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Fraence Hardtstock, 1,* Urbano Sbarigia, 2,* Zeki Kocaata, 1 Thomas Wilke, 1 Shirley V Sylvester 3 1Ingress-Health HWM GmbH, Wismar 23966, Germany; 2Janssen Pharmaceutica, Beerse 2340, Belgium; 3Janssen Pharmaceuticals, Titusville, NJ 8560, USA*These authors contributed equally to this workCorrespondence: Fraence HardtstockIngress-Health HWM GmbH, Alter Holzhafen 19, Wismar 23966, GermanyTel +49-3841-758-1024Fax +49-3841-7581011Email fraence.hardtstock@ingress-health.comBackground: Current antiviral therapies for chronic hepatitis B (CHB) rarely achieve functional cure, thus often requiring lifelong therapy. A therapy achieving functional cure in a significant percentage of patients could change the treatment landscape substantially. However, the acceptability of functional cure by patients is unknown, especially if associated with additional treatment burden.Methods: A Discrete Choice Experiment (DCE) including patients with CHB was performed between 2018 and 2019 in Germany. Patient inclusion criteria were confirmed CHB; age of at least 18 years; no history of hepatocellular carcinoma; no HIV or HCV/HDV co-infection. The final DCE included the following attributes: route of administration (oral administration by tablets; subcutaneous injection + tablets; intramuscular electroporation + tablets), side effect frequency (0/1/3 days per month), functional cure (1%/30%/50% of patients), frequency of physician visits (monthly, half-yearly) and travel time to treating physician (15/45 min).Results: The main analysis sample consisted of 108 patients with CHB (mean age: 49.1 years, female: 37.0%, average time since CHB diagnosis: 14.0 years, 52.8% with Hepatitis B surface antigen (HBsAg) chronic HBV infection). High efficacy was found to be the main driver of decisions for/against the presented treatment options (impacted 57% of patients’ decisions), followed by therapy regimen (17%), safety profile (12%) and number of physician visits (11%). Latent class analysis revealed first insights into different decision patterns, with age, gender and previous side-effect experience affecting patients’ decisions.Conclusion: In comparison to all other treatment-related attributes such as therapy regimen or safety profile, patients with CHB showed a strong preference towards a scenario where a substantial number of patients benefit from sustained disease remission, which mimics functional cure.Keywords: hepatitis B, antiviral therapies, sustained virologic response, functional cure, discrete choice experiment, patient preferences

Sabrina Müller, 1 Tjalf Ziemssen, 2 Curt Diehm, 3 Tobias Duncker, 4 Philipp Hoffmanns, 5 Inga-Marion Thate-Waschke, 6 Markus Schürks, 6 Thomas Wilke 7 1Ingress-Health, Wismar 23966, Germany; 2Zentrum für klinische Neurowissenschaften, Klinik und Poliklinik für Neurologie, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Dresden 01307, Germany; 3Private Practice, Ettlingen 76275, Germany; 4Institut für Augenheilkunde Halle, Halle 06114, Germany; 5Private Practice, Rheinstetten 76287, Germany; 6Bayer Vital GmbH, Leverkusen 51368, Germany; 7Institut für Pharmakoökonomie und Arzneimittelogistik, Wismar 23966, GermanyCorrespondence: Sabrina MüllerIngress-Health, Alter Holzhafen 19, Wismar 23966, GermanyEmail sabrina.mueller@ingress-health.comIntroduction: The aim of this study was to examine physicians’ preferences regarding adherence-promoting programs (APPs), and to investigate which APP characteristics influence the willingness of physicians to implement these in daily practice.Materials and Methods: A discrete choice experiment was conducted among general practitioners, cardiologists, neurologists and ophthalmologists in Germany. The design considered five attributes with two or three attribute levels each: validation status of the APP; possibility for physicians to receive acertificate; type of intervention; time commitment per patient and quarter oftheyear to carry out the APP; reimbursement for APP participation, per included patient and quarter oftheyear.A multinomial logit model was run to estimate physicians’ utility for each attribute and to evaluate the influence of different levels on the probability of choosing a specific APP. The relative importance of the attributes was compared between different pre-defined subgroups.Results: In total, 222 physicians were included in the analysis. The most important characteristics of APPs were time commitment to carry out the program (34.8% importance), reimbursement (33.3%), and validation status of the program (23.7%). The remaining attributes (type of intervention: 3.6%; possibility to receive a certificate: 4.7%) were proven to be less important for a physician’s decision to participate in an APP. Physicians on average preferred APP alternatives characterized by little time commitment (β=1.456, p< 0.001), high reimbursement for work (β=1.392, p< 0.001), “positive validation status” (β=0.990, p< 0.001), the “possibility to get a certificate” (β=0.197, p< 0.001), and the provision of “tools for both physicians and patients” (β=0.150, p< 0.001).Conclusion: For the majority of the physicians participating in this survey, the willingness to implement an APP is determined by the associated time commitment and reimbursement. Considering physicians’ preferences regarding different APP features in the promoting process of these programs may enhance physicians’ participation and engagement.Keywords: adherence promoting programs, adherence interventions, compliance programs, discrete choice experiment

