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Hammarlund-Udenaes, Margareta
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Publications (10 of 70) Show all publications
Gustafsson, S., Eriksson, J., Syvänen, S., Eriksson, O., Hammarlund-Udenaes, M. & Antoni, G. (2017). Combined PET and microdialysis for in vivo estimation of drug blood-brain barrier transport and brain unbound concentrations. NeuroImage, 155, 177-186.
Open this publication in new window or tab >>Combined PET and microdialysis for in vivo estimation of drug blood-brain barrier transport and brain unbound concentrations
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2017 (English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 155, 177-186 p.Article in journal (Refereed) Published
Abstract [en]

Methods to investigate blood-brain barrier transport and pharmacologically active drug concentrations in the human brain are limited and data translation between species is challenging. Hence, there is a need to further develop the read-out of techniques like positron emission tomography ( PET) for studying neuropharmacokinetics. PET has a high translational applicability from rodents to man and measures total drug concentrations in vivo. The aim of the present study was to investigate the possibility of translating total drug concentrations, acquired through PET, to unbound concentrations, resembling those measured in the interstitial fluid by microdialysis sampling. Simultaneous PET scanning and brain microdialysis sampling were performed in rats throughout a 60 min infusion of [N-methyl-C-11] oxycodone in combination with a therapeutic dose of oxycodone and during a 60 min follow up period after the end of infusion. The oxycodone concentrations acquired with PET were converted into unbound concentrations by compensating for brain tissue binding and brain intracellular distribution, using the unbound volume of distribution in brain (Vu, brain), and were compared to microdialysis measurements of unbound concentrations. A good congruence between the methods was observed throughout the infusion. However, an accumulating divergence in the acquired PET and microdialysis data was apparent and became more pronounced during the elimination phase, most likely due to the passage of radioactive metabolites into the brain. In conclusion, the study showed that PET can be used to translate non-invasively measured total drug concentrations into unbound concentrations as long as the contribution of radiolabelled metabolites is minor or can be compensated for.

Keyword
Blood-brain barrier, Unbound concentration, Positron emission tomography, Microdialysis, Pharmacokinetics, Oxycodone
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-332421 (URN)10.1016/j.neuroimage.2017.04.068 (DOI)000405460900015 ()28467891 (PubMedID)
Available from: 2017-11-02 Created: 2017-11-02 Last updated: 2017-11-02Bibliographically approved
Chen, X., Keep, R. F., Liang, Y., Zhu, H.-J., Hammarlund-Udenaes, M., Hu, Y. & Smith, D. E. (2017). Influence of peptide transporter 2 (PEPT2) on the distribution of cefadroxil in mouse brain: A microdialysis study. Biochemical Pharmacology, 131, 89-97.
Open this publication in new window or tab >>Influence of peptide transporter 2 (PEPT2) on the distribution of cefadroxil in mouse brain: A microdialysis study
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2017 (English)In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 131, 89-97 p.Article in journal (Refereed) Published
Abstract [en]

Peptide transporter 2 (PEPT2) is a high-affinity low-capacity transporter belonging to the proton-coupled oligopeptide transporter family. Although many aspects of PEPT2 structure-function are known, including its localization in choroid plexus and neurons, its regional activity in brain, especially extracellular fluid (ECF), is uncertain. In this study, the pharmacokinetics and regional brain distribution of cefadroxil, a beta-lactam antibiotic and PEN 2 substrate, were investigated in wildtype and Pept2 null mice using in vivo intracerebral microdialysis. Cefadroxil was infused intravenously over 4 h at 0.15 mg/min/kg, and samples obtained from plasma, brain ECF, cerebrospinal fluid (CSF) and brain tissue. A permeability surface area experiment was also performed in which 0.15 mg/min/kg cefadroxil was infused intravenously for 10 min, and samples obtained from plasma and brain tissues. Our results showed that PEPT2 ablation significantly increased the brain ECF and CSF levels of cefadroxil (2- to 2.5-fold). In contrast, there were no significant differences between wildtype and Pept2 null mice in the amount of cefadroxil in brain cells. The unbound volume of distribution of cefadroxil in brain was 60% lower in Pept2 null mice indicating an uptake function for PEPT2 in brain cells. Finally, PEPT2 did not affect the influx clearance of cefadroxil, thereby, ruling out differences between the two genotypes in drug entry across the blood-brain barriers. These findings demonstrate, for the first time, the impact of PEPT2 on brain ECF as well as the known role of PEPT2 in removing peptide-like drugs, such as cefadroxil, from the CSF to blood.

