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| 2. |
- Bonate, Peter L., et al.
(författare)
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Training the next generation of pharmacometric modelers : a multisector perspective
- 2023
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Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Nature. - 1567-567X .- 1573-8744. ; 51:1, s. 5-31
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Tidskriftsartikel (refereegranskat)abstract
- The current demand for pharmacometricians outmatches the supply provided by academic institutions and considerable investments are made to develop the competencies of these scientists on-the-job. Even with the observed increase in academic programs related to pharmacometrics, this need is unlikely to change in the foreseeable future, as the demand and scope of pharmacometrics applications keep expanding. Further, the field of pharmacometrics is changing. The field largely started when Lewis Sheiner and Stuart Beal published their seminal papers on population pharmacokinetics in the late 1970’s and early 1980’s and has continued to grow in impact and use since its inception. Physiological-based pharmacokinetics and systems pharmacology have grown rapidly in scope and impact in the last decade and machine learning is just on the horizon. While all these methodologies are categorized as pharmacometrics, no one person can be an expert in everything. So how do you train future pharmacometricians? Leading experts in academia, industry, contract research organizations, clinical medicine, and regulatory gave their opinions on how to best train future pharmacometricians. Their opinions were collected and synthesized to create some general recommendations.
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| 3. |
- Foerster, Sunniva, et al.
(författare)
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In vitro antimicrobial combination testing of and evolution of resistance to the first-in-class spiropyrimidinetrione zoliflodacin combined with six therapeutically relevant antimicrobials for Neisseria gonorrhoeae
- 2019
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Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press. - 0305-7453 .- 1460-2091. ; 74:12, s. 3521-3529
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Resistance in Neisseria gonorrhoeae to all gonorrhoea therapeutic antimicrobials has emerged. Novel therapeutic antimicrobials are imperative and the first-in-class spiropyrimidinetrione zoliflodacin appears promising. Zoliflodacin could be introduced in dual antimicrobial therapies to prevent the emergence and/or spread of resistance. We investigated the in vitro activity of and selection of resistance to zoliflodacin alone and in combination with six gonorrhoea therapeutic antimicrobials against N. gonorrhoeae.METHODS: The international gonococcal reference strains WHO F (WT) and WHO O, WHO V and WHO X (strains with different AMR profiles) were examined. Zoliflodacin was evaluated alone or combined with ceftriaxone, cefixime, spectinomycin, gentamicin, tetracycline, cethromycin or sitafloxacin in chequerboard assays, time-kill curve analysis and selection-of-resistance studies.RESULTS: Zoliflodacin alone or in combination with all six antimicrobials showed rapid growth inhibition against all examined strains. The time-kill curve analysis indicated that tetracycline or cethromycin combined with zoliflodacin can significantly decrease the zoliflodacin kill rate in vitro. The frequency of selected zoliflodacin-resistance mutations was low when evaluated as a single agent and further reduced for all antimicrobial combinations. All resistant mutants contained the GyrB mutations D429N, K450T or K450N, resulting in zoliflodacin MICs of 0.5-4 mg/L.CONCLUSIONS: Zoliflodacin, alone or in combination with sexually transmitted infection therapeutic antimicrobials, rapidly kills gonococci with infrequent resistance emergence. Zoliflodacin remains promising for gonorrhoea oral monotherapy and as part of dual antimicrobial therapy with low resistance emergence potential. A Phase III trial evaluating efficacy and safety of zoliflodacin for uncomplicated gonorrhoea treatment is planned in 2019.
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| 5. |
- Jagtap, Pratik D., et al.
(författare)
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The Association of Biomolecular Resource Facilities Proteome Informatics Research Group Study on Metaproteomics (iPRG-2020)
- 2023
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Ingår i: Journal of biomolecular techniques : JBT. - : Association of Biomolecular Resource Facilities. - 1943-4731. ; 34:3
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Tidskriftsartikel (refereegranskat)abstract
- Metaproteomics research using mass spectrometry data has emerged as a powerful strategy to understand the mechanisms underlying microbiome dynamics and the interaction of microbiomes with their immediate environment. Recent advances in sample preparation, data acquisition, and bioinformatics workflows have greatly contributed to progress in this field. In 2020, the Association of Biomolecular Research Facilities Proteome Informatics Research Group launched a collaborative study to assess the bioinformatics options available for metaproteomics research. The study was conducted in 2 phases. In the first phase, participants were provided with mass spectrometry data files and were asked to identify the taxonomic composition and relative taxa abundances in the samples without supplying any protein sequence databases. The most challenging question asked of the participants was to postulate the nature of any biological phenomena that may have taken place in the samples, such as interactions among taxonomic species. In the second phase, participants were provided a protein sequence database composed of the species present in the sample and were asked to answer the same set of questions as for phase 1. In this report, we summarize the data processing methods and tools used by participants, including database searching and software tools used for taxonomic and functional analysis. This study provides insights into the status of metaproteomics bioinformatics in participating laboratories and core facilities.
