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The immense concentrations of vertebrate species in tropical mountains remain a prominent but unexplained pattern in biogeography. A long-standing hypothesis suggests that montane biodiversity hotspots result from endemic species aggregating within ecologically stable localities. Here, the persistence of ancient lineages coincides with frequent speciation events, making such areas both ‘cradles’ (where new species arise) and ‘museums’ (where old species survive). Although this hypothesis refers to processes operating at the scale of valleys, it remains supported primarily by patterns generated from coarse-scale distribution data. Using high-resolution occurrence and phylogenetic data on Andean hummingbirds, we find that old and young endemic species are not spatially aggregated. The young endemic species tend to have non-overlapping distributions scattered along the Andean treeline, a long and narrow habitat where populations easily become fragmented. By contrast, the old endemic species have more aggregated distributions, but mainly within pockets of cloud forests at lower elevations than the young endemic species. These findings contradict the premise that biogeographical cradles and museums should overlap in valley systems where pockets of stable climate persist through periods of climate change. Instead, Andean biodiversity hotspots may derive from large-scale fluctuating climate complexity in conjunction with local-scale variability in available area and habitat connectivity.

Functional traits can determine pairwise species interactions, such as those between plants and pollinators. However, the effects of biogeography and evolutionary history on trait-matching and trait-mediated resource specialization remain poorly understood.We compiled a database of 93 mutualistic hummingbird-plant networks (including 181 hummingbird and 1,256 plant species), complemented by morphological measures of hummingbird bill and floral corolla length. We divided the hummingbirds into their principal clades and used knowledge on hummingbird biogeography to divide the networks into four biogeographical regions: Lowland South America, Andes, North & Central America, and the Caribbean islands. We then tested: (a) whether hummingbird clades and biogeographical regions differ in hummingbird bill length, corolla length of visited flowers and resource specialization, and (b) whether hummingbirds' bill length correlates with the corolla length of their food plants and with their level of resource specialization.Hummingbird clades dominated by long-billed species generally visited longer flowers and were the most exclusive in their resource use. Bill and corolla length and the degree of resource specialization were similar across mainland regions, but the Caribbean islands had shorter flowers and hummingbirds with more generalized interaction niches. Bill and corolla length correlated in all regions and most clades, that is, trait-matching was a recurrent phenomenon in hummingbird-plant associations. In contrast, bill length did not generally mediate resource specialization, as bill length was only weakly correlated with resource specialization within one hummingbird clade (Brilliants) and in the regions of Lowland South America and the Andes in which plants and hummingbirds have a long co-evolutionary history. Supplementary analyses including bill curvature confirmed that bill morphology (length and curvature) does not in general predict resource specialization.These results demonstrate how biogeographical and evolutionary histories can modulate the effects of functional traits on species interactions, and that traits better predict functional groups of interaction partners (i.e. trait-matching) than resource specialization. These findings reveal that functional traits have great potential, but also key limitations, as a tool for developing more mechanistic approaches in community ecology.A free Plain Language Summary can be found within the Supporting Information of this article.

Made available in DSpace on 2022-04-28T19:41:18Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-01-01 Idea Wild Villum Fonden Many ecosystems have been modified by humans, creating novel habitats that include human-provided resources. Gardens adjacent to native habitats may affect plant–pollinator interactions by altering the determinants of interactions and species specialization. Here, we characterized a network comprising plants and hummingbirds interacting in a birdwatching garden with human-provided resources (nectar feeders and exotic plants) and adjacent Andean cloud forest in Colombia. Specifically, we investigated the proportion of hummingbirds visiting feeders and native/exotic plants to evaluate the connection between the habitats and the ecological determinants of the interaction network. Hummingbirds relied heavily on artificial nectar feeders in the garden, leaving the natural cloud forest for resources. Morphological matching was the single most important predictor of the observed pairwise interactions, for both hummingbirds and plants. At the species level, longer flowering phenology and a higher amount of sugar in nectar led to a higher degree for plants (i.e. the number of visiting hummingbird species). In contrast, a longer floral corolla was associated with lower specialization. Abundance was the best predictor of the number of partners for hummingbirds. The garden created for birdwatching attracted most, but not all, hummingbird species beyond their natural cloud forest habitat. Interestingly, the most frequently visited plants in the garden were native, especially the endemic and endangered tree Zygia lehmannii (Fabaceae). Our results show that some ecological mechanisms determining interactions in natural communities still hold in intensively modified habitats. Furthermore, a compromise between conservation and hummingbirds’ attraction to birding lodges/gardens is possible, for instance by favouring native and endemic plant species that are highly attractive for pollinators. Programa de Doctorado en Ciencias-Biología Departamento de Biología Facultad de Ciencias Naturales y Exactas Universidad del Valle Sede Meléndez, Calle 13 # 100-00 Grupo Ecología y Diversidad Vegetal Departamento de Biología Facultad de Ciencias Naturales Universidad del Valle, Calle 13 # 100-00 Laboratório de Ecologia da Polinização e Interações – LEPI Instituto de Biociências Universidade Estadual Paulista “Júlio de Mesquita Filho”, Distrito de Rubião Junior s/n; Cx. Postal 510 Center for Global Mountain Biodiversity GLOBE Institute University of Copenhagen, Universitetsparken 15 Centro de Síntese Ecológica e Conservação Departamento de Genética Ecologia e Evolução ICB Universidade Federal de Minas Gerais, CEP 31270-901 Laboratório de Ecologia da Polinização e Interações – LEPI Instituto de Biociências Universidade Estadual Paulista “Júlio de Mesquita Filho”, Distrito de Rubião Junior s/n; Cx. Postal 510 Villum Fonden: 25925

Animal pollinators are globally threatened by anthropogenic land use change and agricultural intensification. The yield of many food crops is therefore negatively impacted because they benefit from biotic pollination. This is especially the case in the tropics. For instance, fruit set of Coffea arabica has been shown to increase by 10–30% in plantations with a high richness of bee species, possibly influenced by the availability of surrounding forest habitat. Here, we performed a global literature review to (1) assess how much animal pollination enhances coffee fruit set, and to (2) examine the importance of the amount of forest cover, distance to nearby forest and forest canopy density for bee species richness and coffee fruit set. Using a systematic literature review, we identified eleven case studies with a total of 182 samples where fruit set of C. arabica was assessed. We subsequently gathered forest data for all study sites from satellite imagery. We modelled the effects of open (all forest with a canopy density of ≥25%), closed (≥50%) and dense (≥75%) forests on pollinator richness and fruit set of coffee. Overall, we found that animal pollination increases coffee fruit set by ~18% on average. In only one of the case studies, regression results indicate a positive effect of dense forest on coffee fruit set, which increased with higher forest cover and shorter distance to the forest. Against expectations, forest cover and distance to open forest were not related to bee species richness and fruit set. In summary, we provide strong empirical support for the notion that animal pollinators increase coffee fruit set. Forest proximity had little overall influence on bee richness and coffee fruit set, except when farms were surrounded by dense tropical forests, potentially because these may provide high-quality habitats for bees pollinating coffee. We, therefore, advocate that more research is done to understand the biodiversity value of dense forest for pollinators, notably assessing the mechanisms underlying the importance of forest for pollinators and their pollination services.

