| 1. |
- Ahlbäck Öberg, Shirin, Professor, 1964-, et al.
(författare)
-
Svenska lärosäten : organisering, finansiering, positionering
- 2022
-
Ingår i: Statsvetenskaplig Tidskrift. - Lund : Fahlbeckska stiftelsen. - 0039-0747. ; 124:1, s. 5-18
-
Tidskriftsartikel (refereegranskat)abstract
- Våren 2021 tog riksdagen ställning till den elfte forskningspolitiska propositionen i ordningen, Forskning, frihet, framtid – kunskap och innovation för Sverige (prop. 2020/21:60). Bara genom att studera forskningspropositionernas rubriker kan man enkelt avläsa vilka primära mål sittande regering har med sin forskningspolitik. Förra gången det begav sig stod samverkan högst på agendan. På propositionens 167 sidor nämndes ”samverkan” hela 224 gånger, medan en konkurrent som ”frihet” i stort lyste med sin frånvaro och enbart nämndes sex gånger (prop. 2016/17:50). I den nu aktuella forskningspropositionen har emellertid ”frihet” getts en mer framträdande roll än någonsin tidigare – vilket även framgår av rubriken – och omnämns hela 141 gånger (”samverkan” är dock mer än dubbelt så vanligt) (prop. 2020/21:60). Skälet till att frihetsfrågan fått en så framträdande roll denna gång är förstås de förslag om att föra in akademisk frihet i högskolelagen som Styr- och resursutredningen presenterat i sitt betänkande (”Struten”, se SOU 2019:6). Men hur ska vi förstå denna politiska strävan efter att stärka den akademiska friheten? I detta specialnummer tar vi ett bredare grepp om hur högskolepolitiken utvecklats över tid, och frågar oss vad som utmärker denna frihet. Vem är det som ska ges frihet? Hur ser balansen mellan formell och reell frihet ut? Vad utmärker dem som skänks frihet – oftast lärosätena – och hur skiljer de sig åt?
|
|
| 2. |
- Amilon, Carl, et al.
(författare)
-
Population Pharmacodynamic Modeling of Eflornithine-Based Treatments Against Late-Stage Gambiense Human African Trypanosomiasis and Efficacy Predictions of L-eflornithine-Based Therapy
- 2022
-
Ingår i: The AAPS journal. - : Springer Science and Business Media LLC. - 1550-7416. ; 24:3
-
Tidskriftsartikel (refereegranskat)abstract
- (Carl Amilon and Mikael Boberg contributed equally to this work) Eflornithine is a recommended treatment against late-stage gambiense human African trypanosomiasis, a neglected tropical disease. Standard dosing of eflornithine consists of repeated intravenous infusions of a racemic mixture of L- and D-eflornithine. Data from three clinical studies, (i) eflornithine intravenous monotherapy, (ii) nifurtimox-eflornithine combination therapy, and (iii) eflornithine oral monotherapy, were pooled and analyzed using a time-to-event pharmacodynamic modeling approach, supported by in vitro activity data of the individual enantiomers. Our aim was to assess (i) the efficacy of the eflornithine regimens in a time-to-event analysis and (ii) the feasibility of an L-eflornithine-based therapy integrating clinical and preclinical data. A pharmacodynamic time-to-event model was used to estimate the total dose of eflornithine, associated with 50% reduction in baseline hazard, when administered as monotherapy or in the nifurtimox-eflornithine combination therapy. The estimated total doses were 159, 60 and 291 g for intravenous eflornithine monotherapy, nifurtimox-eflornithine combination therapy and oral eflornithine monotherapy, respectively. Simulations suggested that L-eflornithine achieves a higher predicted median survival, compared to when racemate is administered, as treatment against late-stage gambiense human African trypanosomiasis. Our findings showed that oral L-eflornithine-based monotherapy would not result in adequate efficacy, even at high dose, and warrants further investigations to assess the potential of oral L-eflornithine-based treatment in combination with other treatments such as nifurtimox. An all-oral eflornithine-based regimen would provide easier access to treatment and reduce burden on patients and healthcare systems in gambiense human African trypanosomiasis endemic areas. Graphical abstract.
|
|
| 3. |
- Bhatt, Deepak Kumar, et al.
