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Background: This study aimed to describe the clinical and cost-effectiveness evidence supporting reimbursementdecisions of new cancer drugs and analyze the influence of trial characteristics and the cost per quality-adjusted lifeyears (QALYs) on the likelihood of reimbursement in Sweden.Patients and methods: Data were extracted from all appraisal dossiers for new cancer drugs seeking reimbursement inSweden and claiming added therapeutical value between the years 2010 and 2020. The data were analyzed usingdescriptive statistics, and logistic regression models were also used with the cost per QALY, study design,comparator, and evidence on final outcomes in the clinical trials as predictors of reimbursement.Results: All 60 included appraisals were based on trial evidence that assessed at least one final outcome (overallsurvival [OS] or quality of life [QoL]), although rarely as a primary outcome. Of the appraisals with a final decision(n ¼ 58), 79% were approved for reimbursement. Among the reimbursed drugs, only half had trial evidencedemonstrating improved OS or QoL. Only one drug had trial evidence supporting improvements in both OS andQoL. The average cost per QALY for reimbursed cancer drugs was estimated to be 748 560 SEK (V73 583). A highercost per QALY was found to decrease the likelihood of reimbursement by 9.4% for every 100 000 SEK (V9830)higher cost per QALY (P ¼ 0.03). For cost-effectiveness models without direct evidence of improvements in finaloutcomes, a larger QALY gain was observed compared with those with evidence mainly relying on intermediate andsurrogate outcomes.Conclusions: There are substantial uncertainties in the clinical and cost-effectiveness evidence underlyingreimbursement decisions of new cancer drugs. Decision makers should be cautious of the limited evidence onpatient-centered outcomes and the implications of allocating resources to expensive treatments with uncertainvalue for money.

In 2016, the Fingerprint Working Group (EFP-WG) of the European Network of Forensic Science Institutes (ENFSI), officially established an advisory group with the task of organising proficiency tests (PTs), as well as collaborative exercises (CEs) as a way of raising standards within the fingerprint profession. This article will provide an overview of the Visualisation collaborative exercise and the Comparison proficiency test, which were carried out in 2016. Both the exercise and the test were organised and co-funded by the Prevention of and Fight against Crime Programme of the European Union [1] , [2] , [3] , Direct Grant “Towards the Vision for European Forensic Science 2020 (TVEFS-2020)” HOME/2013/ISEC/MO/ENFSI/4000005962, work package T3 “Proficiency Tests and Collaborative Exercises for the Fingerprint Domain”. The characteristics of the testing programme are summarised, followed by an overview of the knowledge that has been gained, including lessons learnt.

Background: Accumulating data indicate that higher rifampicin doses may be more effective and shorten tuberculosis treatment duration. This study evaluated the safety, tolerability, pharmacokinetics, and 14-day early bactericidal activity (EBA) of increasing doses of rifampicin. Methods: We performed a dose-escalation study in treatment-naive adult smear-positive tuberculosis patients. Patients received, in consecutive cohorts, 40 or 50mg/kg rifampicin once daily in monotherapy (day 1-7), supplemented with standard doses of isoniazid, pyrazinamide and ethambutol between day 8-14. Safety, tolerability, pharmacokinetics, and EBA were assessed. Findings: In the 40mg/kg cohort (n=15), 13 patients experienced adverse events (AEs) during monotherapy (n=36), resulting in one treatment discontinuation in the combination phase. In the 50mg/kg group (n=17), all patients experienced AEs during monotherapy. There were more AEs in total (n=93) compared to 40mg/kg, and eleven patients withdrew or stopped study medication. AEs were mostly mild or moderate (≤grade 3) and tolerability related, i.e. gastrointestinal disorders, pruritis, hyperbilirubinemia and jaundice. A more than proportional increase in rifampicin exposure with dose was observed, in line with previous cohorts. EBA increased considerably with dose; with the highest seen in the 50mg/kg cohort. Interpretation: Our research concludes a journey that started in the 1960s. Rifampicin up to 40mg/kg was well tolerated. Although associated with an increased bactericidal effect, the tolerability of a 50mg/kg dose was poor. Rifampicin at 40mg/kg appears to be the optimal dose for evaluation in a phase IIB/C treatment shortening trial. Trial Registration: Here we report the results of the final cohorts of the PanACEA HIGHRIF1 trial (clinicaltrials.gov NCT01392911). Funding Statement: This publication was produced by PanACEA, which is part of the European and Developing Countries Clinical Trials Partnership (EDCTP) 1 programme [project code IP.2007.32011.012 (HIGHRIF)] and the EDCTP2 programme supported by the European Union (grant number TRIA2015-1102-PanACEA). Declaration of Interests: We declare no competing interests. Ethics Approval Statement: The study protocol was approved by the applicable ethical review boards and by the South African Health Products Regulatory Authority and was conducted according to international and South African Good Clinical Practice guidelines.