Aims: Urethral closure function is essential for urinary continence in women and decreased urethral pressure is associated with stress urinary incontinence (SUI). For decades, the effects of serotonergic drugs on central neural control of urethral closure have been investigated and discussed. Epidemiological studies suggest that the use of selective serotonin reuptake inhibitors (SSRIs), such as citalopram, is associated with SUI. However, the literature findings are conflicting. This study aimed to evaluate citalopram's effect on opening urethral pressure (OUP) in healthy women. Methods: We conducted a randomized, double-blind, placebo- and active-controlled crossover study in 24 healthy women. On three study days, which were separated by 8 days of washout, the subjects received single doses of either 40 mg citalopram (and placeboreboxetine), 8 mg reboxetine (and placebocitalopram), or two placebos. Study drugs were administered at a 1-h interval due to a difference in estimated time to peak plasma concentration (tmax). We measured OUP with urethral pressure reflectometry under both resting and squeezing conditions of the pelvic floor at estimated tmax for both study drugs (one timepoint). Results: Compared to placebo, citalopram increased OUP by 6.6 cmH20 (95% confidence interval [CI] 0.04–13.1, p = 0.048) in resting condition. In squeezing condition, OUP increased by 7.1 cmH20 (95% CI: 1.3–12.9, p = 0.01). Reboxetine increased OUP by 30.0 cmH20 in resting condition compared to placebo (95% CI: 23.5–36.5, p < 0.001), and 27.0 cmH20 (95% CI: 21.2–32.8, p < 0.001) in squeezing condition. Conclusion: Citalopram increased OUP slightly compared to placebo suggesting that SSRI treatment does not induce or aggravate SUI.

Summary The Udzungwa Forest Partridge Xenoperdix udzungwensis was discovered in 1991 in the geologically old and eco-climatically stable Udzungwa Mountains (hereafter the Udzungwas) in Tanzania - a global biodiversity hotspot in the Eastern Arc Mountains of East Africa. The partridge is categorised as globally ‘Endangered’ and this study aims at assessing its population status and habitat requirements in the two separate montane forests where it was discovered c.30 years ago and for the first time using systematic playback technique. We estimate the partridge population at c.2,800 individuals (1,680–3,860) confined to less than 150 km2 and now confined to a single forest and with a clearly declining distribution within the last few decades since its discovery. The species is confined to evergreen closed (semi-closed) canopy forest habitat with leaf litter and sedges on the forest floor for feeding and cover. The partridge has become an emblem for the high concentration of endemic species of the Udzungwa Mountains National Park. At the same time there is a risk that this species could go extinct without notice if the Tanzanian authorities do not tackle two envisaged main drivers, namely fragmentation of the evergreen forest area over the last few centuries and current illegal hunting. Hence it seems crucial to allow natural expansion of its forest habitat in the Udzungwas and to eliminate hunting in the other forest within its recently known distribution where the population has presumably been extirpated. The partridge is remarkable as its closest relatives are in South-east Asia and it is used as a flagship species for the Udzungwas, which has one of the highest concentrations of endemic species on earth.

Climate-driven range shifts may cause local extinctions, while the accompanying loss of biotic interactions may trigger secondary coextinctions. At the same time, climate change may facilitate colonizations from regional source pools, balancing out local species loss. At present, how these extinction-coextinction-colonization dynamics affect biological communities under climate change is poorly understood. Using 84 communities of interacting plants and hummingbirds, we simulated patterns in climate-driven extinctions, coextinctions and colonizations under future climate change scenarios. Our simulations showed clear geographic discrepancies in the communities' vulnerability to climate change. Andean communities were the least affected by future climate change, as they experienced few climate-driven extinctions and coextinctions while having the highest colonization potential. In North America and lowland South America, communities had many climate-driven extinctions and few colonization events. Meanwhile, the pattern of coextinction was highly dependent on the configuration of networks formed by interacting hummingbirds and plants. Notably, North American communities experienced proportionally fewer coextinctions than other regions because climate-driven extinctions here primarily affected species with peripheral network roles. Moreover, coextinctions generally decreased in communities where species have few overlapping interactions, that is, communities with more complementary specialized and modular networks. Together, these results highlight that we should not expect colonizations to adequately balance out local extinctions in the most vulnerable ecoregions.

Background: Coronavirus disease 19 (COVID-19) is spreading globally and treatment options remain limited. A formulation of niclosamide, a potent anti-SARS-CoV-2 agent and a broad-spectrum antiviral treatment candidate, optimized for inhalation and intranasal administration (UNI91104) was developed.Methods: We conducted a randomized, placebo-controlled, double-blind, single-centre, dose-ascending Phase 1 trial to assess the safety of UNI91104 in Denmark (NCT04576312). Healthy volunteers were randomly assigned to a ascending single dose in cohort 1-4 and five doses over 2.5 days in cohort 5. Inclusion criteria included a minimum 80% of predicted lung function. Exclusion criteria included severe, clinically significant allergies and current acute or chronic condition especially airway diseases. Safety was evaluated through adverse events (AEs) and pulmonary function tests including forced expiratory volume in one second (FEV1) and fractional exhaled nitric oxide (FeNO) tests. The primary endpoints were defined as the frequency of reported AEs and the change of safety variables relative to pre-dose. Data from all enroled healthy volunteers receiving any amount of IMP was included in the primary analyses. The pharmacokinetics of UNI91104 was determined.Findings: The trial was conducted between 29 June 2020 and 08 August 2020. Thirty-four healthy volunteers received UNI91104 and ten placebo. No serious AEs or discontinuation were reported. Mild irritation in the upper respiratory tract following inhalation of UNI91104 was reported as most frequent AE (45 events in 26 healthy volunteers, 59% of all healthy volunteers). Nasal application was well-tolerated. There was no evidence of difference in the change of mean levels of pulmonary function tests between active and placebo group across all cohorts. Five healthy volunteers (11.4%) (1 on placebo) had signs of increased transient FeNO and 4 on active (9.1%) experienced asymptomatic drops in FEV1, which resolved spontaneously or were reversible with a β2-agonist. Niclosamide exhibited dose-proportional pharmacokinetics following inhalation and intranasal administration.Interpretation: UNI91104, a promising candidate for inhalation and intranasal therapy against COVID-19 and other viral respiratory tract infections is well-tolerated in healthy volunteers and warrants further testing in patient trials.Funding: The study was funded by Innovationsfonden Denmark and UNION therapeutics.

Interactions between species are influenced by different ecological mechanisms, such as morphological matching, phenological overlap and species abundances. How these mechanisms explain interaction frequencies across environmental gradients remains poorly understood. Consequently, we also know little about the mechanisms that drive the geographical patterns in network structure, such as complementary specialization and modularity. Here, we use data on morphologies, phenologies and abundances to explain interaction frequencies between hummingbirds and plants at a large geographical scale. For 24 quantitative networks sampled throughout the Americas, we found that the tendency of species to interact with morphologically matching partners contributed to specialized and modular network structures. Morphological matching best explained interaction frequencies in networks found closer to the equator and in areas with low-temperature seasonality. When comparing the three ecological mechanisms within networks, we found that both morphological matching and phenological overlap generally outperformed abundances in the explanation of interaction frequencies. Together, these findings provide insights into the ecological mechanisms that underlie geographical patterns in resource specialization. Notably, our results highlight morphological constraints on interactions as a potential explanation for increasing resource specialization towards lower latitudes.