Place, publisher, year, edition, pages
PERGAMON-ELSEVIER SCIENCE LTD, 2017
Keyword
Microdialysis, Peptide transporter 2, Blood-cerebrospinal fluid barrier, Cefadroxil, Brain extracellular fluid
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-321784 (URN)10.1016/j.bcp.2017.02.005 (DOI)000399256700008 ()28192085 (PubMedID)
Available from: 2017-05-11 Created: 2017-05-11 Last updated: 2018-01-13Bibliographically approved
Agrawal, M., Ajazuddin, A., Tripathi, D. K., Saraf, S., Saraf, S., Antimisiaris, S. G., . . . Alexander, A. (2017). Recent advancements in liposomes targeting strategies to cross blood-brain barrier (BBB) for the treatment of Alzheimer's disease. Journal of Controlled Release, 260, 61-77.
Open this publication in new window or tab >>Recent advancements in liposomes targeting strategies to cross blood-brain barrier (BBB) for the treatment of Alzheimer's disease
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2017 (English)In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 260, 61-77 p.Article, review/survey (Refereed) Published
Abstract [en]

In this modern era, with the help of various advanced technologies, medical science has overcome most of the health-related issues successfully. Though, some diseases still remain unresolved due to various physiological barriers. One such condition is Alzheimer; a neurodegenerative disorder characterized by progressive memory impairment, behavioral abnormalities, mood swing and disturbed routine activities of the person suffering from. It is well known to all that the brain is entirely covered by a protective layer commonly known as blood brain barrier (BBB) which is responsible to maintain the homeostasis of brain by restricting the entry of toxic substances, drug molecules, various proteins and peptides, small hydrophilic molecules, large lipophilic substances and so many other peripheral components to protect the brain from any harmful stimuli. This functionally essential structure creates a major hurdle for delivery of any drug into the brain. Still, there are some provisions on BBB which facilitate the entry of useful substances in the brain via specific mechanisms like passive diffusion, receptor-mediated transcytosis, carrier-mediated transcytosis etc. Another important factor for drug transport is the selection of a suitable drug delivery systems like, liposome, which is a novel drug carrier system offering a potential approach to resolving this problem. Its unique phospholipid bilayer structure (similar to physiological membrane) had made it more compatible with the lipoidal layer of BBB and helps the drug to enter the brain. The present review work focused on various surface modifications with functional ligand (like lactoferrin, transferrin etc.) and carrier molecules (such as glutathione, glucose etc.) on the liposomal structure to enhance its brain targeting ability towards the successful treatment of Alzheimer disease.

Keyword
Alzheimer, beta amyloid, Liposome, Lactoferrin, Transferrin, Glutathione
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-335804 (URN)10.1016/j.jconrel.2017.05.019 (DOI)000405482100006 ()28549949 (PubMedID)
Available from: 2018-01-22 Created: 2018-01-22 Last updated: 2018-01-22
Bäckström, E., Lundqvist, A., Boger, E., Svanberg, P., Ewing, P., Hammarlund-Udenaes, M. & Fridén, M. (2016). Development of a Novel Lung Slice Methodology for Profiling of Inhaled Compounds. Journal of Pharmaceutical Sciences, 105(2), 838-845.
Open this publication in new window or tab >>Development of a Novel Lung Slice Methodology for Profiling of Inhaled Compounds
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2016 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 105, no 2, 838-845 p.Article in journal (Refereed) Published
Abstract [en]

The challenge of defining the concentration of unbound drug at the lung target site after inhalation limits the possibility to optimize target exposure by compound design. In this study, a novel rat lung slice methodology has been developed and applied to study drug uptake in lung tissue, and the mechanisms by which this occurs. Freshly prepared lung slices (500 μm) from drug-naive rats were incubated with drugs followed by determination of the unbound drug volume of distribution in lung (Vu,lung), as the total concentration of drug in slices divided by the buffer (unbound) concentration. Vu,lung determined for a set of inhaled drug compounds ranged from 2.21 mL/g for salbutamol to 2970 mL/g for dibasic compound A. Co-incubation with monensin, a modulator of lysosomal pH, resulted in inhibition of tissue uptake of basic propranolol to 13%, indicating extensive lysosomal trapping. Partitioning into cells was particularly high for the cation MPP+ and the dibasic compound A, likely because of the carrier-mediated transport and lysosomal trapping. The results show that different factors are important for tissue uptake and the presented method can be used for profiling of inhaled compounds, leading to a greater understanding of distribution and exposure of drug in the lung.

