| 1. |
- Thomas, HS, et al.
(författare)
-
- 2019
-
swepub:Mat__t
|
|
| 2. |
|
|
| 3. |
- Shepherd, L., et al.
(författare)
-
Infection-related and -unrelated malignancies, HIV and the aging population
- 2016
-
Ingår i: HIV Medicine. - : Wiley. - 1464-2662 .- 1468-1293. ; 17:8, s. 590-600
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives: HIV-positive people have increased risk of infection-related malignancies (IRMs) and infection-unrelated malignancies (IURMs). The aim of the study was to determine the impact of aging on future IRM and IURM incidence. Methods: People enrolled in EuroSIDA and followed from the latest of the first visit or 1 January 2001 until the last visit or death were included in the study. Poisson regression was used to investigate the impact of aging on the incidence of IRMs and IURMs, adjusting for demographic, clinical and laboratory confounders. Linear exponential smoothing models forecasted future incidence. Results: A total of 15 648 people contributed 95 033 person-years of follow-up, of whom 610 developed 643 malignancies [IRMs: 388 (60%); IURMs: 255 (40%)]. After adjustment, a higher IRM incidence was associated with a lower CD4 count [adjusted incidence rate ratio (aIRR) CD4 count < 200 cells/μL: 3.77; 95% confidence interval (CI) 2.59, 5.51; compared with ≥ 500 cells/μL], independent of age, while a CD4 count < 200 cells/μL was associated with IURMs in people aged < 50 years only (aIRR: 2.51; 95% CI 1.40–4.54). Smoking was associated with IURMs (aIRR: 1.75; 95% CI 1.23, 2.49) compared with never smokers in people aged ≥ 50 years only, and not with IRMs. The incidences of both IURMs and IRMs increased with older age. It was projected that the incidence of IRMs would decrease by 29% over a 5-year period from 3.1 (95% CI 1.5–5.9) per 1000 person-years in 2011, whereas the IURM incidence would increase by 44% from 4.1 (95% CI 2.2–7.2) per 1000 person-years over the same period. Conclusions: Demographic and HIV-related risk factors for IURMs (aging and smoking) and IRMs (immunodeficiency and ongoing viral replication) differ markedly and the contribution from IURMs relative to IRMs will continue to increase as a result of aging of the HIV-infected population, high smoking and lung cancer prevalence and a low prevalence of untreated HIV infection. These findings suggest the need for targeted preventive measures and evaluation of the cost−benefit of screening for IURMs in HIV-infected populations.
|
|
| 4. |
- Underwood, J, et al.
(författare)
-
Validation of a Novel Multivariate Method of Defining HIV-Associated Cognitive Impairment
- 2019
-
Ingår i: Open forum infectious diseases. - : Oxford University Press (OUP). - 2328-8957. ; 6:6, s. ofz198-
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe optimum method of defining cognitive impairment in virally suppressed people living with HIV is unknown. We evaluated the relationships between cognitive impairment, including using a novel multivariate method (NMM), patient– reported outcome measures (PROMs), and neuroimaging markers of brain structure across 3 cohorts.MethodsDifferences in the prevalence of cognitive impairment, PROMs, and neuroimaging data from the COBRA, CHARTER, and POPPY cohorts (total n = 908) were determined between HIV-positive participants with and without cognitive impairment defined using the HIV-associated neurocognitive disorders (HAND), global deficit score (GDS), and NMM criteria.ResultsThe prevalence of cognitive impairment varied by up to 27% between methods used to define impairment (eg, 48% for HAND vs 21% for NMM in the CHARTER study). Associations between objective cognitive impairment and subjective cognitive complaints generally were weak. Physical and mental health summary scores (SF-36) were lowest for NMM-defined impairment (P < .05).There were no differences in brain volumes or cortical thickness between participants with and without cognitive impairment defined using the HAND and GDS measures. In contrast, those identified with cognitive impairment by the NMM had reduced mean cortical thickness in both hemispheres (P < .05), as well as smaller brain volumes (P < .01). The associations with measures of white matter microstructure and brain-predicted age generally were weaker.ConclusionDifferent methods of defining cognitive impairment identify different people with varying symptomatology and measures of brain injury. Overall, NMM-defined impairment was associated with most neuroimaging abnormalities and poorer self-reported health status. This may be due to the statistical advantage of using a multivariate approach.
|
|
| 5. |
- Horwich, A, et al.