BackgroundPeptide-based vaccination is a rational option for immunotherapy of prostate cancer. In this first-in-man phase I/II study, we assessed the safety, tolerability and immunological impact of a synthetic long peptide vaccine targeting Ras homolog gene family member C (RhoC) in patients with prostate cancer. RhoC is a small GTPase overexpressed in advanced solid cancers, metastases and cancer stem cells.MethodsTwenty-two patients who had previously undergone radical prostatectomy received subcutaneous injections of 0.1 mg of a single RhoC-derived 20mer peptide emulsified in Montanide ISA-51 every 2 weeks for the first six times, then five times every 4 weeks for a total treatment time of 30 weeks. The drug safety and vaccine-specific immune responses were assessed during treatment and thereafter within a 13-month follow-up period. Serum level of prostate-specific antigen was measured up to 26 months postvaccination.ResultsMost patients (18 of 21 evaluable) developed a strong CD4 T cell response against the vaccine, which lasted at least 10 months following the last vaccination. Three promiscuouslypresented HLA-class II epitopes were identified. Vaccine-specific CD4 T cells were polyfunctional and effector memory T cells that stably expressed PD-1 (CD279) and OX-40 (CD134), but not LAG-3 (CD223). One CD8 T cell response was detected in addition. The vaccine was well tolerated and no treatment-related adverse events of grade ≥3 were observed.ConclusionTargeting of RhoC induced a potent and long-lasting T cell immunity in the majority of the patients. The study demonstrates an excellent safety and tolerability profile. Vaccination against RhoC could potentially delay or prevent tumor recurrence and metastasis formation.Trial registration numberNCT03199872.

Midazolam is a first-line drug for the treatment of status epilepticus, both by buccal and intravenous administration. In children and adolescents with obesity, midazolam pharmacokinetics may be altered, and the current dosing guidelines may therefore be insufficient. The objective of this study was to investigate the pharmacokinetics of midazolam, after intravenous administration, in obese and non-obese adolescents aged 11–18 years. All trial participants received a 1-µg midazolam microdose as an intravenous bolus. 13 blood samples were collected per participant at pre-specified timepoints. Plasma concentration–time data were fitted to pharmacokinetic models using non-linear mixed-effects modeling. Covariates such as weight, age, and body mass index standard deviation score were tested to explain the inter-individual variability associated with the pharmacokinetic parameters. Sixty-seven adolescents were included in the analysis. The pharmacokinetics of midazolam was best described with a two-compartment model. The rate of distribution was faster, and the peripheral volume of distribution was larger in adolescents with a high body mass index standard deviation score compared with adolescents with a lower standard deviation score. Simulations revealed that long-term infusions based on total body weight could lead to high plasma concentrations in adolescents with obesity. Furthermore, simulated plasma concentrations after a fixed buccal dose indicated that adolescents with obesity may be at risk of sub-therapeutic midazolam plasma concentrations. The body mass index standard deviation score was shown to have a significant influence on the peripheral volume of distribution and the inter-compartmental clearance of midazolam. The current dosing guidelines for status epilepticus, where the midazolam dose is adjusted to total body weight or age, may lead to supra- and sub-therapeutic plasma concentrations, respectively, in adolescents with obesity. EudraCT: 2014-004554-34.

Competitive pressure from invasive species tends to have a particularly strong impact on remote islands, and knowledge of such phenomena can be crucial to the conservation of endemic biodiversity. Of the two hummingbird species inhabiting Robinson Crusoe Island, Juan Fernandez Archipelago, Chile, one (Green-backed Firecrown, Sephanoides sephaniodes) has a wide mainland distribution while the other (Juan Fernandez Firecrown, Sephanoides fernandensis) is endemic and critically endangered. Even though habitat degradation and predation by exotic mammal species are known to pose major threats, little attention has been given to the influence of interspecific competition for floral nectar resources. In this study, we investigated the existence of interspecific competition by testing for spatial segregation of the two species using point counts dispersed within their suitable habitats. We additionally considered the influence of habitat type and flower abundance, which could also cause spatial segregation between the species. We found a negative association between the point count abundance of the two hummingbirds species, which remained consistent when accounting for the role of habitat type and flower abundance. Together, this could be an indication of interspecific competition in which individuals of S. fernandensis may benefit from aggregation by sharing the individual costs of chasing the vastly more abundant S. sephaniodes.

Abundant pollinators are often more generalised than rare pollinators. This could be because abundance drives generalisation: neutral effects suggest that more abundant species will be more generalised simply because they have more chance encounters with potential interaction partners. On the other hand, generalisation could drive abundance, as generalised species could have a competitive advantage over specialists, being able to exploit a wider range of resources and gain a more balanced nutrient intake. Determining the direction of the abundance-generalisation relationship is therefore a ‘chicken-and-egg’ dilemma. Here we determine the direction of the relationship between abundance and generalisation in plant-hummingbird pollination networks sampled from a variety of locations across the Americas. For the first time we resolve the direction of the abundance-generalisation relationship using independent data on animal abundance. We find evidence that hummingbird pollinators are generalised because they are abundant, and little evidence that hummingbirds are abundant because they are generalised. Additionally, a null model analysis suggests this pattern is due to neutral processes: most patterns of species-level abundance and generalisation were well explained by a null model that assumed interaction neutrality. These results suggest that neutral processes play a key role in driving broad patterns of generalisation in animal pollinators across large spatial scales.DeclarationsFunding – BIS is supported by the Natural Environment Research Council as part of the Cambridge Earth System Science NERC DTP [NE/L002507/1]. JVB was funded by CERL - Engineer Research and Development Center. PKM was funded by the São Paulo Research Foundation (FAPESP grant #2015/21457-4). PAC was funded by the David Lack studentship from the British Ornithologists’ Union and Wolfson College, University of Oxford. CL was funded by the ESDEPED-UAT grant. MAM acknowledges the Consejo Nacional para Investigaciones Científicas y Tecnológicas (Costa Rica), German Academic Exchange Service and the research funding program ‘LOEWE-Landes-Offensive zur Entwicklung Wissenschaftlichö konomischer Exzellenz’ of Hesse’s Ministry of Higher Education, Research, and the Arts (Germany). ROP was funded by CONACyT (project 258364). MAR was supported by the State of São Paulo Research Foundation (FAPESP) within the BIOTA/FAPESP, The Biodiversity Institute Program (www.biota.org.br) and the ‘Parcelas Permanentes’ project, as well as by Coordenação de Pessoal de Nível Superior (CAPES), Fundo de Apoio ao Ensino e à Pesquisa (FAEP)/Funcamp/Unicamp and The Nature Conservancy (TNC) of Brazil. LCR was supported by CNPq and Capes. MS was funded by CNPq (grant #302781/2016-1). AMMG is supported through a Marie Skłodowska-Curie Individual Fellowship (H2020-MSCA-IF-2016-704409). LVD was supported by the Natural Environment Research Council (grants NE/K015419/1 and NE/N014472/1). AMMG, JS, CR and BD thank the Danish National Research Foundation for its support of the Center for Macroecology, Evolution and Climate (grant no. DNRF96). WJS is funded by Arcadia.