Background: According to current guidelines, an appropriate drug treatment is the backbone for an effective management of cardiovascular (CV) comorbidities in patients with type 2 diabetes mellitus (T2DM). Question and objective:The main objective of this study was to assess the degree of real-world [zum vollständigen Text gelangen Sie über die oben angegebene URL]

Thomas Wilke,1 Nils Picker,2 Sabrina Mueller,2 Silke Geier,3 Johannes Foersch,4 Jens Aberle,5 Stephan Martin,6 Matthias Riedl,7 Maximilian Gabler31IPAM, University of Wismar 23966 Wismar, Germany; 2Real-World Evidence and Health Economics, Ingress-Health HWM GmbH, Wismar 23966, Germany; 3HP Country Commercial - Market Access, Boehringer Ingelheim Pharma GmbH & Co. Kg, Ingelheim Am Rhein 55216, Germany; 4HP Country Medical Affairs, Boehringer Ingelheim Pharma GmbH & Co. Kg, Ingelheim Am Rhein 55216, Germany; 5Department of Internal Medicine III, Universitätsklinikum Hamburg-Eppendorf (UKE), Hamburg 20246, Germany; 6German Diabetes Center, Leibniz Institute at Heinrich Heine University, Düsseldorf 40591, Germany; 7Center for Diabetology, Internal and Nutritional Medicine, Medicum Hamburg MVZ GmbH, Hamburg 20097, GermanyBackground: A substantial share of type 2 diabetes mellitus (T2DM) patients receive insulin. However, little is known about the real-world treatment patterns around insulin initiation.Methods: This was a retrospective claims data analysis. T2DM patients who initiated an insulin therapy between 01/01/2013 and 31/12/2015 were identified in the German AOK PLUS dataset. For validation of results, additional data on a similar T2DM patient population were collected in a Germany-wide medical chart review.Results: A total of 284,878 T2DM patients were identified. Of these, 27,340 (9.6%) initiated an insulin treatment during the inclusion period (mean age: 72.2 years; 51.4% female). Mean/median weight and BMI of patients with available clinical data was 85.8/84.0 kg (SD:18.9) and 30.6/29.8 kg/m2, (SD:6.1), respectively at baseline. Mean/median HbA1c-value at baseline was 8.4/8.0% (SD: 1.8). Most commonly prescribed antidiabetic drugs (AD) within 6 months before insulin initiation were metformin (MET; 54.0%), DPP-4 inhibitors (DPP-4i; 37.6%), and sulfonylureas (SU; 29.5%). As high as 23.2% of the patients did not receive any AD prescription within 6 months before insulin initiation. A total of 10,953 of above 27,340 insulin starters (40.1%) initiated their insulin therapy without concomitant ADs (insulin monotherapy); 43% of these patients did not receive any AD before insulin initiation. Of the remaining 16,387 patients (59.9%), 4070 patients (14.9%) received MET only as concomitant AD, 6385 (23.4%) received MET plus at least one further AD, and 5932 (21.7%) received at least one further AD excluding MET. Throughout the first year of treatment, prescribed insulin dosage increased over time, resulting in approximately 43.3–77.9 IUs per observed patient day after 12 months of insulin treatment.Conclusions: Characteristics of German T2DM patients initiating insulin deviate substantially from the average German population, especially in terms of weight. We identified an unexpectedly high number of patients without previous AD therapy receiving insulin monotherapy, which is not in line with the clinical guidelines.Keywords: T2DM, antidiabetic treatment, claims data, chart review