As early as 2004, the Fingerprint Working Group (EFP-WG) of the European Network of Forensic Science Institutes (ENFSI) has organised proficiency tests (PT’s), as well as collaborative exercises (CE’s), as a way of raising standards within the fingerprint profession. This article provides an overview of the three collaborative exercises carried out in 2015. The characteristics of the testing programme are summarised, followed by an overview of the knowledge that has been gained, including depicting what lessons have been learnt.

Anatolia and the Near East have long been recognized as the epicenter of the Neolithic expansion through archaeological evidence. Recent archaeogenetic studies on Neolithic European human remains have shown that the Neolithic expansion in Europe was driven westward and northward by migration from a supposed Near Eastern origin [1-5]. However, this expansion and the establishment of numerous culture complexes in the Aegean and Balkans did not occur until 8,500 before present (BP), over 2,000 years after the initial settlements in the Neolithic core area [6-9]. We present ancient genome-wide sequence data from 6,700-year-old human remains excavated from a Neolithic context in Kumtepe, located in northwestern Anatolia near the well-known (and younger) site Troy [10]. Kumtepe is one of the settlements that emerged around 7,000 BP, after the initial expansion wave brought Neolithic practices to Europe. We show that this individual displays genetic similarities to the early European Neolithic gene pool and modern-day Sardinians, as well as a genetic affinity to modern-day populations from the Near East and the Caucasus. Furthermore, modern-day Anatolians carry signatures of several admixture events from different populations that have diluted this early Neolithic farmer component, explaining why modern-day Sardinian populations, instead of modern-day Anatolian populations, are genetically more similar to the people that drove the Neolithic expansion into Europe. Anatolia's central geographic location appears to have served as a connecting point, allowing a complex contact network with other areas of the Near East and Europe throughout, and after, the Neolithic.

Nitrogen (N) deposition has important negative impacts on natural and semi-natural ecosystems, impacting on biotic interactions across trophic levels. Low-nutrient systems are particularly sensitive to changes in N inputs and are therefore more vulnerable to N deposition. Carnivorous plants are often part of these ecosystems partly because of the additional nutrients obtained from prey. We studied the impact of N deposition on the nutrition of the carnivorous plant Drosera rotundifolia growing on 16 ombrotrophic bogs across Europe. We measured tissue N, phosphorus (P) and potassium (K) concentrations and prey and root N uptake using a natural abundance stable isotope approach. Our aim was to test the impact of N deposition on D. rotundifolia prey and root N uptake, and nutrient stoichiometry. D. rotundifolia root N uptake was strongly affected by N deposition, possibly resulting in reduced N limitation. The contribution of prey N to the N contained in D. rotundifolia ranged from 20 to 60%. N deposition reduced the maximum amount of N derived from prey, but this varied below this maximum. D. rotundifolia tissue N concentrations were a product of both root N availability and prey N uptake. Increased prey N uptake was correlated with increased tissue P concentrations indicating uptake of P from prey. N deposition therefore reduced the strength of a carnivorous plant-prey interaction, resulting in a reduction in nutrient transfer between trophic levels. We suggest that N deposition has a negative impact on D. rotundifolia and that responses to N deposition might be strongly site specific.