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| 6. |
- Leone, Marc, et al.
(författare)
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Update in antibiotic therapy in intensive care unit : report from the 2019 Nîmes International Symposium
- 2019
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Ingår i: Anaesthesia Critical Care & Pain Medicine. - : Elsevier BV. - 2352-5568. ; 38:6, s. 647-656
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Forskningsöversikt (refereegranskat)abstract
- The 2019 Nîmes International Symposium in Antibiotic Therapy Optimisation aimed at determining the best approaches of a number of the antibiotic management strategies for critically ill patients. Experts reviewed the latest literature relating to requirements for an optimal antibiotic stewardship program, risks of sub-therapeutic dosing of antibiotics in critically ill patients, persisting issues about efficiency of combination therapy and the value of de-escalation, new perspectives of pharmacokinetics, drug toxicities including collateral damages-associated with antibiotics, the place of nebulisation of antibiotics, management of patients receiving extracorporeal therapies and the place of new antibiotics. In this paper, each of these issues is discussed with key messages presented after a brief review of evidence.
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| 7. |
- McCusker, Gillian Young, et al.
(författare)
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Evaluating Arctic clouds modelled with the Unified Model and Integrated Forecasting System
- 2023
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Ingår i: Atmospheric Chemistry And Physics. - 1680-7316 .- 1680-7324. ; 23:8, s. 4819-4847
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Tidskriftsartikel (refereegranskat)abstract
- By synthesising remote-sensing measurements made in the central Arctic into a model-gridded Cloudnet cloud product, we evaluate how well the Met Office Unified Model (UM) and the European Centre for Medium-Range Weather Forecasting (ECMWF) Integrated Forecasting System (IFS) capture Arctic clouds and their associated interactions with the surface energy balance and the thermodynamic structure of the lower troposphere. This evaluation was conducted using a 4-week observation period from the Arctic Ocean 2018 expedition, where the transition from sea ice melting to freezing conditions was measured. Three different cloud schemes were tested within a nested limited-area model (LAM) configuration of the UM – two regionally operational single-moment schemes (UM_RA2M and UM_RA2T) and one novel double-moment scheme (UM_CASIM-100) – while one global simulation was conducted with the IFS, utilising its default cloud scheme (ECMWF_IFS).Consistent weaknesses were identified across both models, with both the UM and IFS overestimating cloud occurrence below 3 km. This overestimation was also consistent across the three cloud configurations used within the UM framework, with >90 % mean cloud occurrence simulated between 0.15 and 1 km in all the model simulations. However, the cloud microphysical structure, on average, was modelled reasonably well in each simulation, with the cloud liquid water content (LWC) and ice water content (IWC) comparing well with observations over much of the vertical profile. The key microphysical discrepancy between the models and observations was in the LWC between 1 and 3 km, where most simulations (all except UM_RA2T) overestimated the observed LWC.Despite this reasonable performance in cloud physical structure, both models failed to adequately capture cloud-free episodes: this consistency in cloud cover likely contributes to the ever-present near-surface temperature bias in every simulation. Both models also consistently exhibited temperature and moisture biases below 3 km, with particularly strong cold biases coinciding with the overabundant modelled cloud layers. These biases are likely due to too much cloud-top radiative cooling from these persistent modelled cloud layers and were consistent across the three UM configurations tested, despite differences in their parameterisations of cloud on a sub-grid scale. Alarmingly, our findings suggest that these biases in the regional model were inherited from the global model, driving a cause–effect relationship between the excessive low-altitude cloudiness and the coincident cold bias. Using representative cloud condensation nuclei concentrations in our double-moment UM configuration while improving cloud microphysical structure does little to alleviate these biases; therefore, no matter how comprehensive we make the cloud physics in the nested LAM configuration used here, its cloud and thermodynamic structure will continue to be overwhelmingly biased by the meteorological conditions of its driving model.
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| 8. |
- Meredith, Jere E, et al.
(författare)
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Characterization of novel CSF Tau and ptau biomarkers for Alzheimer's disease.
