of calcium phosphate has no positive effect.
Bone marrow mononuclear cells (BMCs) are suitable for bone tissue engineering. Comparative data regarding the needs of BMC for the adhesion on biomaterials and biocompatibility to various biomaterials are lacking to a large extent. Therefore, we evaluated whether a surface coating would enhance BMC adhesion and analyze the biocompatibility of three different kinds of biomaterials. BMCs were purified from human bone marrow aspirate samples. Beta tricalcium phosphate (β-TCP, without coating or coated with fibronectin or human plasma), demineralized bone matrix (DBM), and bovine cancellous bone (BS) were assessed. Seeding efficacy on β-TCP was 95% regardless of the surface coating. BMC demonstrated a significantly increased initial adhesion on DBM and β-TCP compared to BS. On day 14, metabolic activity was significantly increased in BMC seeded on DBM in comparison to BMC seeded on BS. Likewise increased VEGF-synthesis was observed on day 2 in BMC seeded on DBM when compared to BMC seeded on BS. The seeding efficacy of BMC on uncoated biomaterials is generally high although there are differences between these biomaterials. Beta-TCP and DBM were similar and both superior to BS, suggesting either as suitable materials for spatial restriction of BMC used for regenerative medicine purposes in vivo.
Dieser Entwurf eines Verhaltenskodex richtet sich an Hochschulen, die mittels Learning Analytics die Qualität des Lernens und Lehrens verbessern wollen. Der Kodex kann als Vorlage zur Erstellung von organisationsspezifischen Verhaltenskodizes dienen. Er sollte an Hochschulen, die Learning Analytics einführen wollen, durch Konsultationen mit allen Interessengruppen überprüft und an die Ziele sowie die bestehende Praxis innerhalb der jeweiligen Hochschulen angepasst werden. Der Kodex wurde auf Grundlage einer Analyse bestehender europäischer Kodizes (Engelfriet, Manderveld & Jeunink, 2017; Westerlaken, Manderveld & Jorna, 2019; Sclater & Bailey, 2015; Open University UK, 2014; University of Edinburgh, 2018) und der in Deutschland geltenden Rechtsgrundlage vom Innovationsforum Trusted Learning Analytics des hessenweiten Projektes „Digital gestütztes Lehren und Lernen in Hessen“ entwickelt.
Suitable and reproducible experimental models of translational research in reconstructive surgery that allow in-vivo investigation of diverse molecular and cellular mechanisms are still limited. To this end we created a novel murine model of acute hindlimb ischemia-reperfusion to mimic a microsurgical free flap procedure. Thirty-six C57BL6 mice (n = 6/group) were assigned to one control and five experimental groups (subject to 6, 12, 96, 120 hours and 14 days of reperfusion, respectively) following 4 hours of complete hindlimb ischemia. Ischemia and reperfusion were monitored using Laser-Doppler Flowmetry. Hindlimb tissue components (skin and muscle) were investigated using histopathology, quantitative immunohistochemistry and immunofluorescence. Despite massive initial tissue damage induced by ischemia-reperfusion injury, the structure of the skin component was restored after 96 hours. During the same time, muscle cells were replaced by young myotubes. In addition, initial neuromuscular dysfunction, edema and swelling resolved by day 4. After two weeks, no functional or neuromuscular deficits were detectable. Furthermore, upregulation of VEGF and tissue infiltration with CD34-positive stem cells led to new capillary formation, which peaked with significantly higher values after two weeks. These data indicate that our model is suitable to investigate cellular and molecular tissue alterations from ischemia-reperfusion such as occur during free flap procedures.
Für die Pflanzenarten der Anhänge II und IV der FFH-Richtlinie wurde im Rahmen der FFH-Berichtspflicht Deutschlands an die EU-Kommission ein Monitoringsystem eingerichtet. Hierfür sind die Bundesländer verantwortlich. In Sachsen-Anhalt gibt es aktuell drei Vorkommen von Angelica palustris, eines von Apium repens, 107 von Cypripedium calceolus, 20 von Jurinea cyanoides, fünf von Liparis loeselii und fünf von Orthotrichum rogeri. Für alle Vorkommen dieser Arten wurden in den Jahren 2011/2012 Monitoringflächen eingerichtet (für Cypripedium calceolus nur an 10 Vorkommen, für Jurinea cyanoides an 18 Vorkommen). Diese Vorkommen wurden erfasst und bewertet. Für Coleanthus subtilis, Lindernia procumbens und Luronium natans konnten die in den zurückliegenden Jahren letztmalig bestätigten Vorkommen aktuell (2011/2012) nicht nachgewiesen werden. Aufgrund des natürlicherweise unsteten Auftretens dieser Arten wurden an den letzten bekannten Fundorten Monitoringflächen eingerichtet. Die drei Hauptkriterien des Monitorings: Zustand der Population, Habitatstruktur und Beeinträchtigungen sowie artspezifische Unterkriterien sind durch bundeseinheitliche Vorgaben festgelegt, ebenso die Häufigkeit der Erfassung dieser Kriterien während der jeweils sechsjährigen Berichtsperiode. Darüber hinaus sieht das Landesmonitoring teilweise eine detailliertere Untersuchungstiefe und -frequenz vor.