Background: Exosome vesicles can transfer molecular information previously shown to stimulate tumor development; however, the mechanism of exosome uptake is unknown. Results: Mammalian cells internalize exosomes through lipid raft-mediated endocytosis negatively regulated by caveolin-1. Conclusion: Our findings provide novel insights into cellular uptake of exosomes. Significance: Our data provide potential strategies for how the exosome uptake pathway may be targeted., The role of exosomes in cancer can be inferred from the observation that they transfer tumor cell derived genetic material and signaling proteins, resulting in e.g. increased tumor angiogenesis and metastasis. However, the membrane transport mechanisms and the signaling events involved in the uptake of these virus-like particles remain ill-defined. We now report that internalization of exosomes derived from glioblastoma (GBM) cells involves nonclassical, lipid raft-dependent endocytosis. Importantly, we show that the lipid raft-associated protein caveolin-1 (CAV1), in analogy with its previously described role in virus uptake, negatively regulates the uptake of exosomes. We find that exosomes induce the phosphorylation of several downstream targets known to associate with lipid rafts as signaling and sorting platforms, such as extracellular signal-regulated kinase-1/2 (ERK1/2) and heat shock protein 27 (HSP27). Interestingly, exosome uptake appears dependent on unperturbed ERK1/2-HSP27 signaling, and ERK1/2 phosphorylation is under negative influence by CAV1 during internalization of exosomes. These findings significantly advance our general understanding of exosome-mediated uptake and offer potential strategies for how this pathway may be targeted through modulation of CAV1 expression and ERK1/2 signaling.

Analysis of ancient cattle husbandry is compromised by the need for conventional analysis of sex and age at death to use different elements of the skeleton, usually from different individuals. We demonstrate a technique using aDNA acquired from cattle mandibles and combined with age-at-death estimation based on dental eruption in the same specimens. Application to small sample groups from two sites in Na h-Eileanan Siar (the Scottish Western Isles) show a high success rate, and demonstrates the potential for a more nuanced interpretation of ancient cattle husbandry.

Domestication of animals and plants marked a turning point in human prehistory. To date archaeology, archaeozoology and genetics have shed light on when and where all of our major livestock species were domesticated. Phenotypic changes associated with domestication have occurred in all farm animals. Coat colour is one of the traits that have been subjected to the strongest human selection throughout history. Here we use genotyping of coat colour SNPs in horses to investigate whether there were any regional differences or preferences for specific colours associated with specific cultural traditions in Iron Age Sweden. We do this by identifying the sex and coat colour of horses sacrificed at Skedemosse, Öland (Sweden) during the Iron Age, as well as in horses from two sites in Uppland, Ultuna and Valsgärde (dated to late Iron Age). We show that bay, black and chestnut colours were all common and two horses with tobiano spotting were found. We also show how the combination of sex identification with genotyping of just a few SNPs underlying the basic coat colours can be used to identify the minimum number of individuals at a site on a higher level than morphological methods alone. Although separated by 500 km and from significantly different archaeological contexts the horses at Skedemosse and Ultuna are quite homogenous when it comes to coat colour phenotypes, indicating that there were no clear geographical variation in coat colouration in Sweden during the late Iron Age and early Viking Age.

Sex identification of skeletal remains based on morphology is a common practice in Zooarchaeology. Knowledge of the sex distribution of slaughtered or hunted animals may help in the interpretation ...

Precision processing in MOEMS (micro-opto-electromechanical systems) packaging has been studied based on electrochemical processes with the purpose of establishing technology for low-cost multifunctional encapsulation of microsystems and assembly of opto-electric access links in polymer. The electrochemically based processes studied in this paper include: 1. Electroforming of a polymer moulding tool (stamper) in a nickel sulphamate electrolyte on a high-precision 3D etched silicon template. 2. Patterning of 3D surfaces by an electrophoretic photoresist. 3. Precision plating of Au and Sn for self-alignment of chips by eutectic Au–Sn solder. The results show that nickel stampers with adequately low internal stress can be electroformed on 3D silicon wafers. Furthermore, 3D polymer samples manufactured by the nickel stampers can be patterned with metal lines down to 20 μm width using electrophoretic photoresist. Finally, eutectic Au–Sn solder bumps are realized by electroplating of Au and Sn followed by reflowing, satisfying the demands on dimension and alloy composition control over a 4 in. Si wafer.