(författare)
-
EAU–ESMO consensus statements on the management of advanced and variant bladder cancer - an international collaborative multi-stakeholder effort : under the auspices of the EAU and ESMO Guidelines Committees
- 2019
-
Ingår i: Annals of Oncology. - : Oxford University Press. - 0923-7534 .- 1569-8041. ; 30:11, s. 1697-1727
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial.OBJECTIVE: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management.DESIGN: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts before voting during a consensus conference.SETTING: Online Delphi survey and consensus conference.PARTICIPANTS: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), 7-9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus).RESULTS AND LIMITATIONS: Overall, 116 statements were included in the Delphi survey. Of these, 33 (28%) statements achieved level 1 consensus and 49 (42%) statements achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease and the evolving role of checkpoint inhibitor therapy in metastatic disease.CONCLUSIONS: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time where further evidence is available to guide our approach.
|
|
| 6. |
|
|
| 7. |
- Heywood, I., et al.
(författare)
-
Inflation of 430-parsec bipolar radio bubbles in the Galactic Centre by an energetic event
- 2019
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 573:7773, s. 235-237
-
Tidskriftsartikel (refereegranskat)abstract
- The Galactic Centre contains a supermassive black hole with a mass of four million Suns1 within an environment that differs markedly from that of the Galactic disk. Although the black hole is essentially quiescent in the broader context of active galactic nuclei, X-ray observations have provided evidence for energetic outbursts from its surroundings2. Also, although the levels of star formation in the Galactic Centre have been approximately constant over the past few hundred million years, there is evidence of increased short-duration bursts3, strongly influenced by the interaction of the black hole with the enhanced gas density present within the ring-like central molecular zone4 at Galactic longitude |l| < 0.7 degrees and latitude |b| < 0.2 degrees. The inner 200-parsec region is characterized by large amounts of warm molecular gas5, a high cosmic-ray ionization rate6, unusual gas chemistry, enhanced synchrotron emission7,8, and a multitude of radio-emitting magnetized filaments9, the origin of which has not been established. Here we report radio imaging that reveals a bipolar bubble structure, with an overall span of 1 degree by 3 degrees (140 parsecs × 430 parsecs), extending above and below the Galactic plane and apparently associated with the Galactic Centre. The structure is edge-brightened and bounded, with symmetry implying creation by an energetic event in the Galactic Centre. We estimate the age of the bubbles to be a few million years, with a total energy of 7 × 1052 ergs. We postulate that the progenitor event was a major contributor to the increased cosmic-ray density in the Galactic Centre, and is in turn the principal source of the relativistic particles required to power the synchrotron emission of the radio filaments within and in the vicinity of the bubble cavities.
|
|
| 8. |
- Fages, A., et al.
(författare)
-
Tracking Five Millennia of Horse Management with Extensive Ancient Genome Time Series
- 2019
-
Ingår i: Cell. - : Elsevier BV. - 0092-8674. ; 177:6
-
Tidskriftsartikel (refereegranskat)abstract
- Horse domestication revolutionized warfare and accelerated travel, trade, and the geographic expansion of languages. Here, we present the largest DNA time series for a non-human organism to date, including genome-scale data from 149 ancient animals and 129 ancient genomes (>= 1-fold coverage), 87 of which are new. This extensive dataset allows us to assess the modem legacy of past equestrian civilisations. We find that two extinct horse lineages existed during early domestication, one at the far western (Iberia) and the other at the far eastern range (Siberia) of Eurasia. None of these contributed significantly to modern diversity. We show that the influence of Persian-related horse lineages increased following the Islamic conquests in Europe and Asia. Multiple alleles associated with elite-racing, including at the MSTN "speed gene," only rose in popularity within the last millennium. Finally, the development of modem breeding impacted genetic diversity more dramatically than the previous millennia of human management.
|
|
| 9. |
|
|
| 10. |
|
|
| 11. |
- Camilo, F., et al.