National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-278039 (URN)10.1002/jps.24575 (DOI)000381768500050 ()26178700 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 316736AstraZeneca
Available from: 2016-02-23 Created: 2016-02-23 Last updated: 2018-01-10Bibliographically approved
Lindqvist, A., Jönsson, S. & Hammarlund-Udenaes, M. (2016). Exploring Factors Causing Low Brain penetration of the Opioid Peptide DAMGO through Experimental Methods and Modeling. Molecular Pharmaceutics, 13(4), 1258-1266.
Open this publication in new window or tab >>Exploring Factors Causing Low Brain penetration of the Opioid Peptide DAMGO through Experimental Methods and Modeling
2016 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 13, no 4, 1258-1266 p.Article in journal (Refereed) Published
Abstract [en]

To advance the development of peptide analogues for improved treatment of pain, we need to learn more about the blood brain barrier transport of these substances. A low penetration into the brain, with an unbound brain to blood ratio, K-p,K-uu, of 0.08, is an important reason for the lack of effect of the enkephalin analogue DAMGO (H-Tyr-D-Ala-Gly-MePhe-Gly-ol) according to earlier findings. The aim of this study was to investigate the role of efflux transporters, metabolism in the brain, and/or elimination through interstitial fluid bulk flow for the brain exposure of DAMGO. The in vivo brain distribution of DAMGO was evaluated using microdialysis in the rat. Data were analyzed with population modeling which resulted in a clearance into the brain of 1.1 and an efflux clearance 14 mu L/min/g_brain. The efflux clearance was thus much higher than the bulk flow known from the literature. Coadministration with the efflux transporter inhibitors cyclosporin A and elacridar in vivo did not affect K-p,K-uu. The permeability of DAMGO in the Caco-2 assay was very low, of the same size as mannitol. The efflux ratio was <2 and not influenced by cyclosporin A or elacridar. These results indicate that the well-known efflux transporters Pgp and Bcrp are not responsible for the higher efflux of DAMGO, which opens up for an important role of other transporters at the BBB.

Keyword
CNS, blood-brain barrier, microdialysis, permeability, Pgp, population modeling, NONMEM, elacridar, cyclosporine A, efflux, pharmacokinetics
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-267592 (URN)10.1021/acs.molpharmaceut.5b00835 (DOI)000373550600007 ()26898546 (PubMedID)
Funder
Swedish Research Council
Available from: 2015-11-24 Created: 2015-11-24 Last updated: 2018-01-10Bibliographically approved
Melander, E., Eriksson, C., Jansson, B., Göransson, U. & Hammarlund-Udenaes, M. (2016). Improved method for quantitative analysis of the cyclotide kalata B1 in plasma and brain homogenate. Paper presented at 3rd International Conference on Circular Proteins (ICCP), NOV 01-04, 2015, AUSTRALIA. Biopolymers, 106(6), 910-916.
Open this publication in new window or tab >>Improved method for quantitative analysis of the cyclotide kalata B1 in plasma and brain homogenate
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2016 (English)In: Biopolymers, ISSN 0006-3525, E-ISSN 1097-0282, Vol. 106, no 6, 910-916 p.Article in journal, Meeting abstract (Refereed) Published
Abstract [en]

This study provides a new method for quantifying the cyclotide kalata B1 in both plasma and brain homogenate. Cyclotides are ultra-stable peptides with three disulfide bonds that are interesting from a drug development perspective as they can be used as scaffolds. In this study we describe a new validated LC-MS/MS method with high sensitivity and specificity for kalata B1. The limit of quantification was 2 ng/mL in plasma and 5 ng/gmL in brain homogenate. The method was linear in the range 2-10,000 ng/mL for plasma and 5-2000 ng/g for brain. Liquid Chromatographic separation was performed on a HyPurity C18 column, 50 3 4.6 mm, 3 mm particle size. The method had inter-and intra-day precision and accuracy levels <15% and 12% respectively. Applying the method to in vivo plasma samples and brain homogenate samples from equilibrium dialysis yielded satisfying results and was able to describe the plasma pharmacokinetics and brain tissue binding of kalata B1. The described method is quick, reproducible and well suited to quantifying kalata B1 in biological matrices.

Keyword
brain, cyclotides, kalata B1, liquid chromatography, mass spectrometry, pharmacokinetics
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-317707 (URN)10.1002/bip.22984 (DOI)000393465500016 ()27603276 (PubMedID)
Conference
3rd International Conference on Circular Proteins (ICCP), NOV 01-04, 2015, AUSTRALIA
Funder
Swedish Research Council, 2012-5063 2011-4339
Available from: 2017-03-17 Created: 2017-03-17 Last updated: 2018-01-13Bibliographically approved
Lindqvist, A., Rip, J., van Kregten, J., Gaillard, P. J. & Hammarlund-Udenaes, M. (2016). In vivo Functional Evaluation of Increased Brain Delivery of the Opioid Peptide DAMGO by Glutathione-PEGylated Liposomes. Pharmaceutical research, 33(1), 177-185.
Open this publication in new window or tab >>In vivo Functional Evaluation of Increased Brain Delivery of the Opioid Peptide DAMGO by Glutathione-PEGylated Liposomes
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2016 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 33, no 1, 177-185 p.Article in journal (Refereed) Published
Abstract [en]

Purpose:

The purpose of this study was to evaluate formulation factors causing improvement in brain delivery of a small peptide after encapsulation into a targeted nanocarrier in vivo.