Providing hummingbirds with artificial feeders containing sugar solution is common practice throughout the Americas. Although feeders can affect hummingbird foraging behavior and abundance, it is poorly understood how far this effect may extend. Moreover, it remains debated whether nectar-feeders have a negative impact on hummingbird-pollinated plants by reducing flower visitation rates and pollen transfer close to the feeders. Here, we investigated the effects of distance to nectar-feeders on a local hummingbird assemblage and the pollination of Psychotria nuda (Rubiaceae), a hummingbird-pollinated plant endemic to the Brazilian Atlantic Rainforest. At increasing distance (0–1000 m) from a feeding-station, where hummingbirds have been fed continuously for the past 13 years, we quantified hummingbird abundance, and rates of flower visitation and pollen deposition on P. nuda. We found that hummingbird abundance was unrelated to distance from the feeders beyond ca. 75 m, but increased steeply closer to the feeders; the only exception was the small hummingbird Phaethornis ruber, which remained absent from the feeders. Plants of P. nuda within ca.125 m from the feeders received increasingly more visits, coinciding with the higher hummingbird abundance, whereas visitation rate beyond 125 m showed no distance-related trend. Despite this, pollen deposition was not associated with distance from the feeders. Our findings illustrate that artificial nectar-feeders may locally increase hummingbird abundance, and possibly affect species composition and pollination redundancy, without necessarily having a disruptive effect on pollination services and plants’ reproductive fitness. This may apply not only to hummingbirds, but also to other animal pollinators.

In some hospitals, clinical pharmacists review the medication to find drug-related problems (DRPs) in acutely admitted patients. We aimed to identify the nature of identified DRPs and investigate factors of potential importance for the clinical implementation of pharmacist suggestions. In 100 randomly selected medication review notes, we retrospectively evaluated the clinical implementation and classified 1) timing and communication of the review; 2) DRPs and related suggestions for the physician; and 3) DRPs’ potential clinical relevance to patients as ‘beneficial’, ‘somewhat beneficial’, ‘no relevance’ or ‘other relevance’. Of 327 DRPs (0-13 DRPs/patient), 48% were implemented. The clinical implementation was higher if the medication review note was made prior to (instead of after) the physician's admission, and even higher if the suggestions were communicated verbally (instead of only in writing) to the physicians (44 versus 79%, P

BackgroundMidazolam is a first-line drug for treatment of status epilepticus,1 2 both by buccal and intravenous administration. In children with obesity, the midazolam pharmacokinetics may be altered, and the current dosing guidelines may therefore be insufficient.The aim of the study was to investigate the pharmacokinetics of midazolam, after intravenous administration, in obese and non-obese children, aged 11–18 years.MethodsTrial subjects were divided into groups by Body Mass Standard Deviation Score (SDS). All children received 1 µg midazolam administered an intravenous bolus dose. Thirteen blood samples were collected per participant at prespecified timepoints over 9 hours. Plasma concentration-time data was fitted to pharmacokinetic models using non-linear mixed effects modelling (NONMEM, 7.4).ResultsSeventy-two children were enrolled in the study, of these 67 children were included in the analysis. The pharmacokinetics of midazolam was best described with a two-compartment model. The changes in pharmacokinetics in children with obesity were best described with a linear function of BMI SDS on inter-compartmental clearance and peripheral volume. Thus, the rate of distribution was faster, and the peripheral volume of distribution was larger in children with obesity as compared to non-obese children. Simulations revealed that long-term infusions based on total body weight, could lead to high plasma concentrations in children with obesity. Furthermore, simulated plasma concentrations after a fixed buccal dose showed that children with obesity may be at risk of subtherapeutic plasma concentrations.ConclusionBMI SDS was shown to have a significant influence on the peripheral volume of distribution and the inter-compartmental clearance of midazolam. The current Danish dosing guidelines for status epilepticus (http://www.paediatri.dk), where midazolam dose is adjusted to total body weight or age, may lead to both supra- and subtherapeutic doses respectively, in children with obesity. However, confirmatory studies are needed.ReferencesSmith R, Brown J. Midazolam for status epilepticus. Aust Prescr. februar 2017;40(1):23–5.Ulvi H, Yoldas T, Müngen B, Yigiter R. Continuous infusion of midazolam in the treatment of refractory generalized convulsive status epilepticus. Neurol Sci Off J Ital Neurol Soc Ital Soc Clin Neurophysiol oktober 2002;23(4):177–82.Disclosure(s)Nothing to disclose

Background: The relative frequency of wind- and animal-pollinated plants a non-randomly distributed across the globe and numerous hypotheses have been raised for the greater occurrence of wind pollination in some habitats and towards higher latitudes. To date, however, there has been no comprehensive global investigation of these hypotheses.\ud \ud Aims: Investigating a range of hypotheses for the role of biotic and abiotic factors as determinants of the global variation in animal vs. wind pollination.\ud \ud Methods: We analysed 67 plant communities ranging from 70º north to 34º south. For these we determined habitat type, species richness, insularity, topographic heterogeneity, current climate and late-quaternary climate change. The predictive effects of these factors on the proportion of wind- and animal-pollinated plants were tested using correlations, ordinary least squares (OLS) and logistic regression analyses with information-theoretic model selection.\ud \ud Results: The proportion of animal-pollinated plant species was positively associated with plant species richness and current temperature. Furthermore, in forest, animal pollination was positively related to precipitation. Historical climate was only weakly and idiosyncratically correlated with animal pollination.\ud \ud Conclusion: Results were consistent with the hypothesised reduced chance for wind-transported pollen reaching conspecific flowers in species-rich communities, fewer constraints on nectar production in warm and wet habitats, and reduced relative effectiveness of wind dispersal in humid areas. There was little evidence of a legacy of historical climate change affecting these patterns.

Ecological communities that experience stable climate conditions have been speculated to preserve more specialized interspecific associations and have higher proportions of smaller ranged species (SRS). Thus, areas with disproportionally large numbers of SRS are expected to coincide geographically with a high degree of community-level ecological specialization, but this suggestion remains poorly supported with empirical evidence. Here, we analysed data for hummingbird resource specialization, range size, contemporary climate, and Late Quaternary climate stability for 46 hummingbird–plant mutualistic networks distributed across the Americas, representing 130 hummingbird species ( ca 40% of all hummingbird species). We demonstrate a positive relationship between the proportion of SRS of hummingbirds and community-level specialization, i.e. the division of the floral niche among coexisting hummingbird species. This relationship remained strong even when accounting for climate, furthermore, the effect of SRS on specialization was far stronger than the effect of specialization on SRS, suggesting that climate largely influences specialization through species' range-size dynamics. Irrespective of the exact mechanism involved, our results indicate that communities consisting of higher proportions of SRS may be vulnerable to disturbance not only because of their small geographical ranges, but also because of their high degree of specialization.

The Danish Society of Clinical Pharmacology was founded in 1976, and mainly thanks to the persistent efforts of the society, clinical pharmacology became an independent medical speciality in Denmark in 1996. Since then, clinical pharmacology has gone from strength to strength. In the Danish healthcare system, clinical pharmacology has established itself as an indispensible part of the efforts to promote the rational, safe and economic use of drugs. Clinical pharmacologists are active in drug committees both in hospitals and in the primary sector. All clinical pharmacology centres offer a local medicines information service. Some centres have established an adverse drug effect manager function. Only one centre offers a therapeutic drug monitoring service. Clinical pharmacologists are responsible for the toxicological advice at the Danish Poison Information Centre at Bispebjerg University Hospital in the Capital Region. The Department of Clinical Pharmacology at Aarhus University Hospital works closely together with forensic toxicologists and pathologists, covering issues regarding illicit substances, forensic pharmacology, post-mortem toxicology, expert testimony and research. Therapeutic geriatric and psychiatric teach-inns for specialist and junior doctors are among the newest initiatives organized by clinical pharmacologists. Clinical pharmacologists work also in the Danish Medicines Agency and in the Danish pharmaceutical industry, and the latter has in particular a great growth potential for creating new jobs and career opportunities for clinical pharmacologists. As of July 2016, the Danish Society of Clinical Pharmacology has 175 members, and 70 of these are specialists in clinical pharmacology corresponding to approximately 2.5 specialists per 1000 doctors (Denmark has in total 28,000 doctors) or approximately 12 specialists per one million inhabitants.