It is of vital importance to be able to sex identify cattle remains to understand the strategies and importance of cattle husbandry in an ancient society. This is usually done from osteoarchaeological assemblages and often relies on measurements of metapodials. The breadth measurement of the distal trochlea is considered an easy way to identify the sex. Bones from males appears to be easily distinguishable from female counterparts, although it has been complicated to find an external control for the morphological results. Here we investigate the reliability of these particular morphometrics for sex identifying cattle bones with molecular genetics. We use a sex discriminating single nucleotide polymorphism in the ZFXY gene and we apply it to DNA from the bones. To keep the fragment size short and suitable for ancient DNA we base the test on a SNP. The test confirms the osteological sex identification in all cases were DNA could be retrieved. This molecular method can also be used when no fragments suitable for osteological sex identification can be found or when the measurements are non-conclusive.

We present detailed continuous wave (cw) and transient photoinduced absorption (PA) measurements in thin films of a novel alternating polyfluorene copolymer, poly[2,7-(9,9-dioctyl-fluorene)-alt-5,5-(4',7'-di-2-thienyl-2',1',3-benzo-thiadiazole)] (DiO-PFDTBT), and its blends with the sol. fullerene deriv. [6,6]-phenyl-C61-butyric acid Me ester (PCBM) in wt. ratios of 1:0, 4:1 and 1:4. We measure the frequency, intensity and temp. dependence of the PA signal in the frequency domain, and compare with the results obtained from the transient PA decay measurements in the time domain. In all blends, the PA spectrum shows a broad high energy PA band ranging from .apprx.1 eV to 2 eV as well as a low energy band peaking at .apprx.0.35 eV. We attribute the low energy band to the P1 transition of polarons and part of the high energy band to the correlated P2 transition of polarons. Both frequency and time domain measurements show that the high energy band has two decay components, a faster component in the microsecond time regime and a slower component in the millisecond time regime. The slow component is strongly dispersive, whereas the fast component is practically non-dispersive. [on SciFinder (R)]

The aim of the investigation was to study the influence of the superoxide anion on pancreatic islet blood flow in rats. For this purpose, blood flow measurements were conducted with a microsphere technique 10 min after intravenous administration of different doses of superoxide dismutase (5, 15, 50, 100 or 1000 kU/kg body weight). In separate experiments, diethyldithiodicarbamate, an inhibitor of endogenous superoxide dismutase, was given to nontreated control rats or to rats subjected to a bilateral abdominal vagotomy before the injection. Only the highest dose of superoxide dismutase increased both whole pancreatic and islet blood flow. A 50% augmentation of fractional islet blood flow was seen. Administration of diethyldithiocarbamate induced marked hyperglycemia, which was partly prevented by vagotomy. Diethyldithiocarbamate decreased the whole pancreatic blood flow, while islet blood flow was maintained in both control and vagotomized rats. Consequently, a pronounced increase in fractional islet blood flow was noted in both these groups. We conclude that administration of superoxide dismutase and its inhibitor diethyldithiocarbamate influences pancreatic blood perfusion. In particular, superoxide dismutase causes a general increase in the whole pancreatic and islet blood flow, and an augmented fractional islet blood flow, presumably by a decrease in the local concentration of O(2)(z.rad;-), leading to increased concentration of NO. Diethyldithiocarbamate, on the other hand, by increasing the levels of O(2)(z.rad;-), decreases the whole pancreatic blood flow, whereas islet blood flow remains unaffected.

Steady-state and rime-resolved photoluminescence (PL) is used to probe different states of order in highly regular poly(3-(2'-methoxy-5'-octylphenyl)thiophene) (POMeOPT). In a good solvent (chloroform) the polymer has a PL yield of 0.33 and in a solvent with low solubility (mixture of chloroform and toluene) a new phase appears with higher PL yield (0.50). The new phase is attributed to micro-crystals formed by the regular part of the polymer which have low solubility in toluene. The crystallites have highly structured and redshifted electronic transitions compared with chains which are dissolved. (C) 2001 Published by Elsevier Science B.V.

Electrodeposition of Co–W alloys and the possibility for compositional modulation from single ammoniacal electrolytes were studied. The influence of pH, current density, W:Co ratio, tartrate concentration and temperature on the composition of the deposit and the cathode current efficiency were investigated by a Taguchi experimental plan. It was found that the alloy composition is sensitive to solution chemistry, current density and temperature. It has also been shown that it is possible to reduce the tungsten content in the deposit by current modulation and the use of anodic pulses during deposition, i.e. selective etching. With cross-sectional TEM analysis, it has been shown that the selective etching deposition technique can be utilised to grow layered structures with wavelengths in the nanometer range. The microstructure in the electrodeposited Co–W alloys varied as a function of increasing W content, from crystalline Co over Co3W and Co7W6 to nanocrystalline Co, as determined by XRD.