Thomas Wilke,1 Sabrina Mueller,2 Sabine Bauer,2 Silvia Pitura,3 Leona Probst,3 Boris A Ratsch,3 Hans Salwender4 1Institut für Pharmakoökonomie und Arzneimittellogistik (IPAM), 23966 Wismar, Germany; 2Ingress-Health, 23966 Wismar, Germany; 3Takeda Pharma Vertrieb GmbH & Co. KG, 10117 Berlin, Germany; 4Asklepios Kliniken Hamburg GmbH, 22763 Hamburg, Germany Background and objectives: This study describes preferences of German relapsed refractory multiple myeloma (RRMM) patients with novel proteasome inhibitor-based combination treatments.Methods: Patients with a minimum age of 18 years and a diagnosis of RRMM were included. Their preferences were assessed using a discrete choice experiment design, which was developed based on a literature review and two patient focus group discussions. The final discrete choice experiment design consisted of four attributes, namely “therapy application regimen,” “time without progression of disease,” “possibility of grade ≥3 adverse events (AEs) affecting the blood,” and “possibility of grade ≥3 AE heart failure.”Results: Analysis was based on 84 patients (36.9% females, mean age 62.7 years, mean multiple myeloma disease duration 5.5 years). Among the tested attributes, “therapy application regimen” was assigned the highest importance for treatment decisions (38.8%), the second important attribute was “time without progression of disease” (38.7%), followed by “possibility of AE heart failure” (13.9%) and “possibility of AEs affecting the blood” (8.6%). Patients preferred oral intake once a day and once a week over other application modes such as oral intake once a day and once a week plus twice-weekly infusions. Furthermore, they preferred longer disease progression-free time and lower risk of grade ≥3 AEs. The highest overall utility was derived for ixazomib + lenalidomide + dexamethasone (utility: 3.218), compared with lenalidomide + dexamethasone (2.769), and carfilzomib + lenalidomide + dexamethasone (1.928).Conclusion: RRMM patients prefer treatments with an all-oral application, a longer disease-progression-free time, and a lower probability of AEs. If patients face tradeoffs, they accept a lower progression-free time and/or higher AE rates to get an all-oral therapy. Keywords: MM patient’s treatment preferences, relapsed refractory multiple myeloma, RRMM, discrete choice experiment, DCE

Background: Osteoporosis (OP) and its associated fractures have a significant impact on patients��� quality of life and are impacting their morbidity and mortality. For OP patients at high risk of fracture, guidelines recommend a pharmacological OP treatment. The aim of this study was to describe the real-world medication treatment of postmenopausal women with severe OP at high risk of fracture, their risk to experience a new fracture after having at least one previous fracture, and to assess the associated healthcare resource use (HCRU). Methods: This retrospective cohort study was based on anonymized German claims data (AOK PLUS). All included OP patients were female, ���55 years old, and had a vertebral and/or femoral fracture. We conducted a cross-sectional analysis in 2018 and a longitudinal analysis, starting with an incident vertebral/femoral fracture (after or simultaneously with the first observed OP diagnosis). In both analyses, patient characteristics, rate of new incident fractures, OP treatment patterns, and HCRU associated with the treatment of patients were investigated. Results: In the cross-sectional setting, 12,180 patients with a mean age of 83.59 years were observed. Of these patients, 14.30% sustained at least one new incident fracture and 34.54% received a pharmaceutical OP treatment during 2018. In this year, 58.50% of the patients had at least one OP-related outpatient visit, and 26.35% had a fracture-related visit. In 160 patients (1.31%), at least one OP-related hospitalization was documented, and in 1,293 patients (10.62%) a fracture-related hospitalization in 2018. In the longitudinal setting, 10,323 patients with a mean age of 83.22 years were included. Of these, 18.96% experienced at least one new incident fracture within the first 12 months after the index fracture, and in total 30.85% in the entire follow-up period (mean 2.03 years). During the 12-month baseline period, 22.12% of the patients received an OP treatment. Three months after the index fracture, the proportion of treated patients remained at 22.30%. During the total follow-up time, 35.54% were prescribed with an OP treatment. Conclusion: We observed a considerable proportion of untreated patients and a high rate of subsequent fractures. The awareness for a proper risk assessment and the appropriate use of available treatments should be increased., Hintergrund: Osteoporose (OP) und die damit verbundenen Frakturen haben einen signifikanten Einfluss auf die Lebensqualit��t von OP-Patienten und beeinflussen ebenso deren Morbidit��t und Mortalit��t. Leitlinien empfehlen f��r OP-Patienten mit hohem Frakturrisiko eine spezifische medikament��se Therapie. Das Ziel dieser Studie war es, die Behandlungspraxis und das Risiko erneuter Frakturen von postmenopausalen Frauen mit manifester OP mit deutlich erh��htem Frakturrisiko zu beschreiben sowie die damit verbundenen Ressourcenverbr��uche zu ermitteln. Methoden: Diese retrospektive Kohortenstudie basierte auf anonymen Krankenkassendaten (AOK PLUS). S��mtliche eingeschlossenen OP-Patienten waren weiblich, ���55 Jahre alt und erlitten bereits eine vertebrale oder femorale Fraktur. In der Studie wurden zwei verschiedene Analysen durchgef��hrt: eine Querschnittsanalyse f��r das Jahr 2018 und eine L��ngsschnittanalyse beginnend mit der Indexfraktur (nach erster beobachteter OP-Diagnose in 2015���2017). In beiden Analysen wurden die Patientencharakteristika, die Rate neuer Frakturen, die medikament��se OP-Behandlung sowie die assoziierten Ressourcenverbr��uche untersucht. Ergebnisse: In der Querschnittsanalyse wurden 12.180 Patientinnen mit einem durchschnittlichen Alter von 83,59 Jahren beobachtet. Von diesen Patientinnen erlitten in 2018 14,30% mindestens eine neue Fraktur und 34,54% erhielten eine medikament��se OP-Behandlung. Im Beobachtungszeitraum besuchten 58,50% OP-bezogen einen ambulanten Arzt, 26,35% der Arztbesuche waren frakturbezogen. 160 (1,31%) bzw. 1.293 Patientinnen (10,62%) hatten 2018 einen station��ren Aufenthalt mit OP- oder Fraktur-Bezug (prim��re Diagnose). In die L��ngsschnittanalyse wurden 10.323 Patientinnen mit einem Durchschnittsalter von 83,22 Jahren eingeschlossen. Innerhalb der ersten 12 Monate nach der Indexfraktur erlitten 18,96% mindestens eine weitere neue Fraktur, im gesamten Beobachtungszeitraum (Mittelwert 2,03 Jahre) 30,85%. In den 12 Monaten vor der Indexfraktur erhielten 22,12% der Patientinnen eine medikament��se OP-Behandlung; 3 Monate nach dem Index lag der Anteil der Behandelten fast unver��ndert bei 22,30%. W��hrend des gesamten Beobachtungszeitraums erhielten insgesamt 35,54% der Patientinnen OP-Medikamente. Schlussfolgerung: In der Studie wurden ein betr��chtlicher Anteil unbehandelter Patientinnen und eine hohe Rate an Folgefrakturen beobachtet. Das Bewusstsein f��r eine leitliniengerechte Risikobewertung und den zweckm����igen Einsatz der verf��gbaren Behandlungsoptionen sollte verbessert werden.