Aim: To investigate the role of alien plants in mutualistic plant-hummingbird networks, assessing the importance of species traits, floral abundance and insularity on alien plant integration. Location: Mainland and insular Americas. Methods: We used species-level network indices to assess the role of alien plants in 21 quantitative plant-hummingbird networks where alien plants occur. We then evaluated whether plant traits, including previous adaptations to bird pollination, and insularity predict these network roles. Additionally, for a subset of networks for which floral abundance data were available, we tested whether this relates to network roles. Finally, we tested the association between hummingbird traits and the probability of interaction with alien plants across the networks. Results: Within the 21 networks, we identified 32 alien plant species and 352 native plant species. On average, alien plant species attracted more hummingbird species (i.e. aliens had a higher degree) and had a higher proportion of interactions across their hummingbird visitors than native plants (i.e. aliens had a higher species strength). At the same time, an average alien plant was visited more exclusively by certain hummingbird species (i.e. had a higher level of complementary specialization). Large alien plants and those occurring on islands had more evenly distributed interactions, thereby acting as connectors. Other evaluated plant traits and floral abundance were unimportant predictors of network roles. Short-billed hummingbirds had higher probability of including alien plants in their interactions than long-billed species. Main conclusions: Once incorporated into plant-hummingbird networks, alien plants appear strongly integrated and, thus, may have a large influence on network dynamics. Plant traits and floral abundance were generally poor predictors of how well alien species are integrated. Short-billed hummingbirds, often characterized as functionally generalized pollinators, facilitate the integration of alien plants. Our results show that plant-hummingbird networks are open for invasion. © 2016 John Wiley & Sons Ltd.

Rationale and objectives To study the magnetic resonance imaging signal intensity of the liver and gall bladder before and after ingestion of a new oral manganese containing contrast medium at three different field strengths. Materials and methods Twelve healthy male volunteers (mean age, 24.9 years; range, 20–39 years) underwent abdominal magnetic resonance imaging (T2W COR, T1W COR, T1W TRA) at 0.23T, 0.6T, and 1.5 T before and after the contrast administration. The duration of fasting was identical before the two studies. Volunteers were randomized into two equal groups (n = 6) to ingest either half or full strength CMC-001 providing either 0.8 or 1.6.g MnCl2 plus absorption promoters. The CMC-001 dose was dissolved in 400 mL water and ingested 2 1 2 hours before imaging. The resulting images were evaluated with regard to visualization of the liver and the gall bladder by three radiologists. The signal intensity of the liver was also measured. Blood and urine samples were collected before and after ingestion of CMC-001. Results The intake of CMC-001 caused a significant increase in the signal intensity of the liver at all three field strengths and at both dosages (up to 90%) on the T1W images. The internal structure of the liver was significantly better delineated. The bile in gall bladder was bright after ingestion of the low dose, but dark after the full dose. On the T2W images, CMC-001 lowered the signal intensity of liver with up to 30%. CMC-001 had a slight metallic taste, but of no importance according to the volunteers. No systematic adverse reactions caused by the contrast medium were registered. No changes in the blood levels of various routine parameters were measured. Conclusion It is possible to increase the signal intensity of the liver significantly by oral intake of essential nutritional elements including manganese. The imaging window is more than 2 hours.

To study the distribution of the thiopurine methyltransferase (TPMT) genotype among azathioprine (Aza)-tolerant and -intolerant patients with various disorders, and to investigate a possible relationship with the Aza metabolite levels.Forty-six Aza-tolerant and six Aza-intolerant patients had the TPMT genotype distribution determined using a polymerase chain reaction (PCR) assay and the forty-six Aza-tolerant patients had the Aza metabolite levels determined using a high-pressure liquid chromatography (HPLC) analysis.One non-functional TPMT mutant allele was demonstrated in 2 of the 46 Aza-tolerant patients (4.4%) and one or two non-functional mutant alleles in 2 of the 6 Aza-intolerant patients (33.3%). Of the 4 patients, with one or two non-functional mutant alleles 2 (50%) were intolerant to Aza compared with 4 of the 48 patients (8.3%) with no mutations detected. The time to hepatotoxicity did not differ significantly between the 2 patients with one or two non-functional mutant alleles and the remaining 3 patients ( P=0.5). The TPMT genotype distribution differed slightly in the three different categories of disorders ( P=0.05). The median E-6-TGN level among the 2 TPMT heterozygous patients was 275 pmol/8x10(8) RBC (range 240-310), whereas the remaining 44 patients had a median E-6-TGN level of 110 pmol/8x10(8) RBC (range 0-440) ( P=0.07).Although TPMT genotyping cannot be recommended on behalf of the present study, it is to be expected that half of the patients with one or two non-functional TPMT mutant alleles will develop Aza intolerance leading to withdrawal of therapy. Thus, clinicians may anticipate about 5% of the patients to develop intolerance to Aza therapy solely for that reason.

Aims In chronic renal failure, the clearance of most ACE inhibitors including enalapril is reduced. Hence, with conventional dosage, plasma enalaprilat may be markedly elevated. It is unclear whether this excess of drug exposure affords an improved control of blood pressure. The aim of the present study was to evaluate short-term blood pressure response to two different plasma levels of enalaprilat. Methods As part of an open, randomized, controlled trial of the effect of high and low dosage of enalapril on the progression of renal failure, short-term blood pressure response was evaluated. Data were analysed in all patients completing 3 months of follow-up. The patients were allocated to two trough plasma concentrations of enalaprilat, either above 50 ng ml−1 (high) (n = 17) or below 10 ng ml−1 (low) (n = 18), and the daily dose of enalapril titrated accordingly. Results Median (range) glomerular filtration rate (GFR) at baseline was 18 (7.9) in the high enalaprilat concentration group and 17 (7.3) ml min−1 1.73 m2 in the low concentration group (NS). Nine patients in each group were on treatment with enalapril at baseline with a median daily dose of 5 mg in both the high (5–10) and low (2.5–20) concentration group. At 3 months’ follow-up, the dose was 10 (2.5–30) and 1.9 (1.25–5) mg (P

Summary Background : Inter-individual response to azathioprine is partly due to inter-individual variation in the thiopurine methyltransferase (TPMT) activity. The TPMT genotype, which reflects the TPMT activity, has previously been studied in healthy Caucasians, with the most common variant allele being TPMT*3A. TPMT genotyping in adult patients with Crohn's disease has never been performed systematically. Aim : To determine the TPMT genotype distribution in adult patients with Crohn's disease. Methods : One hundred and twenty randomly selected Danish patients (64 females and 56 males) with azathioprine-dependent Crohn's disease were included, and a polymerase chain reaction assay was used for TPMT genotyping. The patients were genotyped for the low-level genotype G460A and A719G transitions. Results : One hundred and nine patients (90.3%; 95% confidence interval, 84.1–95.3) had a wild-type/ wild-type genotype, whereas 10 patients (8.3%; 95% confidence interval, 4.1–14.8) had one non-functional mutant allele and one patient (0.8%; 95% confidence interval, 0.02–4.6) had two non-functional mutant alleles. Only the TPMT*3A variant allele was found. Conclusions : The study showed a TPMT genotype distribution amongst adult Danish patients with Crohn's disease which was similar to the distribution of TPMT variant alleles normally found in healthy Caucasians.