(författare)
-
Age- and Genotype-Dependent Variability in the Protein Abundance and Activity of Six Major Uridine Diphosphate-Glucuronosyltransferases in Human Liver
- 2019
-
Ingår i: Clinical Pharmacology and Therapeutics. - : Wiley. - 0009-9236 .- 1532-6535. ; 105:1, s. 131-141
-
Tidskriftsartikel (refereegranskat)abstract
- © 2018 The American Society for Clinical Pharmacology and Therapeutics. The ontogeny of hepatic uridine diphosphate-glucuronosyltransferases (UGTs) was investigated by determining their protein abundance in human liver microsomes isolated from 136 pediatric (0-18 years) and 35 adult (age >18 years) donors using liquid chromatography / tandem mass spectrometry (LC-MS/MS) proteomics. Microsomal protein abundances of UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15 increased by ∼8, 55, 35, 33, 8, and 3-fold from neonates to adults, respectively. The estimated age at which 50% of the adult protein abundance is observed for these UGT isoforms was between 2.6-10.3 years. Measured in vitro activity was generally consistent with the protein data. UGT1A1 protein abundance was associated with multiple single nucleotide polymorphisms exhibiting noticeable ontogeny-genotype interplay. UGT2B15 rs1902023 (*2) was associated with decreased protein activity without any change in protein abundance. Taken together, these data are invaluable to facilitate the prediction of drug disposition in children using physiologically based pharmacokinetic modeling as demonstrated here for zidovudine and morphine.
|
|
| 4. |
- Boberg, Mikael, et al.
(författare)
-
Age-Dependent Absolute Abundance of Hepatic Carboxylesterases (CES1 and CES2) by LC-MS/MS Proteomics: Application to PBPK Modeling of Oseltamivir In Vivo Pharmacokinetics in Infants
- 2017
-
Ingår i: Drug Metabolism and Disposition. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0090-9556 .- 1521-009X. ; 45:2, s. 216-223
-
Tidskriftsartikel (refereegranskat)abstract
- The age-dependent absolute protein abundance of carboxylesterase (CES) 1 and CES2 in human liver was investigated and applied to predict infant pharmacokinetics (PK) of oseltamivir. The CES absolute protein abundance was determined by liquid chromatography-tandem mass spectrometry proteomics in human liver microsomal and cytosolic fractions prepared from tissue samples obtained from 136 pediatric donors and 35 adult donors. Two surrogate peptides per protein were selected for the quantification of CES1 and CES2 protein abundance. Purified CES1 and CES2 protein standards were used as calibrators, and the heavy labeled peptides were used as the internal standards. In hepatic microsomes, CES1 and CES2 abundance (in picomoles per milligram total protein) increased approximately 5-fold (315.2 vs. 1664.4) and approximately 3-fold (59.8 vs. 174.1) from neonates to adults, respectively. CES1 protein abundance in liver cytosol also showed age-dependent maturation. Oseltamivir carboxylase activity was correlated with protein abundance in pediatric and adult liver microsomes. The protein abundance data were then used to model in vivo PK of oseltamivir in infants using pediatric physiologically based PK modeling and incorporating the protein abundance-based ontogeny function into the existing pediatric Simcyp model. The predicted pediatric area under the curve, maximal plasma concentration, and time for maximal plasma concentration values were below 2.1-fold of the clinically observed values, respectively.
|
|
| 5. |
- Boberg, Mikael, et al.
(författare)
-
Chiral Chromatographic Isolation on Milligram Scale of the Human African Trypanosomiasis Treatment D- and L-Eflornithine.
- 2020
-
Ingår i: ACS omega. - : American Chemical Society (ACS). - 2470-1343. ; 5:37, s. 23885-23891
-
Tidskriftsartikel (refereegranskat)abstract
- Eflornithine is a recommended treatment against the otherwise fatal parasitic disease late stage human African trypanosomiasis (HAT), also known as Gambian sleeping sickness. It is administered repeatedly as a racemic mixture intravenously (IV) together with oral nifurtimox. Racemic eflornithine has been investigated in clinical trials for oral dosing. However, due to low systemic exposures at a maximum tolerated oral dose, the drug is continued to be administered IV. The eflornithine enantiomers, D- and L-eflornithine, have different affinities to the target enzyme ornithine decarboxylase, suggesting that the pharmacodynamics of the enantiomers may differ. The aim of this study was to develop a method for isolation of d- and l-eflornithine from a racemic mixture. Several chiral stationary phases (CSPs) were evaluated for enantioselectivity using supercritical fluid chromatography (SFC) or high-performance liquid chromatography (HPLC). None of the tested CSPs rendered separation of the enantiomers in SFC mode. Separation of the enantiomers with SFC on the CSP Chiralpak IG was only achieved on an analytical scale after derivatization with ortho-phthalaldehyde (OPA). This was the first reported enantioselective SFC method for an eflornithine derivate. However, due to poor stability, the eflornithine-OPA derivates degraded and no chemically pure enantiomers were obtained. The CSP that showed enantioselectivity in HPLC mode was Chirobiotic R, which resulted in a successful isolation on a semipreparative milligram scale. The isolated eflornithine enantiomers will be tested in nonclinical in vitro and in vivo studies to support and assess the feasibility of a future clinical program with an oral HAT treatment.
|
|
| 6. |
- Boberg, Mikael, et al.