- 2013
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 8:10
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral spinal fluid (CSF) Aβ42, tau and p181tau are widely accepted biomarkers of Alzheimer's disease (AD). Numerous studies show that CSF tau and p181tau levels are elevated in mild-to-moderate AD compared to age-matched controls. In addition, these increases might predict preclinical AD in cognitively normal elderly. Despite their importance as biomarkers, the molecular nature of CSF tau and ptau is not known. In the current study, reverse-phase high performance liquid chromatography was used to enrich and concentrate tau prior to western-blot analysis. Multiple N-terminal and mid-domain fragments of tau were detected in pooled CSF with apparent sizes ranging from <20 kDa to ~40 kDa. The pattern of tau fragments in AD and control samples were similar. In contrast, full-length tau and C-terminal-containing fragments were not detected. To quantify levels, five tau ELISAs and three ptau ELISAs were developed to detect different overlapping regions of the protein. The discriminatory potential of each assay was determined using 20 AD and 20 age-matched control CSF samples. Of the tau ELISAs, the two assays specific for tau containing N-terminal sequences, amino acids 9-198 (numbering based on tau 441) and 9-163, exhibited the most significant differences between AD and control samples. In contrast, CSF tau was not detected with an ELISA specific for a more C-terminal region (amino acids 159-335). Significant discrimination was also observed with ptau assays measuring amino acids 159-p181 and 159-p231. Interestingly, the discriminatory potential of p181 was reduced when measured in the context of tau species containing amino acids 9-p181. Taken together, these results demonstrate that tau in CSF occurs as a series of fragments and that discrimination of AD from control is dependent on the subset of tau species measured. These assays provide novel tools to investigate CSF tau and ptau as biomarkers for other neurodegenerative diseases.
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| 9. |
- Neely, G Gregory, et al.
(författare)
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A Genome-wide Drosophila Screen for Heat Nociception Identifies alpha 2 delta 3 as an Evolutionarily Conserved Pain Gene
- 2010
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Ingår i: Cell. - : Elsevier Science B.V., Amsterdam.. - 0092-8674 .- 1097-4172. ; 143:4, s. 628-638
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Tidskriftsartikel (refereegranskat)abstract
- Worldwide, acute, and chronic pain affects 20% of the adult population and represents an enormous financial and emotional burden. Using genome-wide neuronal-specific RNAi knockdown in Drosophila, we report a global screen for an innate behavior and identify hundreds of genes implicated in heat nociception, including the alpha 2 delta family calcium channel subunit straightjacket (stj). Mice mutant for the stj ortholog CACNA2D3 (alpha 2 delta 3) also exhibit impaired behavioral heat pain sensitivity. In addition, in humans, alpha 2 delta 3 SNP variants associate with reduced sensitivity to acute noxious heat and chronic back pain. Functional imaging in alpha 2 delta 3 mutant mice revealed impaired transmission of thermal pain-evoked signals from the thalamus to higher-order pain centers. Intriguingly, in alpha 2 delta 3 mutant mice, thermal pain and tactile stimulation triggered strong cross-activation, or synesthesia, of brain regions involved in vision, olfaction, and hearing.
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| 10. |
- Palmquist, Eva, 1977-
(författare)
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Environmental intolerance : psychological risk and health factors
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Environmental intolerance (EI) is an embracing term for a number of conditions characterized by a wide range of non-specific symptoms attributed to certain environmental exposures (e.g. pungent/odorous chemicals, residing in a certain building, electromagnetic fields and everyday sounds). EI often leads to lifestyle alterations (e.g. not taking part of activities formerly engaged in) and functional impairment (e.g. not being able to work, social deprivation). The etiology of the conditions is largely unknown, though there is growing empirical evidence for associations between mental ill-health and EI. However, mainly cross-sectional studies have been conducted which cannot demonstrate temporality. Further on, the prognosis for EI is not well-known.This thesis includes four studies based on cross-sectional (Study 1) and longitudinal (Study 2-4) data from the Västerbotten Environmental Health Study (VEHS). The VEHS contains data from three data collections performed on the same set of respondents in 2010 (T1; n=3406), 2013 (T2; n=2336) and 2016 (T3; n=1837). In Study 1 the co-prevalence between EI attributed to chemicals, certain buildings, EMFs and sounds was investigated. The co-prevalence between all types of self-reported EI was greater than predictions based on coincidence, indicating that the different types of EI are associated, possibly sharing the same pathogenesis or that the afflicted individuals share some common predisposition to acquire the conditions. In Study 2 coping strategies and social support in EI were investigated and particularly whether certain combinations of different types of coping and social support may be important in recovering from EI. The participants who recovered from EI showed different combinations of coping strategies and social support than those who did not recover. In Study 3 the temporality between EI (attributed to chemicals, buildings and sounds) and psychological factors was investigated. The results showed that stress, anxiety, depression and burnout are risk factors for EI attributed to chemicals and sounds, but not for EI attributed to buildings. Changing perspective, EI attributed to buildings was a significant predictor of burnout, whereas EI attributed to sounds and chemicals were not. In Study 4 the prognosis of EI during a six-year period was studied. The probability of recovering from a state of specific EI was 44.3%, the probability of a specific EI to spread to other types of EI was 12.8%, and the probability of relapse was 3.9%. The participants who recovered showed lower levels of emotional and behavioral disruption than those who did not recover. The participants who showed spreading from one to several EIs perceived more stress than those who remained in a state of a specific EI, but had lower levels of burnout.Based on the findings of the studies in the thesis it is suggested that psychotherapy focusing on reducing the emotional and behavioral reactions of exposure might be helpful. Even though the causation of EI is unknown, negative expectations about exposure might accumulate symptoms, setting a vicious circle into motion. The task of the psychologist might be to break this circle.
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