Methods:

The evaluation was performed in rats using microdialysis, which enabled continuous sampling of the released drug in both the brain (striatum) and blood. Uptake in brain could thereby be studied in terms of therapeutically active, released drug.

Results:

We found that encapsulation of the peptide DAMGO in fast-releasing polyethylene glycol (PEG)ylated liposomes, either with or without the specific brain targeting ligand glutathione (GSH), doubled the uptake of DAMGO into the rat brain. The increased brain delivery was observed only when the drug was encapsulated into the liposomes, thus excluding any effects of the liposomes themselves on the blood-brain barrier integrity as a possible mechanism. The addition of a GSH coating on the liposomes did not result in an additional increase in DAMGO concentrations in the brain, in contrast to earlier studies on GSH coating. This may be caused by differences in the characteristics of the encapsulated compounds and the composition of the liposome formulations. 

Conclusions:

We were able to show that encapsulation into PEGylated liposomes of a peptide with limited brain delivery could double the drug uptake into the brain without using a specific brain targeting ligand.  

Keyword
Brain delivery, liposomes, blood-brain barrier, microdialysis, opioid peptide
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-267583 (URN)10.1007/s11095-015-1774-3 (DOI)000367343000014 ()26275529 (PubMedID)
Funder
Swedish Research Council, 521-2011-4339
Available from: 2015-11-24 Created: 2015-11-24 Last updated: 2018-01-10Bibliographically approved
Loryan, I., Melander, E., Svensson, M., Payan, M., König, F., Jansson, B. & Hammarlund-Udenaes, M. (2016). In-depth neuropharmacokinetic analysis of antipsychotics based on a novel approach to estimate unbound target-site concentration in CNS regions: link to spatial receptor occupancy. Molecular Psychiatry, 21(11), 1527-1536.
Open this publication in new window or tab >>In-depth neuropharmacokinetic analysis of antipsychotics based on a novel approach to estimate unbound target-site concentration in CNS regions: link to spatial receptor occupancy
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2016 (English)In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 21, no 11, 1527-1536 p.Article in journal (Refereed) Published
Abstract [en]

The current study provides a novel in-depth assessment of the extent of antipsychotic drugs transport across the blood-brain barrier (BBB) into various brain regions, as well as across the blood-spinal cord barrier (BSCB) and the blood-cerebrospinal fluid barrier (BCSFB). This is combined with an estimation of cellular barrier transport and a systematic evaluation of nonspecific brain tissue binding. The study is based on the new Combinatory Mapping Approach (CMA), here further developed for the assessment of unbound drug neuropharmacokinetics in regions of interest (ROI), referred as CMA-ROI. We show that differences exist between regions in both BBB transport and in brain tissue binding. The most dramatic spatial differences in BBB transport were found for the P-glycoprotein substrates risperidone (5.4-fold) and paliperidone (4-fold). A higher level of transporter-mediated protection was observed in the cerebellum compared with other brain regions with a more pronounced efflux for quetiapine, risperidone and paliperidone. The highest BBB penetration was documented in the frontal cortex, striatum and hippocampus (haloperidol, olanzapine), indicating potential influx mechanisms. BSCB transport was in general characterized by more efficient efflux compared with the brain regions. Regional tissue binding was significantly different for haloperidol, clozapine, risperidone and quetiapine (maximally 1.9-fold). Spatial differences in local unbound concentrations were found to significantly influence cortical 5-HT2A receptor occupancy for risperidone and olanzapine. In conclusion, the observed regional differences in BBB penetration may potentially be important factors contributing to variations in therapeutic effect and side effect profiles among antipsychotic drugs.