Partial cross sections of the 89Y(p, γ )90Zr reaction have been measured to investigate the γ-ray strength function in the neutron–magic nucleus 90Zr. For five proton energies between E p = 3.65 MeV and E p = 4.70 MeV partial cross sections for the population of seven discrete states in 90Zr have been determined by means of in-beam γ-ray spectroscopy. Since these γ-ray transitions are dominantly of E1 character, the present measurement allows an access to the low-lying dipole strength in 90Zr. A γ-ray strength function based on the experimental data could be extracted, which is used to describe the total and partial cross sections of this reaction by Hauser–Feshbach calculations successfully. Significant differences with respect to previously measured strength functions from photoabsorption data point towards deviations from the Brink–Axel hypothesis relating the photo-excitation and de-excitation strength functions.
Background: Dual-source dual-energy computed tomography (DECT) offers the potential for opportunistic osteoporosis screening by enabling phantomless bone mineral density (BMD) quantification. This study sought to assess the accuracy and precision of volumetric BMD measurement using dual-source DECT in comparison to quantitative CT (QCT). Methods: A validated spine phantom consisting of three lumbar vertebra equivalents with 50 (L1), 100 (L2), and 200 mg/cm3 (L3) calcium hydroxyapatite (HA) concentrations was scanned employing third-generation dual-source DECT and QCT. While BMD assessment based on QCT required an additional standardised bone density calibration phantom, the DECT technique operated by using a dedicated postprocessing software based on material decomposition without requiring calibration phantoms. Accuracy and precision of both modalities were compared by calculating measurement errors. In addition, correlation and agreement analyses were performed using Pearson correlation, linear regression, and Bland-Altman plots. Results: DECT-derived BMD values differed significantly from those obtained by QCT (p < 0.001) and were found to be closer to true HA concentrations. Relative measurement errors were significantly smaller for DECT in comparison to QCT (L1, 0.94% versus 9.68%; L2, 0.28% versus 5.74%; L3, 0.24% versus 3.67%, respectively). DECT demonstrated better BMD measurement repeatability compared to QCT (coefficient of variance < 4.29% for DECT, < 6.74% for QCT). Both methods correlated well to each other (r = 0.9993; 95% confidence interval 0.9984–0.9997; p < 0.001) and revealed substantial agreement in Bland-Altman plots. Conclusions: Phantomless dual-source DECT-based BMD assessment of lumbar vertebra equivalents using material decomposition showed higher diagnostic accuracy compared to QCT.
Background: Tuberous sclerosis complex (TSC), a multisystem genetic disorder, affects many organs and systems, characterized by benign growths. This German multicenter study estimated the disease-specific costs and cost-driving factors associated with various organ manifestations in TSC patients. Methods: A validated, three-month, retrospective questionnaire was administered to assess the sociodemographic and clinical characteristics, organ manifestations, direct, indirect, out-of-pocket, and nursing care-level costs, completed by caregivers of patients with TSC throughout Germany. Results: The caregivers of 184 patients (mean age 9.8 ± 5.3 years, range 0.7–21.8 years) submitted questionnaires. The reported TSC disease manifestations included epilepsy (92%), skin disorders (86%), structural brain disorders (83%), heart and circulatory system disorders (67%), kidney and urinary tract disorders (53%), and psychiatric disorders (51%). Genetic variations in TSC2 were reported in 46% of patients, whereas 14% were reported in TSC1. Mean total direct health care costs were EUR 4949 [95% confidence interval (95% CI) EUR 4088–5863, median EUR 2062] per patient over three months. Medication costs represented the largest direct cost category (54% of total direct costs, mean EUR 2658), with mechanistic target of rapamycin (mTOR) inhibitors representing the largest share (47%, EUR 2309). The cost of anti-seizure drugs (ASDs) accounted for a mean of only EUR 260 (5%). Inpatient costs (21%, EUR 1027) and ancillary therapy costs (8%, EUR 407) were also important direct cost components. The mean nursing care-level costs were EUR 1163 (95% CI EUR 1027–1314, median EUR 1635) over three months. Total indirect costs totaled a mean of EUR 2813 (95% CI EUR 2221–3394, median EUR 215) for mothers and EUR 372 (95% CI EUR 193–586, median EUR 0) for fathers. Multiple regression analyses revealed polytherapy with two or more ASDs and the use of mTOR inhibitors as independent cost-driving factors of total direct costs. Disability and psychiatric disease were independent cost-driving factors for total indirect costs as well as for nursing care-level costs. Conclusions: This study revealed substantial direct (including medication), nursing care-level, and indirect costs associated with TSC over three months, highlighting the spectrum of organ manifestations and their treatment needs in the German healthcare setting.
The huge neutron fluxes offer the possibility to use research reactors to produce isotopes of interest, which can be investigated afterwards. An example is the half-lives of long-lived isotopes like 129I. A direct usage of reactor neutrons in the astrophysical energy regime is only possible, if the corresponding ions are not at rest in the laboratory frame. The combination of an ion storage ring with a reactor and a neutron guide could open the path to direct measurements of neutron-induced cross sections on short-lived radioactive isotopes in the astrophysically interesting energy regime.