(författare)
-
Revival of the Magnetar PSR J1622-4950: Observations with MeerKAT, Parkes, XMM-Newton, Swift, Chandra, and NuSTAR
- 2018
-
Ingår i: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 856:2
-
Tidskriftsartikel (refereegranskat)abstract
- New radio (MeerKAT and Parkes) and X-ray (XMM-Newton, Swift, Chandra, and NuSTAR) observations of PSR J1622-4950 indicate that the magnetar, in a quiescent state since at least early 2015, reactivated between 2017 March 19 and April 5. The radio flux density, while variable, is approximately 100 larger than during its dormant state. The X-ray flux one month after reactivation was at least 800 larger than during quiescence, and has been decaying exponentially on a 111 19 day timescale. This high-flux state, together with a radio-derived rotational ephemeris, enabled for the first time the detection of X-ray pulsations for this magnetar. At 5%, the 0.3-6 keV pulsed fraction is comparable to the smallest observed for magnetars. The overall pulsar geometry inferred from polarized radio emission appears to be broadly consistent with that determined 6-8 years earlier. However, rotating vector model fits suggest that we are now seeing radio emission from a different location in the magnetosphere than previously. This indicates a novel way in which radio emission from magnetars can differ from that of ordinary pulsars. The torque on the neutron star is varying rapidly and unsteadily, as is common for magnetars following outburst, having changed by a factor of 7 within six months of reactivation.
|
|
| 12. |
|
|
| 13. |
|
|
| 14. |
|
|
| 15. |
- Einspieler, C, et al.
(författare)
-
Cerebral Palsy: Early Markers of Clinical Phenotype and Functional Outcome
- 2019
-
Ingår i: Journal of clinical medicine. - : MDPI AG. - 2077-0383. ; 8:10
-
Tidskriftsartikel (refereegranskat)abstract
- The Prechtl General Movement Assessment (GMA) has become a cornerstone assessment in early identification of cerebral palsy (CP), particularly during the fidgety movement period at 3–5 months of age. Additionally, assessment of motor repertoire, such as antigravity movements and postural patterns, which form the Motor Optimality Score (MOS), may provide insight into an infant’s later motor function. This study aimed to identify early specific markers for ambulation, gross motor function (using the Gross Motor Function Classification System, GMFCS), topography (unilateral, bilateral), and type (spastic, dyskinetic, ataxic, and hypotonic) of CP in a large worldwide cohort of 468 infants. We found that 95% of children with CP did not have fidgety movements, with 100% having non-optimal MOS. GMFCS level was strongly correlated to MOS. An MOS > 14 was most likely associated with GMFCS outcomes I or II, whereas GMFCS outcomes IV or V were hardly ever associated with an MOS > 8. A number of different movement patterns were associated with more severe functional impairment (GMFCS III–V), including atypical arching and persistent cramped-synchronized movements. Asymmetrical segmental movements were strongly associated with unilateral CP. Circular arm movements were associated with dyskinetic CP. This study demonstrated that use of the MOS contributes to understanding later CP prognosis, including early markers for type and severity.
|
|
| 16. |
- Balaz, M., et al.