Aims Grapefruit juice inhibits CYP3A4 in the intestinal wall leading to a reduced intestinal first pass metabolism and thereby an increased oral bioavailability of certain drugs. For example, it has been shown that the oral bioavailability of midazolam, a CYP3A4 substrate, increased by 52% in healthy subjects after ingestion of grapefruit juice. However, this interaction has not been studied in patients with impaired liver function. Accordingly, the effect of grapefruit juice on the AUC of midazolam and the metabolite α-hydroxymidazolam was studied in patients with cirrhosis of the liver. Methods An open randomized two-way crossover study was performed. Ten patients (3 females, 7 males) with liver cirrhosis based on biopsy or clinical criteria participated. Six patients had a Child-Pugh score of A, one B and three C. Tap water (200 ml) or grapefruit juice were consumed 60 and 15 min before midazolam (15 mg) was administered orally. Plasma samples were analysed for midazolam and α-hydroxymidazolam. Results Grapefruit juice increased the AUC of midazolam by 106% (16, 197%) (mean (95% confidence interval)) and the AUC of the metabolite α-hydroxymidazolam decreased to 25% (12, 37%) (P

To distinguish between local and systemic drug effects, we compared pain scores, analgesic consumption and plasma concentrations after local vs i.v. administration of meloxicam 7.5 mg in patients with inguinal hernia repair.In a double-blind, randomized study 56 patients received either local or i.v. meloxicam 7.5 mg. Postoperative pain was assessed with a visual analogue scale (VAS) at rest, on mobilization, and on coughing, the need for supplementary analgesics (fentanyl i.v. and/or acetaminophen-codeine tablets) was recorded, and blood samples were drawn during 24 hr after meloxicam administration.No significant differences were found between groups with respect to pain scores, or in the consumption of supplementary analgesics. Following local application of meloxicam, the peak plasma concentration (C(max)) of 0.5 +/- 0.2 mg*L(-1) achieved after 1.8 +/- 0.5 hr was much lower than the C(max) of 2.5 +/- 0.9 mg*L(-1) achieved immediately after i.v. administration (P0.05). Mean meloxicam plasma concentration after infiltration was significantly lower than after i.v. doses for the first three hours after administration (P0.05).We showed no differences in pain scores and analgesic consumption between local and i.v. administration of meloxicam 7.5 mg during the first 24 hr after herniorrhaphy, while plasma concentration of meloxicam was lower after local administration. These results indicate a lack of difference in pain relief after concentrating meloxicam at the hernia wound or after achieving high blood levels rapidly (i.v.). Local administration of meloxicam may confer an advantage over systemic administration by eliciting lower incidences of systemic adverse effects.

Background: Our aim was to study the pharmacokinetics and pain scores following administration of single oral doses of either diclofenac or high-dose acetaminophen (paracetamol). Methods: In the morning, the day after tonsillectomy, children 5-15 years of age were randomized in a double-blind manner to receive either diclofenac 1-2 mg.kg -1 (n = 11) or acetaminophen 22.5 mg.kg -1 (n = 10). Postoperative pain was assessed by self-report and blood samples were drawn every 30 min for 4 h after medication. Results: Large interindividual differences in maximum plasma diclofenac concentrations (C max ) were found. Mean C max was 2.4±1.3 μg.ml -1 and mean t max was 2±0.5 h. No significant reduction in pain score with diclofenac was seen at any of the assessments during the study period. Eight of 10 children achieved C max of acetaminophen within the 10-20 μg.ml -1 antipyretic range. Mean tabs was 0.7±0.3 h and mean C max and t max were 12.7±3.8 μg ml -1 and 1.4±0.5 h, respectively. No significant reduction in pain score with acetaminophen was seen at any of the assessments during the study period. Conclusions: The achieved concentrations of diclofenac and acetaminophen were not able to significantly reduce the children's pain score during the 5 h postingestion study period. Analgesic plasma acetaminophen concentrations may be higher than those required for antipyresis.

Background/Aims: Consecutive patients originally diagnosed with acute non-A, non-B hepatitis were followed up to assess the long-term morbidity and mortality and to re-evaluate the etiology in surviving patients. Methods: Follow-up was performed in 178 patients with acute non-A, non-B hepatitis enrolled in the Copenhagen Hepatitis Acuta Programme in the period 1969–1987. Mortality and morbidity were assessed using: i) death certificates and ii) diagnoses at discharge following all somatic admissions. All patients who were alive were offered a re-examination encompassing clinical, biochemical and virological evaluation. Results: After a median of 23 years, 71 (40%) had died and seven (4%) were untraceable. Overall mortality and mortality due to cirrhosis and accidents, mainly intoxication with drugs, were significantly higher compared to those of an age- and sex-matched Danish population. Chronic hepatitis had been diagnosed in 19 (11%) and cirrhosis in 16 (9%). Of 100 patients who were alive, 57 accepted a re-examination. Anti-HCV was detected in 24 (42%) and 19 (33%) were HCV-RNA positive. Of the viremic patients, 11 (58%) had elevated P-ALT, but only three (16%) had already been diagnosed with HCV infection. A history of intravenous drug use was tantamount to anti-HCV positivity. Conclusions: Danish patients with community-acquired acute non-A, non-B hepatitis had an increased mortality due to liver cirrhosis during the first years after the acute infection. Alcohol was the etiological agent in several cases, but HCV infection may also have been present. However, the long-term HCV-related morbidity and mortality were low.