Mediterranean mid-altitude sites are critical for the survival of plant species allowing for elevational vegetation shifts in response to high-amplitude climate variability. Pollen records from the southern Balkans have underlined the importance of the region in preserving plant diversity over at least the last half a million years. So far, there are no records of vegetation and climate dynamics from Balkan refugia with an Early Pleistocene age. Here we present a unique palynological archive from such a refugium, the Lake Ohrid basin, recording continuously floristic diversity and vegetation succession under obliquity-paced climate oscillations. Palynological data are complemented by biomarker, diatom, carbonate isotope and sedimentological data to identify the mechanisms controlling shifts in the aquatic and terrestrial ecosystems within the lake and its catchment. The study interval encompasses four complete glacial-interglacial cycles (1365–1165 ka; MIS 43–35). Within the first 100 kyr of lake ontogeny, lake size and depth increase before the lake system enters a new equilibrium state as observed in a distinct shift in biotic communities and sediment composition. Several relict tree genera such as Cedrus, Tsuga, Carya, and Pterocarya played an important role in ecological succession cycles, while total relict abundance accounts for up to half of the total arboreal vegetation. The most prominent biome during interglacials is cool mixed evergreen needleleaf and deciduous broadleaf forests, while cool evergreen needleleaf forests dominate within glacials. A rather forested landscape with a remarkable plant diversity provide unique insights into Early Pleistocene ecosystem resilience and vegetation dynamics. © 2019

Sabrina Müller,1 Thomas Wilke,1 Andreas Fuchs,2 Ulf Maywald,2 Jan-Paul Flacke,3 Harald Heinisch,4 Klaus Krüger5 1Institute for Pharmacoeconomics and Medication Logistics, University of Wismar, Wismar, 2AOK PLUS, Dresden, 3Roche Pharma AG, Grenzach-Wyhlen, 4Chugai Pharma Europe Ltd, Frankfurt/M, 5Praxiszentrum St Bonifatius, Munich, Germany Objective: This study aimed to assess the level of nonpersistence (NP) and nonadherence (NA) to methotrexate (MTX) therapy in German patients with rheumatoid arthritis (RA). Materials and methods: Based on German claims data, RA patients who received a MTX therapy (subgroup: treatment-naive patients) were analyzed. NP was defined as treatment gap >12weeks. Regarding NA, it is the overall medication possession ratio (MPR) during an observational period of 12 or 24months after therapy, and the MPR is calculated only for the periods of therapy continuation; NA was defined as MPR