(författare)
-
Enantiospecific antitrypanosomal in vitro activity of eflornithine. : L-eflornithine against human African trypanosomiasis
- 2021
-
Ingår i: PLoS Neglected Tropical Diseases. - : Public Library of Science (PLoS). - 1935-2735. ; 15:7
-
Tidskriftsartikel (refereegranskat)abstract
- The polyamine synthesis inhibitor eflornithine is a recommended treatment for the neglected tropical disease Gambian human African trypanosomiasis in late stage. This parasitic disease, transmitted by the tsetse fly, is lethal unless treated. Eflornithine is administered by repeated intravenous infusions as a racemic mixture of L-eflornithine and D-eflornithine. The study compared the in vitro antitrypanosomal activity of the two enantiomers with the racemic mixture against three Trypanosoma brucei gambiense strains. Antitrypanosomal in vitro activity at varying drug concentrations was analysed by non-linear mixed effects modelling. For all three strains, L-eflornithine was more potent than D-eflornithine. Estimated 50% inhibitory concentrations of the three strains combined were 9.1 μM (95% confidence interval [8.1; 10]), 5.5 μM [4.5; 6.6], and 50 μM [42; 57] for racemic eflornithine, L-eflornithine and D-eflornithine, respectively. The higher in vitro potency of L-eflornithine warrants further studies to assess its potential for improving the treatment of late-stage Gambian human African trypanosomiasis.
|
|
| 7. |
- Boberg, Mikael
(författare)
-
Oral eflornithine treatment of late-stage human African trypanosomiasis
- 2022
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Human African trypanosomiasis is a fatal disease unless treated. It is a parasitic vector borne disease endemic in sub-Saharan African countries. Eflornithine is a recommended treatment for gambiense human African trypanosomiasis (g-HAT) in the later disease stage when the parasites have infected the central nervous system. Eflornithine is currently dosed as a racemic mixture of D- and L-eflornithine via repeated intravenous infusions, which comes with several disadvantages. The work in this thesis aimed to assess the feasibility of an oral eflornithine treatment. A chiral liquid chromatography method was developed for separation and preparation of the D- and L-eflornithine enantiomers from the racemic mixture. The acquired enantiopure material was used to determine that L-eflornithine had higher antiparasitic in vitro potency compared to D-eflornithine. The in vitro findings were used with a mathematical modeling approach to predict survival in late-stage g-HAT patients treated with L-eflornithine using pharmacodynamic time-to-event modeling. The in vivo pharmacokinetics in the rat after oral or intravenous doses of enantiopure L-eflornithine was characterized using nonlinear mixed effects modeling and compared to the racemic mixture. Moreover, the distribution of D- and L-eflornithine to the third brain ventricle from the systemic circulation was examined using in vivo microdialysis. Clinical pharmacokinetics in plasma and cerebrospinal fluid for L-eflornithine was modeled using literature data. The pharmacokinetic model was used to predict drug exposure and estimate the probability of target attainment for oral L-eflornithine-based treatments against late-stage g-HAT. L-eflornithine administered as monotherapy dosed at 750 mg/kg/day four or twelve times daily could serve as efficacious regimens. In combination with nifurtimox, dose regimens of L-eflornithine at 375 mg/kg/day dosed two, four or twelve times daily could be efficacious. These results are based on in vitro and preclinical in vivo data as well as clinical data using a translational modeling and simulation approach. Future clinical pharmacokinetic studies are warranted to assess the feasibility of an oral L-eflornithine-based treatment and to establish optimal treatment strategies against late-stage g-HAT.
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
- Clements, C. C., et al.