Made available in DSpace on 2015-03-18T15:52:33Z (GMT). No. of bitstreams: 0 Previous issue date: 2014-11-01Bitstream added on 2015-03-18T16:29:28Z : No. of bitstreams: 1 WOS000344476500012.pdf: 1197331 bytes, checksum: bc084f306396871f48167363b5b8b10d (MD5) Carlsberg Foundation Danish Research Council \ Natural Sciences Weis-Fogh fund at Department of Zoology, University of Cambridge Faculty of Science and Technology at Aarhus University Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Danish National Research Foundation Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) MADALGO - Center for Massive Data Algorithmics, a Center of the Danish National Research Foundation Aarhus University Research Foundation via the Center for Interdisciplinary Geospatial Informatics Research - CIGIR Arcadia Island biogeography has greatly contributed to our understanding of the processes determining species' distributions. Previous research has focused on the effects of island geography (i.e., island area, elevation, and isolation) and current climate as drivers of island species richness and endemism. Here, we evaluate the potential additional effects of historical climate on breeding land bird richness and endemism in Wallacea and the West Indies. Furthermore, on the basis of species distributions, we identify island biogeographical network roles and examine their association with geography, current and historical climate, and bird richness/endemism. We found that island geography, especially island area but also isolation and elevation, largely explained the variation in island species richness and endemism. Current and historical climate only added marginally to our understanding of the distribution of species on islands, and this was idiosyncratic to each archipelago. In the West Indies, endemic richness was slightly reduced on islands with historically unstable climates; weak support for the opposite was found in Wallacea. In both archipelagos, large islands with many endemics and situated far from other large islands had high importance for the linkage within modules, indicating that these islands potentially act as speciation pumps and source islands for surrounding smaller islands within the module and, thus, define the biogeographical modules. Large islands situated far from the mainland and/or with a high number of nonendemics acted as links between modules. Additionally, in Wallacea, but not in the West Indies, climatically unstable islands tended to interlink biogeographical modules. The weak and idiosyncratic effect of historical climate on island richness, endemism, and network roles indicates that historical climate had little effects on extinction-immigration dynamics. This is in contrast to the strong effect of historical climate observed on the mainland, possibly because surrounding oceans buffer against strong climate oscillations and because geography is a strong determinant of island richness, endemism and network roles. Univ Copenhagen, Nat Hist Museum Denmark, Ctr Macroecol Evolut & Climate, DK-2100 Copenhagen O, Denmark Univ Cambridge, Dept Zool, Conservat Sci Grp, Cambridge CB2 3EJ, England Aarhus Univ, Dept Biol Sci, DK-8000 Aarhus C, Denmark Univ Estadual Paulista UNESP, Inst Biociencias, Dept Bot, Plant Phenol & Seed Dispersal Grp, BR-13506900 Rio Claro, SP, Brazil Univ Estadual Campinas UNICAMP, Programa Posgrad Ecol, BR-13083865 Campinas, SP, Brazil Univ Estadual Paulista UNESP, Inst Biociencias, Dept Bot, Plant Phenol & Seed Dispersal Grp, BR-13506900 Rio Claro, SP, Brazil FAPESP: 11/22635-2 CAPES: 99999.012341/2013-04

Macrolides have been proposed to have a positive effect in patients with inflammatory lung diseases, including patients with chronic obstructive pulmonary disease (COPD), who suffer from acute exacerbations. Increased use of macrolides for long-term treatment of patients with COPD has been observed. The evidence of a treatment effect of macrolides in this area is sparse, but some studies suggest that it might be beneficial on the number of exacerbations and the length between them. At present there is not sufficient evidence to issue a general recommendation for prescribing macrolides for the long-term treatment of COPD.

The effects of a pure ginseng preparation on a variety of cognitive functions was compared with those of placebo in a double-masked, randomized, test-retest design. The subjects were healthy volunteers older than 40 years of age who were given the ginseng preparation or placebo for 8 to 9 weeks. Of the 112 subjects who completed the study, 55 received ginseng and 57 received placebo. The ginseng group showed a tendency to faster simple reactions and significantly better abstract thinking than the controls. However, there was no significant difference between the two groups in concentration, memory, or subjective experience.

Drug-induced liver injury has been associated with more than 800 different drugs, leading to hospital admission in 1 of 600 to 3500 admissions. This amounts to 2 to 3% of all hospitalisations due to adverse drug reactions, or about 3% of all jaundiced patients. The prognosis of clinically overt drug hepatotoxicity is relatively serious. The clinical picture is essentially nonspecific, with a highly variable latency period from days to years. Drug hepatotoxicity can mimic almost any kind of liver disease. A thorough drug history, a low threshold of suspicion and the exclusion of other causes of liver disease are important for the detection of drug-induced liver disorders. Treatment consists of discontinuation of suspected drug(s), acetylcysteine in the course of paracetamol (acetaminophen) toxicity, and liver transplantation in selected cases of fulminant liver failure. Guidelines regarding the use of selected drugs such as methotrexate and halothane should be followed. Potentially hepatotoxic drugs should be used cautiously in alcoholic patients with or without liver involvement. Patients with uncompensated liver disease should receive a reduced dose of drugs adjusted to the degree of liver function impairment. The general public should be warned against abuse of hepatotoxic drugs such as paracetamol and anabolic steroids.

Udgivelsesdato: 2009 PURPOSE: To evaluate the effect of a combined or a single educational intervention on the prescribing behaviour of general practitioners (GPs). The primary endpoint was effect on inappropriate prescribing according to the Medication Appropriateness Index (MAI). METHODS: General practitioners were randomised to either (1) a combined intervention consisting of an interactive educational meeting plus feedback on participating patients' medication, (2) a single intervention with an interactive educational meeting or (3) a control group (no intervention). Elderly (>65 years) patients exposed to polypharmacy (>/=5 medications) were identified and approached for inclusion. Data on medications prescribed over a 3-month period were collected, and the GPs provided detailed information on their patients before and after the intervention. A pre- and post-MAI were scored for all medications. RESULTS: Of the 277 GPs invited to participate; 41 (14.8%) volunteered. Data were obtained from 166 patients before and after the intervention. Medication appropriateness improved in the combined intervention group but not in the single intervention group. The mean change in MAI and number of medications was -5 [95% confidence interval (CI) -7.3 to -2.6] and -1.03 (95% CI -1.7 to -0.30) in the combined intervention group compared with the group with the educational meeting only and the no intervention group. CONCLUSIONS: A combined intervention consisting of an interactive educational meeting plus recommendations given by clinical pharmacologists/pharmacists concerning specific patients can improve the appropriateness of prescribing among elderly patients exposed to polypharmacy. This study adds to the limited number of well-controlled, randomised studies on overall medication appropriateness among elderly patients in primary care. Important limitations to the study include variability in data provided by participating GPs and a low number of GPs volunteering for the study.

24 consecutive patients (14 females; median age 36, range 18–77) with liver biopsy proven acute non-A, non-B hepatitis (NANBH) were assayed for antibodies to hepatitis C virus (HCV). 14 (58%) were positive initially or during follow-up. Three patients were positive within 4 weeks following onset of symptoms and 7 patients in a serum sample obtained 4–8 weeks after clinical onset. Seroconversion was documented in 7/8 patients in paired sera from the acute phase of the disease. Anti-HCV was detected in 6% and 13% of control patients with acute hepatitis A and toxic hepatitis. NANBH in 6/14 patients (43%) with anti-HCV progressed to chronic liver disease (CLD). In contrast none of the anti-HCV negative patients developed CLD (p=0.02). In addition, 2 anti-HCV positive patients developed fulminant and fatal hepatitis. The predominant route of HCV transmission was intravenous drug abuse. It is concluded that hepatitis may be ascribed to HCV infection in more than half of patients with community aquired NANBH, t...

The study population included 12 healthy male volunteers (mean age: 24.9 years range: 20 39). All underwent abdominal MR imaging (T2W COR, T1W COR, T1W TRA) in both a Panorama 0.23T-V MR unit, a Panorama 0.6T-V MR unit and an Infinion 1.5 T-H MR unit (all Philip Medical Systems, Best, the Netherlands) after randomization. The total examination time in the three units was 2 hours, so 40 min after start of the first examination they switched to another MR-unit and 40 min later the volunteers started their examination in the remaining unit. They had fasted for at least 121⁄2 hours and they had not been allowed to drink fluids for 81⁄2 hours before they underwent the baseline MRI. Seven days after the baseline MRI, the volunteers were randomized (6 in each group) to ingest either half strength CMC-001 (0.8 g manganese chloride (MnCl2)) or full strength (1.6 g manganese chloride (MnCl2)) dissolved in 400 ml water. At time of drinking CMC-001 they had fasted for at least 10 hours and they had not been allowed to drink for 6 hours. 21⁄2 hours after drinking CMC-001 the same imaging procedure as 7 days earlier took place. Thus 41⁄2 hours after drinking all volunteers had been examined at all three field strengths. The resulting images were evaluated with regard to signal intensity in the liver, the bile as well as bowel content by three independent radiologists using a 4 point scoring system (much better/higher, better/higher, unchanged, worse/less).