Mediterranean climates are characterized by strong seasonal contrasts between dry summers and wet winters. Changes in winter rainfall are critical for regional socioeconomic development, but are difficult to simulate accurately1 and reconstruct on Quaternary timescales. This is partly because regional hydroclimate records that cover multiple glacial–interglacial cycles2,3 with different orbital geometries, global ice volume and atmospheric greenhouse gas concentrations are scarce. Moreover, the underlying mechanisms of change and their persistence remain unexplored. Here we show that, over the past 1.36 million years, wet winters in the northcentral Mediterranean tend to occur with high contrasts in local, seasonal insolation and a vigorous African summer monsoon. Our proxy time series from Lake Ohrid on the Balkan Peninsula, together with a 784,000-year transient climate model hindcast, suggest that increased sea surface temperatures amplify local cyclone development and refuel North Atlantic low-pressure systems that enter the Mediterranean during phases of low continental ice volume and high concentrations of atmospheric greenhouse gases. A comparison with modern reanalysis data shows that current drivers of the amount of rainfall in the Mediterranean share some similarities to those that drive the reconstructed increases in precipitation. Our data cover multiple insolation maxima and are therefore an important benchmark for testing climate model performance. © 2019, The Author(s), under exclusive licence to Springer Nature Limited.

The Caspian Sea has been a highly dynamic environment throughout the Quaternary and witnessed major oscillations in lake level, which were associated with changes in salinity and habitat availability. Such environmental pressures are considered to drive strong phylogeographic structures in species by forcing populations into suitable refugia. However, little is actually known on the effect of lake-level fluctuations in the Caspian Sea on its aquatic biota. We compared the phylogeographic patterns of the aquatic Neritidae snail genus Theodoxus across the Pontocaspian region with refugial populations in southern Iran. Three gene fragments were used to determine relationships and divergence times between the sampled populations in both groups. A dated phylogeny and statistical haplotype networks were generated in conjunction with the analyses of molecular variance and calculations of isolation by distance using distance-based redundancy analyses. Extended Bayesian skyline plots were constructed to assess demographic history. Compared with the southern Iranian populations, we found little phylogeographic structure for the Pontocaspian Theodoxus group, with more recent diversification, homogeneity of haplotypes across the Pontocaspian region and a relatively stable demographic history since the Middle Pleistocene. Our results argue against a strong influence of Caspian Sea low stands on the population structure post the early Pleistocene, whereas high stands may have increased the dispersal possibilities and homogenization of haplotypes across the Pontocaspian region during this time. However, during the early Pleistocene, a more dramatic low stand in the Caspian Sea, around a million years ago, may have caused the reduction in Theodoxus diversity to a single lineage in the region. In addition, our results provide new insights into Theodoxus taxonomy and outlooks for regional conservation.

Wilke T, Picker N, Mueller S, et al. Diabetes Metab SyndrObes. 2019;12:1225–1237.On page 1225, affiliation 6 for Professor Stephan Martinwas listed as German Diabetes Center, Leibniz Institute atHeinrich Heine University, Düsseldorf 40591, Germanyhowever it should have been Verbund der KatholischenKliniken Düsseldorf, Westdeutsches Diabetes- undGesundheitszentrum, 40591 Düsseldorf, Germany.Following a review of our data post-publication, we foundthe incorrect affiliation 6 being cited in the publishedpaper. This correction has no impact on the findings ofthe study. The authors apologize for this oversight.Read the original article

This study reviews and synthesises existing information generated within the SCOPSCO (Scientific Collaboration on Past Speciation Conditions in Lake Ohrid) deep drilling project. The four main aims of the project are to infer (i) the age and origin of Lake Ohrid (Former Yugoslav Republic of Macedonia/Republic of Albania), (ii) its regional seismotectonic history, (iii) volcanic activity and climate change in the central northern Mediterranean region, and (iv) the influence of major geological events on the evolution of its endemic species. The Ohrid basin formed by transtension during the Miocene, opened during the Pliocene and Pleistocene, and the lake established de novo in the still relatively narrow valley between 1.9 and 1.3 Ma. The lake history is recorded in a 584 m long sediment sequence, which was recovered within the framework of the International Continental Scientific Drilling Program (ICDP) from the central part (DEEP site) of the lake in spring 2013. To date, 54 tephra and cryptotephra horizons have been found in the upper 460 m of this sequence. Tephrochronology and tuning biogeochemical proxy data to orbital parameters revealed that the upper 247.8 m represent the last 637 kyr. The multi-proxy data set covering these 637 kyr indicates long-term variability. Some proxies show a change from generally cooler and wetter to drier and warmer glacial and interglacial periods around 300 ka. Short-term environmental change caused, for example, by tephra deposition or the climatic impact of millennial-scale Dansgaard-Oeschger and Heinrich events are superimposed on the long-term trends. Evolutionary studies on the extant fauna indicate that Lake Ohrid was not a refugial area for regional freshwater animals. This differs from the surrounding catchment, where the mountainous setting with relatively high water availability provided a refuge for temperate and montane trees during the relatively cold and dry glacial periods. Although Lake Ohrid experienced significant environmental change over the last 637 kyr, preliminary molecular data from extant microgastropod species do not indicate significant changes in diversification rate during this period. The reasons for this constant rate remain largely unknown, but a possible lack of environmentally induced extinction events in Lake Ohrid and/or the high resilience of the ecosystems may have played a role. © Author(s) 2017.