(författare)
-
Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation
- 2019
-
Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 29:4
-
Tidskriftsartikel (refereegranskat)abstract
- Recent research focusing on brown adipose tissue (BAT) function emphasizes its importance in systemic metabolic homeostasis. We show here that genetic and pharmacological inhibition of the mevalonate pathway leads to reduced human and mouse brown adipocyte function in vitro and impaired adipose tissue browning in vivo. A retrospective analysis of a large patient cohort suggests an inverse correlation between statin use and active BAT in humans, while we show in a prospective clinical trial that fluvastatin reduces thermogenic gene expression in human BAT. We identify geranylgeranyl pyrophosphate as the key mevalonate pathway intermediate driving adipocyte browning in vitro and in vivo, whose effects are mediated by geranylgeranyltransferases (GGTases), enzymes catalyzing geranylgeranylation of small GTP-binding proteins, thereby regulating YAP1/TAZ signaling through F-actin modulation. Conversely, adipocyte-specific ablation of GGTase I leads to impaired adipocyte browning, reduced energy expenditure, and glucose intolerance under obesogenic conditions, highlighting the importance of this pathway in modulating brown adipocyte functionality and systemic metabolism.
|
|
| 17. |
- Cantù, Claudio, et al.
(författare)
-
Mutations in Bcl9 and Pygo genes cause congenital heart defects by tissue-specific perturbation of Wnt/beta-catenin signaling
- 2018
-
Ingår i: Genes & Development. - : COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT. - 0890-9369 .- 1549-5477. ; 32:21-22, s. 1443-1458
-
Tidskriftsartikel (refereegranskat)abstract
- Bcl9 and Pygopus (Pygo) are obligate Wnt/beta-catenin cofactors in Drosophila, yet their contribution to Wnt signaling during vertebrate development remains unresolved. Combining zebrafish and mouse genetics, we document a conserved, beta-catenin-associated function for BCL9 and Pygo proteins during vertebrate heart development. Disrupting the beta-catenin-BCL9-Pygo complex results in a broadly maintained canonical Wnt response yet perturbs heart development and proper expression of key cardiac regulators. Our work highlights BCL9 and Pygo as selective beta-catenin cofactors in a subset of canonical Wnt responses during vertebrate development. Moreover, our results implicate alterations in BCL9 and BCL9L in human congenital heart defects.
|
|
| 18. |
- Frantz, Laurent A. F., et al.
(författare)
-
Ancient pigs reveal a near-complete genomic turnover following their introduction to Europe
- 2019
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 116:35, s. 17231-17238
-
Tidskriftsartikel (refereegranskat)abstract
- Archaeological evidence indicates that pig domestication had begun by similar to 10,500 y before the present ( BP) in the Near East, and mitochondrial DNA ( mtDNA) suggests that pigs arrived in Europe alongside farmers similar to 8,500 y BP. A few thousand years after the introduction of Near Eastern pigs into Europe, however, their characteristic mtDNA signature disappeared and was replaced by haplotypes associated with European wild boars. This turnover could be accounted for by substantial gene flow from local European wild boars, although it is also possible that European wild boars were domesticated independently without any genetic contribution from the Near East. To test these hypotheses, we obtained mtDNA sequences from 2,099 modern and ancient pig samples and 63 nuclear ancient genomes from Near Eastern and European pigs. Our analyses revealed that European domestic pigs dating from 7,100 to 6,000 y BP possessed both Near Eastern and European nuclear ancestry, while later pigs possessed no more than 4% Near Eastern ancestry, indicating that gene flow from European wild boars resulted in a near-complete disappearance of Near East ancestry. In addition, we demonstrate that a variant at a locus encoding black coat color likely originated in the Near East and persisted in European pigs. Altogether, our results indicate that while pigs were not independently domesticated in Europe, the vast majority of human-mediated selection over the past 5,000 y focused on the genomic fraction derived from the European wild boars, and not on the fraction that was selected by early Neolithic farmers over the first 2,500 y of the domestication process.
|
|
| 19. |
|
|
| 20. |
- Kohlhauer, M., et al.