(författare)
-
Genome-wide association study of patients with a severe major depressive episode treated with electroconvulsive therapy
- 2021
-
Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 26:10
-
Tidskriftsartikel (refereegranskat)abstract
- Although large genome-wide association studies (GWAS) of major depressive disorder (MDD) have identified many significant loci, the SNP-based heritability remains notably low, which might be due to etiological heterogeneity in existing samples. Here, we test the utility of targeting the severe end of the MDD spectrum through genome-wide SNP genotyping of 2725 cases who received electroconvulsive therapy (ECT) for a major depressive episode (MDE) and 4035 controls. A subset of cases (n = 1796) met a narrow case definition (MDE occurring in the context of MDD). Standard GWAS quality control procedures and imputation were conducted. SNP heritability and genetic correlations with other traits were estimated using linkage disequilibrium score regression. Results were compared with MDD cases of mild-moderate severity receiving internet-based cognitive behavioral therapy (iCBT) and summary results from the Psychiatric Genomics Consortium (PGC). The SNP-based heritability was estimated at 29-34% (SE: 6%) for the narrow case definition, considerably higher than the 6.5-8.0% estimate in the most recent PGC MDD study. Our severe MDE cases had smaller genetic correlations with neurodevelopmental disorders and neuroticism than PGC MDD cases but higher genetic risk scores for bipolar disorder than iCBT MDD cases. One genome-wide significant locus was identified (rs114583506, P = 5e-8) in an intron of HLA-B in the major histocompatibility locus on chr6. These results indicate that individuals receiving ECT for an MDE have higher burden of common variant risk loci than individuals with mild-moderate MDD. Furthermore, severe MDE shows stronger relations with other severe adult-onset psychiatric disorders but weaker relations with personality and stress-related traits than mild-moderate MDD. These findings suggest a different genetic architecture at the severest end of the spectrum, and support further study of the severest MDD cases as an extreme phenotype approach to understand the etiology of MDD.
|
|
| 11. |
- Mahjani, Behrang, et al.
(författare)
-
The Genetic Architecture of Obsessive-Compulsive Disorder: Contribution of Liability to OCD From Alleles Across the Frequency Spectrum.
- 2022
-
Ingår i: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 179:3, s. 216-225
-
Tidskriftsartikel (refereegranskat)abstract
- Obsessive-compulsive disorder (OCD) is known to be substantially heritable; however, the contribution of genetic variation across the allele frequency spectrum to this heritability remains uncertain. The authors used two new homogeneous cohorts to estimate the heritability of OCD from inherited genetic variation and contrasted the results with those of previous studies.The sample consisted of 2,090 Swedish-born individuals diagnosed with OCD and 4,567 control subjects, all genotyped for common genetic variants, specifically >400,000 single-nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) ≥0.01. Using genotypes of these SNPs to estimate distant familial relationships among individuals, the authors estimated the heritability of OCD, both overall and partitioned according to MAF bins.Narrow-sense heritability of OCD was estimated at 29% (SE=4%). The estimate was robust, varying only modestly under different models. Contrary to an earlier study, however, SNPs with MAF between 0.01 and 0.05 accounted for 10% of heritability, and estimated heritability per MAF bin roughly followed expectations based on a simple model for SNP-based heritability.These results indicate that common inherited risk variation (MAF ≥0.01) accounts for most of the heritable variation in OCD. SNPs with low MAF contribute meaningfully to the heritability of OCD, and the results are consistent with expectation under the "infinitesimal model" (also referred to as the "polygenic model"), where risk is influenced by a large number of loci across the genome and across MAF bins.
|
|
| 12. |
- Xiong, Y., et al.
(författare)
-
Polygenic risk scores of lithium response and treatment resistance in major depressive disorder
- 2023
-
Ingår i: Translational Psychiatry. - 2158-3188. ; 13:1
-
Tidskriftsartikel (refereegranskat)abstract
- Treatment response and resistance in major depressive disorder (MDD) are suggested to be heritable. Due to significant challenges in defining treatment-related phenotypes, our understanding of their genetic bases is limited. This study aimed to derive a stringent definition of treatment resistance and to investigate the genetic overlap between treatment response and resistance in MDD. Using electronic medical records on the use of antidepressants and electroconvulsive therapy (ECT) from Swedish registers, we derived the phenotype of treatment-resistant depression (TRD) and non-TRD within similar to 4500 individuals with MDD in three Swedish cohorts. Considering antidepressants and lithium are first-line treatment and augmentation used for MDD, respectively, we generated polygenic risk scores (PRS) of antidepressants and lithium response for individuals with MDD and evaluated their associations with treatment resistance by comparing TRD with non-TRD. Among 1778 ECT-treated MDD cases, nearly all (94%) used antidepressants before their first ECT and the vast majority had at least one (84%) or two (61%) antidepressants of adequate duration, suggesting these MDD cases receiving ECT were resistant to antidepressants. We did not observe a significant difference in the mean PRS of antidepressant response between TRD and non-TRD; however, we found that TRD cases had a significantly higher PRS of lithium response compared to non-TRD cases (OR = 1.10-1.12 under various definitions). The results support the evidence of heritable components in treatment-related phenotypes and highlight the overall genetic profile of lithium-sensitivity in TRD. This finding further provides a genetic explanation for lithium efficacy in treating TRD.
|
|