No abstract available.

The Scientific Collaboration on Past Speciation Conditions in Lake Ohrid (SCOPSCO) project is an international research initiative to study the influence of major geological and environmental events on the biological evolution of lake taxa. SCOPSCO drilling campaigns were carried out in 2011 and 2013. In 2011 we used gravity and piston coring at one of the five proposed drill sites, and in 2013 we undertook deep drilling with the Deep Lake Drilling System (DLDS) of Drilling, Observation and Sampling of the Earth's Continental Crust (DOSECC). In April and May 2013, a total of 2100 m sediments were recovered from four drill sites with water depths ranging from 125 to 260 m. The maximum drill depth was 569 m below the lake floor in the centre of the lake. By retrieving overlapping sediment sequences, 95% of the sediment succession was recovered. Initial data from borehole logging, core logging and geochemical measurements indicate that the sediment succession covers >1.2 million years (Ma) in a quasi-continuous sequence. These early findings suggest that the record from Lake Ohrid will substantially improve the knowledge of long-term environmental change and short-term geological events in the northeastern Mediterranean region, which forms the basis for improving understanding of the influence of major geological and environmental events on the biological evolution of endemic species.

Interferon-γ (IFN-γ) is an important cytokine involved in the regulation of allergen-induced immune responses. We examined the role of IFN-γ in a Brown–Norway rat model of bronchial hyperresponsiveness (BHR) and airway eosinophilia, and its effects on the mRNA expression of T helper type 1 (Th1)/Th2 cytokine. Ovalbumin (OA)-sensitized animals were given either exogenous IFN-γ (105 U/rat over 3 days, intraperitoneally) or anti-IFN-γ blocking antibody (DB-1 0·3 mg/rat, intravenously) prior to exposure to OA aerosol and were studied 18–24 hr later. In sensitized animals, OA induced significant BHR, accumulation of eosinophils, T lymphocytes and neutrophils in bronchoalveolar lavage (BAL) fluid, and also increased eosinophils and CD8+ T cells in the airways. Exogenous IFN-γ attenuated allergen-induced BHR (P

We show that almost all n-bit Boolean functions have bounded-error quantum query complexity at least n/2, up to lower-order terms. This improves over an earlier n/4 lower bound of Ambainis, and shows that van Dam's oracle interrogation is essentially optimal for almost all functions. Our proof uses the fact that the acceptance probability of a T-query algorithm can be written as the sum of squares of degree-T polynomials., 8 pages LaTeX

We use the venerable "fooling set" method to prove new lower bounds on the quantum communication complexity of various functions. Let f:X x Y-->{0,1} be a Boolean function, fool^1(f) its maximal fooling set size among 1-inputs, Q_1^*(f) its one-sided error quantum communication complexity with prior entanglement, and NQ(f) its nondeterministic quantum communication complexity (without prior entanglement; this model is trivial with shared randomness or entanglement). Our main results are the following, where logs are to base 2: * If the maximal fooling set is "upper triangular" (which is for instance the case for the equality, disjointness, and greater-than functions), then we have Q_1^*(f)>=(1/2)log fool^1(f) - 1/2, which is essentially optimal by superdense coding. No super-constant lower bound for equality seems to follow from earlier techniques. * For all f we have Q_1^*(f)>=(1/4)log fool^1(f) - 1/2, which is optimal up to a factor of 2. * NQ(f)>=log \fool^1(f)/2 + 1. We do not know if the factor 1/2 is needed in this result, but it cannot be replaced by 1: we give an example where NQ(f)~0.613 log fool^1(f)., 10 pages LaTeX. Version: corrected an error in Section 2, slightly weakening the result

Fragestellung: In Deutschland gilt die altersbedingte Makuladegeneration (AMD) mit etwa 50% als häufigste Ursache für schwere Sehbehinderungen. Die Therapiemöglichkeiten sind in den letzten Jahren vor allem durch die Anti-VEGF-Therapie gravierend verbessert worden. Die leitlinienkonforme[for full text, please go to the a.m. URL], 26. Internationaler Kongress der Deutschen Ophthalmochirurgen

Transparent polyethylene films can now be produced with antimicrobial and electrically conductive properties as well. This can be achieved by combining several films with the relevant property profiles. The surface conductivity of the films can also be increased by using a suitable new coating technique. The article describes the newly developed special compounds required for this and demonstrates their industrial feasibility.