National Category
Pharmaceutical Sciences Pharmacology and Toxicology
Research subject
Pharmaceutical Pharmacology
Identifiers
urn:nbn:se:uu:diva-277951 (URN)10.1038/mp.2015.229 (DOI)000388719600007 ()26809840 (PubMedID)
Available from: 2016-02-23 Created: 2016-02-23 Last updated: 2018-01-10Bibliographically approved
Bäckström, E., Boger, E., Lundqvist, A., Hammarlund-Udenaes, M. & Fridén, M. (2016). Lung Retention by Lysosomal Trapping of Inhaled Drugs Can Be Predicted In Vitro With Lung Slices. Journal of Pharmaceutical Sciences, 105(11), 3432-3439.
Open this publication in new window or tab >>Lung Retention by Lysosomal Trapping of Inhaled Drugs Can Be Predicted In Vitro With Lung Slices
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2016 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 105, no 11, 3432-3439 p.Article in journal (Refereed) Published
Abstract [en]

Modulating and optimizing the local pharmacokinetics of inhaled drugs by chemical design or formulation is challenged by the lack of predictive in vitro systems and in vivo techniques providing a detailed description of drug location in the lung. The present study investigated whether a new experimental setup of freshly prepared agarose-filled lung slices can be used to estimate lung retention in vitro, by comparing with in vivo lung retention after intratracheal instillation. Slices preloaded with inhaled beta-adrenergic compounds (salbutamol, formoterol, salmeterol, indacaterol or AZD3199) were incubated in a large volume of buffer (w/wo monensin to assess the role of lysosomal trapping), and the amount remaining in slices at different time points was determined with liquid chromatography-tandem mass spectrometry. The in vitro lung retention closely matched the in vivo lung retention (half-lives within 3-fold for 4/5 compounds), and monensin shortened the half-lives for all compounds. The results suggest that freshly prepared rat lungs slices can be used to predict lung retention and that slow kinetics of lysosomal trapping is a key mechanism by which retention in the lung and the effect duration of inhaled beta-adrenergic bronchodilators are prolonged.

Keyword
pharmacokinetics, pulmonary drug delivery, tissue partition, distribution, pulmonary
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-311212 (URN)10.1016/j.xphs.2016.08.014 (DOI)000388268200023 ()27671235 (PubMedID)
Available from: 2016-12-22 Created: 2016-12-22 Last updated: 2018-01-13Bibliographically approved
Alassaad, A., Melhus, H., Hammarlund-Udenaes, M., Bertilsson, M., Gillespie, U. & Sundström, J. (2015). A tool for prediction of risk of rehospitalisation and mortality in the hospitalised elderly: secondary analysis of clinical trial data. BMJ Open, 5(2), Article ID e007259.
Open this publication in new window or tab >>A tool for prediction of risk of rehospitalisation and mortality in the hospitalised elderly: secondary analysis of clinical trial data
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2015 (English)In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 5, no 2, e007259Article in journal (Refereed) Published
Abstract [en]

Objectives: To construct and internally validate a risk score, the '80+ score', for revisits to hospital and mortality for older patients, incorporating aspects of pharmacotherapy. Our secondary aim was to compare the discriminatory ability of the score with that of three validated tools for measuring inappropriate prescribing: Screening Tool of Older Person's Prescriptions (STOPP), Screening Tool to Alert doctors to Right Treatment (START) and Medication Appropriateness Index (MAI). Setting: Two acute internal medicine wards at Uppsala University hospital. Patient data were used from a randomised controlled trial investigating the effects of a comprehensive clinical pharmacist intervention. Participants: Data from 368 patients, aged 80 years and older, admitted to one of the study wards. Primary outcome measure: Time to rehospitalisation or death during the year after discharge from hospital. Candidate variables were selected among a large number of clinical and drug-specific variables. After a selection process, a score for risk estimation was constructed. The 80+ score was internally validated, and the discriminatory ability of the score and of STOPP, START and MAI was assessed using C-statistics. Results: Seven variables were selected. Impaired renal function, pulmonary disease, malignant disease, living in a nursing home, being prescribed an opioid or being prescribed a drug for peptic ulcer or gastroesophageal reflux disease were associated with an increased risk, while being prescribed an antidepressant drug (tricyclic antidepressants not included) was linked to a lower risk of the outcome. These variables made up the components of the 80+ score. The C-statistics were 0.71 (80+), 0.57 (STOPP), 0.54 (START) and 0.63 (MAI). Conclusions: We developed and internally validated a score for prediction of risk of rehospitalisation and mortality in hospitalised older people. The score discriminated risk better than available tools for inappropriate prescribing. Pending external validation, this score can aid in clinical identification of high-risk patients and targeting of interventions.

National Category
Other Medical Sciences
Identifiers
urn:nbn:se:uu:diva-246233 (URN)10.1136/bmjopen-2014-007259 (DOI)000363455400040 ()
Available from: 2015-03-03 Created: 2015-03-03 Last updated: 2017-12-04Bibliographically approved
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