ObjectivesOpen abdomen (OA) treatment is sometimes necessary after surgery for aortic aneurysm (AA), to prevent or treat abdominal compartment syndrome (ACS). A multicentre study evaluating vacuum-assisted wound closure (100–150 mmHg) and mesh-mediated fascial traction (VAWCM) was performed.MethodsAll patients treated with OA after AA repair (2006–2009) were prospectively registered at four centres; those treated

In this study normoglycemic inbred Wistar-Furth rats were implanted with a syngeneic pancreatico-duodenal graft, i.e. a denervated pancreas. The blood flow to the intact native pancreas and to the transplanted gland was measured with a microsphere technique in anesthetized rats 2 weeks after transplantation. The animals were given an intravenous injection with saline alone, N G -nitro- l -arginine (25 mg/kg body weight) or sodium nitroprusside (10 μg/kg body weight) 10 min before blood flow measurements. Administration of N G -nitro- l -arginine increased mean arterial blood pressure and caused a pronounced decrease in whole pancreatic blood flow in both the native and transplanted gland. The islet blood flow was more markedly decreased by N G -nitro- l -arginine in both the native and transplanted pancreas, and constituted about 4% of whole pancreatic blood flow compared with 10% in the control animals. Sodium nitroprusside markedly decreased mean arterial blood pressure, but did not affect pancreatic or islet blood flow in any of the glands. It is concluded that inhibition of nitric oxide synthase causes a preferential decrease in islet blood flow both in the native pancreas and in the transplanted pancreas. This suggests that nitric oxide which affects islet blood flow is mainly endothelial-derived, and does not emanate from external nervous fibers.

The first recorded cases of the recent epizootic were harbour seals observed at the Danish island of Anholt, 12 April 1988. The disease then spread throughout the sea waters of north-western Europe. The total mortality in Europe up to November 1988, was estimated to be at least 17 000 seals. The mortality rate in Danish-Swedish waters was about 60%. Autopsies including sampling for histology of most organs were performed on 37 harbour seals and 12 grey seals, collected mainly at the Swedish west coast and in the southern Baltic. In most of the harbour seals and in three of the grey seals we found histological changes in the upper and lower respiratory tracts, in the lower urinary tract and in the lymphatic system consistent with those diagnostic of distemper viral infection in the canine. These diagnostic criteria were: presence of intracytoplasmic eosinophilic inclusion bodies of epithelial cells of the trachea and the urinary bladder, interstitial pneumonia, and atrophy of lymphatic organs due to depletion of lymphocytes. Our findings in pathology of a canine distemper-like disease in the seals were presented in late August 1988, together with the Dutch findings in virology by Dr. Osterhaus and collaborators.

At SKL, the number of skimmer cases has increased since 2009. Hence it is important to have a good workflow for the forensic analysis. A successful multidisciplinary collaboration has been developed between DNA, fingerprints and IT forensics. Members of staff from these disciplines perform an initial examination deciding about which parts of the skimmers that are to be analysed for DNA or fingerprints. The combined experience from the different disciplines increases the chances of receiving successful results. For DNA analysis the success rate per case is 69%, which is a relatively high success rate.

We report time-resolved photoluminescence of two polythiophene derivatives with different chain packing. Emission of inter-chain aggregates is distinguished from that of intra-chain singlet excitons. The aggregate luminescence is shifted towards lower energies relative to that of intra-chain exciton by 0.17 eV, and the Huang-Rhys factor of the coupling to the intra-chain C=C vibration is S = 1.5. The excitonic coupling in aggregates is of intermediate strength.

The intake of trans fatty acids by subjects adhering to the normal Swedish diet or to different vegetarian regimes was studied, using chemical analysis of duplicate portions. Trans-octadecenoic acid was 5.0, 3.9, and 1.8% of dietary fatty acid in the normal, lactovegetarian, and vegan diets, respectively, corresponding to 2.0, 1.3, and 0.5% of energy intake. The results are related to the content of trans-octadecenoic acid in some edible fats.