(författare)
-
Protection against cardiac ischemia-reperfusion injury by hypothermia and by inhibition of succinate accumulation and oxidation is additive
- 2019
-
Ingår i: Basic Research in Cardiology. - : Springer Science and Business Media LLC. - 0300-8428 .- 1435-1803. ; 114:3
-
Tidskriftsartikel (refereegranskat)abstract
- Hypothermia induced at the onset of ischemia is a potent experimental cardioprotective strategy for myocardial infarction. The aim of our study was to determine whether the beneficial effects of hypothermia may be due to decreasing mitochondria-mediated mechanisms of damage that contribute to the pathophysiology of ischemia/reperfusion injury. New Zealand male rabbits were submitted to 30min of myocardial ischemia with hypothermia (32 degrees C) induced by total liquid ventilation (TLV). Hypothermia was applied during ischemia alone (TLV group), during ischemia and reperfusion (TLV-IR group) and normothermia (Control group). In all the cases, ischemia was performed by surgical ligation of the left anterior descending coronary artery and was followed by 3h of reperfusion before assessment of infarct size. In a parallel study, male C57BL6/J mice underwent 30min myocardial ischemia followed by reperfusion under either normothermia (37 degrees C) or conventionally induced hypothermia (32 degrees C). In both the models, the levels of the citric acid cycle intermediate succinate, mitochondrial complex I activity were assessed at various times. The benefit of hypothermia during ischemia on infarct size was compared to inhibition of succinate accumulation and oxidation by the complex II inhibitor malonate, applied as the pro-drug dimethyl malonate under either normothermic or hypothermic conditions. Hypothermia during ischemia was cardioprotective, even when followed by normothermic reperfusion. Hypothermia during ischemia only, or during both, ischemia and reperfusion, significantly reduced infarct size (2.8 +/- 0.6%, 24.2 +/- 3.0% and 49.6 +/- 2.6% of the area at risk, for TLV-IR, TLV and Control groups, respectively). The significant reduction of infarct size by hypothermia was neither associated with a decrease in ischemic myocardial succinate accumulation, nor with a change in its rate of oxidation at reperfusion. Similarly, dimethyl malonate infusion and hypothermia during ischemia additively reduced infarct size (4.8 +/- 2.2% of risk zone) as compared to either strategy alone. Hypothermic cardioprotection is neither dependent on the inhibition of succinate accumulation during ischemia, nor of its rapid oxidation at reperfusion. The additive effect of hypothermia and dimethyl malonate on infarct size shows that they are protective by distinct mechanisms and also suggests that combining these different therapeutic approaches could further protect against ischemia/reperfusion injury during acute myocardial infarction.
|
|
| 21. |
|
|
| 22. |
- Schalkwijk, Stein, et al.
(författare)
-
Evaluating darunavir/ritonavir dosing regimens for HIV-positive pregnant women using semi-mechanistic pharmacokinetic modelling
- 2019
-
Ingår i: Journal of Antimicrobial Chemotherapy. - : OXFORD UNIV PRESS. - 0305-7453 .- 1460-2091. ; 74:5, s. 1348-1356
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Darunavir 800mg once (q24h) or 600 mg twice (q12h) daily combined with low-dose ritonavir is used to treat HIV-positive pregnant women. Decreased total darunavir exposure (17%-50%) has been reported during pregnancy, but limited data on unbound exposure are available. Objectives: To evaluate total and unbound darunavir exposures following standard darunavir/ritonavir dosing and to explore the value of potential optimized darunavir/ritonavir dosing regimens for HIV-positive pregnant women. Patients and methods: A population pharmacokinetic analysis was conducted based on data from 85 women. The final model was used to simulate total and unbound darunavir AUC(0-tau) and C-trough during the third trimester of pregnancy, as well as to assess the probability of therapeutic exposure. Results: Simulations predicted that total darunavir exposure (AUC(0-tau)) was 24% and 23% lower in pregnancy for standard q24h and q12h dosing, respectively. Unbound darunavir AUC(0-tau) was 5% and 8% lower compared with post-partum for standard q24h and q12h dosing, respectively. The probability of therapeutic exposure (unbound) during pregnancy was higher for standard q12h dosing (99%) than for q24h dosing (94%). Conclusions: The standard q12h regimen resulted in maximal and higher rates of therapeutic exposure compared with standard q24h dosing. Darunavir/ritonavir 600/100 mg q12h should therefore be the preferred regimen during pregnancy unless (adherence) issues dictate q24h dosing. The value of alternative dosing regimens seems limited.
|
|
| 23. |
- Cserni, G, et al.