Udgivelsesdato: June OBJECTIVE: To describe the prevalence of inappropriate prescribing in primary care in Copenhagen County, according to the Medication Appropriateness Index (MAI) and to identify the therapeutic areas most commonly involved. SETTING: A cross-sectional study was conducted among 212 elderly ( >65 years) polypharmacy patients (five or more different medications) listed to 41 general practitioners (GPs) in the County of Copenhagen. METHOD: Patients exposed to polypharmacy were identified via the database recording the drug subsidy system of Danish pharmacies. For each patient, data were collected on subsidised medications prescribed over 3 months by the patients' own GPs. The GPs were asked to provide baseline information regarding the patients' medical history and detailed information regarding the subsidised and non-subsidised medications prescribed to the patients. A MAI was scored for medication prescribed to the patients. Topical, dermatological medications and medications not used regularly were excluded. RESULTS: 212 patients were prescribed 1621 medications by their GPs at baseline. In all, 640 (39.5%) of the medications had one or more inappropriate ratings in the 10 criteria making up the MAI. The main part of the patients (94.3%) had one or more inappropriate ratings among their medications. A total of 12.3% of the medications were rated as 'not indicated', 6% were rated as 'ineffective', 6.7% were given in an incorrect dose, 0.7% were prescribed with incorrect directions, 1.3% had impractical directions, 0.7% of the drugs had clinically significant drug-drug interactions, 8.6% had clinically significant drug-disease/condition interactions, 3.1% were unnecessary duplications, 16.5% were given in an unacceptable duration and 27.1% of the medications were not the least expensive alternative. The therapeutic groups most commonly involved in inappropriate prescribing were medications for treatment of peptic ulcer, cardiovascular medications, anti-inflammatory medications, antidepressants, hypnotics and anti-asthmatics. CONCLUSION: The overall prescribing quality in primary care in Copenhagen County, Denmark is good. However, the majority of patients used one or more medications with inappropriate ratings. The inappropriate prescribing relates to specific therapeutic groups and criteria, which should be targeted in future interventions.

To evaluate the inter-group and intra-group reliability of a modified Medication Appropriateness Index (MAI) for use in primary care. Elderly (>65 years) polypharmacy (≥5 drugs) patients in Copenhagen County participated in the study. Information concerning their medical history and information regarding each drug taken by them was provided by their own general practitioners. A MAI was scored by two groups of evaluators for every drug. To evaluate inter-group agreement, 211 drugs taken by 30 patients were rated according to the ten criteria making up the MAI. Both evaluator groups provided summaries of comments on the medication of each patient. Intra-group agreement was determined from MAI ratings performed twice at two different times on 86 drugs taken by ten patients. Agreement and chance-adjusted agreement were determined, the latter through kappa statistics. The proportion of positive (ppos) and negative (pneg) agreement was also determined. The overall chance-adjusted inter-group agreement (kappa) was moderate. The agreement was good on the criteria practical directions and drug–disease interaction, moderate on the criteria dosage and duration, fair on the criteria indication, effectiveness, duplication and expense, and poor on the criterion drug–drug interaction. The overall chance-adjusted intra-group agreement was good for all criteria and very good for the criteria indication and practical directions. The MAI is used to quantify appropriate and inappropriate prescribing and changes in prescribing quality in intervention studies. However, caution should be used when comparing results across different settings and evaluators. Our study suggests that the index should only be used in intervention studies if the same group rates the appropriateness pre- and post-intervention.

To study the magnetic resonance imaging signal intensity of the liver and gall bladder before and after ingestion of a new oral manganese containing contrast medium at three different field strengths.Twelve healthy male volunteers (mean age, 24.9 years; range, 20-39 years) underwent abdominal magnetic resonance imaging (T(2)W COR, T(1)W COR, T(1)W TRA) at 0.23 T, 0.6 T, and 1.5 T before and after the contrast administration. The duration of fasting was identical before the two studies. Volunteers were randomized into two equal groups (n = 6) to ingest either half or full strength CMC-001 providing either 0.8 or 1.6.g MnCl(2) plus absorption promoters. The CMC-001 dose was dissolved in 400 mL water and ingested 2.5 hours before imaging. The resulting images were evaluated with regard to visualization of the liver and the gall bladder by three radiologists. The signal intensity of the liver was also measured. Blood and urine samples were collected before and after ingestion of CMC-001.The intake of CMC-001 caused a significant increase in the signal intensity of the liver at all three field strengths and at both dosages (up to 90%) on the T(1)W images. The internal structure of the liver was significantly better delineated. The bile in gall bladder was bright after ingestion of the low dose, but dark after the full dose. On the T(2)W images, CMC-001 lowered the signal intensity of liver with up to 30%. CMC-001 had a slight metallic taste, but of no importance according to the volunteers. No systematic adverse reactions caused by the contrast medium were registered. No changes in the blood levels of various routine parameters were measured.It is possible to increase the signal intensity of the liver significantly by oral intake of essential nutritional elements including manganese. The imaging window is more than 2 hours.

Studies on azathioprine (Aza) treatment in Crohn disease have indicated a positive correlation between clinical remission and a concentration in erythrocytes of the metabolites 6-thioguanine nucleotides (E-6-TGN) above 230 pmol/8 x 10(8) RBC. A concentration of the methylated Aza metabolites (E-6-MMP) above 5000 pmol/8 x 10(8) RBC has been correlated to hepatotoxicity. Thiopurine methyltransferase (TPMT) is responsible for the formation of methylated metabolites and lower E-TGN levels, and TPMT genotyping has been proposed as guidance for dosage. In a cross-sectional study we investigated relationships between the clinical outcome and Aza dose, the TPMT genotype and the Aza metabolite levels among patients with Crohn disease.TPMT genotype (PCR assay), azathioprine metabolite levels (HPLC analysis) and xanthine oxidase (XO) activity were determined once in 71 randomly selected Crohn patients on an unaltered Aza dose for at least 3 months.None of the doses of Aza, TPMT genotype, E-6-TGN-, E-6-MMP levels or XO activity were significantly related to disease activity (H-B score), (P = 0.18, P = 0.69, P = 0.90, P = 0.54, P = 0.29, respectively). Leucopenia and/or hepatotoxicity were not demonstrated in any patient. Four patients had a heterozygous TPMT genotype (6.1%; 95% CI: 1.68%-14.80%). The 4 TPMT heterozygous patients had higher E-6-TGN levels than did the 67 remaining patients (P = 0.008).To explore the applicability of TPMT genotyping, E-6-TGN and E-6-MMP levels for therapeutic drug monitoring, large prospective studies with patient entry at the start of Aza therapy are needed. Until the results of such studies are available, the dose adjustments of Aza should be guided primarily by clinical response and blood counts; metabolite level measurements can only be applied to identify therapeutic non-compliance.