Background: In Germany neovascular AMD is the leading cause for severe visual impairment. In 2/3 of patients visual acuity can be maintained by intravitreal injection of VEGF inhibitors. Based on clinical studies at least 7–8 injections are required in the first year. The PONS study is evaluating[for full text, please go to the a.m. URL], 26. Jahrestagung der Retinologischen Gesellschaft

We study a motion planning problem where items have to be transported from the top room of a tower to the bottom of the tower, while simultaneously other items have to be transported in the opposite direction. Item sets are moved in two baskets hanging on a rope and pulley. To guarantee stability of the system, the weight difference between the contents of the two baskets must always stay below a given threshold. We prove that it is $¿^p_2$ -complete to decide whether some given initial situation of the underlying discrete system can lead to a given goal situation. Furthermore we identify several polynomially solvable special cases of this reachability problem, and we also settle the computational complexity of a number of related questions. Keywords: Planning and scheduling; Computational complexity; Polynomial hierarchy

Report within SAFEGUARD work package 3.1, Final Version 2012-08-17

In the (non-preemptive) Generalized Min Sum Set Cover Problem, we are given $$n$$ ground elements and a collection of sets $$\mathcal{S }= \{S_1, S_2, \ldots , S_m\}$$ where each set $$S_i \in 2^{[n]}$$ has a positive requirement $$\kappa (S_i)$$ that has to be fulfilled. We would like to order all elements to minimize the total (weighted) cover time of all sets. The cover time of a set $$S_i$$ is defined as the first index $$j$$ in the ordering such that the first $$j$$ elements in the ordering contain $$\kappa (S_i)$$ elements in $$S_i$$ . This problem was introduced by Azar et al. (2009) with interesting motivations in web page ranking and broadcast scheduling. For this problem, constant approximations are known by Bansal et al. (2010) and Skutella and Williamson (Oper Res Lett 39(6):433---436, 2011). We study the version where preemption is allowed. The difference is that elements can be fractionally scheduled and a set $$S$$ is covered in the moment when $$\kappa (S)$$ amount of elements in $$S$$ are scheduled. We give a 2-approximation for this preemptive problem. Our linear programming relaxation and analysis are completely different from the aforementioned previous works. We also show that any preemptive solution can be transformed into a non-preemptive one by losing a factor of 6.2 in the objective function. As a byproduct, we obtain an improved $$12.4$$ -approximation for the non-preemptive problem.

European food safety legislation allows for a new type of meat inspection in swine. This ‘risk-based meat inspection without incision’ or ‘supply chain meat inspection’ (SCMI) uses food chain information to derive a veterinary prognosis on the pigs’ health prior to delivery to the slaughterhouse and allows for visual inspection of pig carcasses. Slaughter companies who want to implement SCMI must develop their risk-based system and have it approved by the competent authority. In the Dutch-German border region, slaughter companies implementing SCMI and suppliers delivering pigs in such a system have to consider the prerequisites of a number of competent authorities. In turn competent authorities have to cope with the special conditions and requirements of a cross border economic region. Within the INTERREG-IV-A project SAFEGUARD issues were addressed that arise from the conduct of SCMI in a cross border context. The main objective was to elaborate an up-to-date comparison between Germany and the Netherlands. We used an iterative approach of collecting information from project partners, external experts and scientific literature and providing feedback to the project group during a number of meetings and workshops. We discovered, among others, important differences in ‘involvement of private parties’, ‘data exchange and communication’ and ‘use of epidemiological data’. We conclude that the existence of SCMI systems using different ‘epidemiological data’ from the holding is a barrier to inter-company acceptance of finishing pigs for slaughter. Further, current systems of data exchange fail to give a complete picture of a farm’s health if farms switch deliveries between slaughterhouses. We suggest, that data exchange of food chain information and meat inspection results should be reorganized and harmonized. Further research is needed to assess economic consequences of these issues.

This study reviews and synthesises existing information generated within the SCOPSCO (Scientific Collaboration on Past Speciation Conditions in Lake Ohrid) deep drilling project. The four main aims of the project are to infer (i) the age and origin of Lake Ohrid (Former Yugoslav Republic of Macedonia/Republic of Albania), (ii) its regional seismotectonic history, (iii) volcanic activity and climate change in the central northern Mediterranean region, and (iv) the influence of major geological events on the evolution of its endemic species. The Ohrid basin formed by transtension during the Miocene, opened during the Pliocene and Pleistocene, and the lake established de novo in the still relatively narrow valley between 1.9 and 1.3 Ma. The lake history is recorded in a 584 m long sediment sequence, which was recovered within the framework of the International Continental Scientific Drilling Program (ICDP) from the central part (DEEP site) of the lake in spring 2013. To date, 54 tephra and cryptotephra horizons have been found in the upper 460 m of this sequence. Tephrochronology and tuning biogeochemical proxy data to orbital parameters revealed that the upper 247.8 m represent the last 637 kyr. The multi-proxy data set covering these 637 kyr indicates long-term variability. Some proxies show a change from generally cooler and wetter to drier and warmer glacial and interglacial periods around 300 ka. Short-term environmental change caused, for example, by tephra deposition or the climatic impact of millennial-scale Dansgaard–Oeschger and Heinrich events are superimposed on the long-term trends. Evolutionary studies on the extant fauna indicate that Lake Ohrid was not a refugial area for regional freshwater animals. This differs from the surrounding catchment, where the mountainous setting with relatively high water availability provided a refuge for temperate and montane trees during the relatively cold and dry glacial periods. Although Lake Ohrid experienced significant environmental change over the last 637 kyr, preliminary molecular data from extant microgastropod species do not indicate significant changes in diversification rate during this period. The reasons for this constant rate remain largely unknown, but a possible lack of environmentally induced extinction events in Lake Ohrid and/or the high resilience of the ecosystems may have played a role.

Freshwater and brackish water ecosystems are arguably the most vulnerable ecosystems on earth, due to concentrated human developments in and around them. The Pontocaspian (PC) region located at the border of Europe and Asia contains a variety of brackish water ecosystems and unique inhabitants, known as the PC biota. The current status and trends in PC biodiversity are poorly known, however, deterioration of PC habitats is evident in the Black Sea and Caspian Sea Basins. This thesis aims to support an establishment of effective PC biodiversity conservation regime. I use the Black Sea Basin as a study system and outline current status and trends in PC biodiversity and assess the direct and indirect anthropogenic drivers of the PC biodiversity change. I show that PC biodiversity is severely declining as a result of human action. Identified direct drivers of decline include damming of rivers; habitat modifications; pollution and eutrophication; invasive alien species and climate change. Indirect drivers of PC biodiversity decline include current suboptimal legal arrangements, inadequate institutional design of environmental stakeholder organizations and non-inclusive governance systems, as well as the limited funding availability for PC biodiversity conservation, institutional instability and low recognition of the need for PC biodiversity conservation.

Introduction Clinical guidelines recommend anticoagulation therapy for the treatment of cancer-associated venous thromboembolism (VTE), but little is known about preferences. Therefore, the objective of this discrete choice experiment (DCE) was to elucidate patient preferences regarding anticoagulation convenience attributes. Methods Adult patients with cancer-associated VTE who switched to direct oral anticoagulants were included in a single-arm study (COSIMO). Patients were asked to decide between hypothetical treatment options based on a combination of the following attributes: route of administration (injection/tablet), frequency of intake (once/twice daily), need for regular controls of the international normalized ratio (INR) at least every 3 to 4 weeks (yes/no), interactions with food/alcohol (yes/no), and distance to treating physician (1 vs. 20 km) as an additional neutral attribute. DCE data were collected by structured telephone interviews and analyzed based on a conditional logit regression. Results Overall, 163 patients (mean age 63.7 years, 49.1% female) were included. They strongly preferred oral administration compared with self-injections (importance of this attribute for overall treatment decisions: 73.8%), and a treatment without dietary restrictions (11.8%). Even if these attributes were less important (7.2% and 6.5%, respectively), patients indicated a preference for a shorter distance to the treating physician and once-daily dosing compared with twice-daily intake. “Need for regular controls of INR at least every 3 to 4 weeks” showed no significant impact on the treatment decision (0.7%). Conclusion This study showed that treatment-related decision making in cancer-associated VTE, assuming comparable effectiveness and safety of anticoagulant treatments, is predominantly driven by “route of administration,” with patients strongly preferring oral administration.

Distance automata are automata weighted over the semiring (\mathbb{N} \cup \infty,\min,+) (the tropical semiring). Such automata compute functions from words to \mathbb{N} \cup \infty such as the number of occurrences of a given letter. It is known that testing f 0 and two functions f,g computed by distance automata, answers "yes" if f