(författare)
-
Consistency in recognizing microinvasion in breast carcinomas is improved by immunohistochemistry for myoepithelial markers.
- 2016
-
Ingår i: Virchows Archiv: an international journal of pathology. - : Springer Science and Business Media LLC. - 1432-2307. ; 468:4, s. 473-481
-
Tidskriftsartikel (refereegranskat)abstract
- Microinvasion is the smallest morphologically identifiable stage of invasion. Its presence and distinction from in situ carcinoma may have therapeutic implications, and clinical staging also requires the recognition of this phenomenon. Microinvasion is established on the basis of several morphological criteria, which may be difficult and not perfectly reproducible among pathologists. The aim of this study was to assess the consistency of diagnosing microinvasion in the breast on traditional haematoxylin and eosin (HE) stained slides and to evaluate whether immunohistochemistry (IHC) for myoepithelial markers could improve this. Digital images were generated from representative areas of 50 cases stained with HE and IHC for myoepithelial markers. Cases were specifically selected from the spectrum of in situ to microinvasive cancers. Twenty-eight dedicated breast pathologists assessed these cases at different magnifications through a web-based platform in two rounds: first HE only and after a washout period by both HE and IHC. Consistency in the recognition of microinvasion significantly improved with the use of IHC. Concordance rates increased from 0.85 to 0.96, kappa from 0.5 to 0.85, the number of cases with 100 % agreement rose from 9/50 to 25/50 with IHC and the certainty of diagnosis also increased. The use of IHC markedly improves the consistency of identifying microinvasion. This corroborates previous recommendations to use IHC for myoepithelial markers to clarify cases where uncertainty exists about the presence of microinvasion. Microinvasive carcinoma is a rare entity, and seeking a second opinion may avoid overdiagnosis.
|
|
| 24. |
- Litjens, Carlijn H. C., et al.
(författare)
-
Protein binding of rifampicin is not saturated when using high-dose rifampicin
- 2019
-
Ingår i: Journal of Antimicrobial Chemotherapy. - : OXFORD UNIV PRESS. - 0305-7453 .- 1460-2091. ; 74:4, s. 986-990
-
Tidskriftsartikel (refereegranskat)abstract
- Background Higher doses of rifampicin are being investigated as a means to optimize response to this pivotal TB drug. It is unknown whether high-dose rifampicin results in saturation of plasma protein binding and a relative increase in protein-unbound (active) drug concentrations. Objectives To assess the free fraction of rifampicin based on an in vitro experiment and data from a clinical trial on high-dose rifampicin. Methods Protein-unbound rifampicin concentrations were measured in human serum spiked with increasing total concentrations (up to 64mg/L) of rifampicin and in samples obtained by intensive pharmacokinetic sampling of patients who used standard (10mg/kg daily) or high-dose (35mg/kg) rifampicin up to steady-state. The performance of total AUC(0-24) to predict unbound AUC(0-24) was evaluated. Results The in vitro free fraction of rifampicin remained unaltered (approximate to 9%) up to 21mg/L and increased up to 13% at 41mg/L and 17% at 64mg/L rifampicin. The highest (peak) concentration in vivo was 39.1mg/L (high-dose group). The arithmetic mean percentage unbound to total AUC(0-24)in vivo was 13.3% (range=8.1%-24.9%) and 11.1% (range=8.6%-13.6%) for the standard group and the high-dose group, respectively (P=0.214). Prediction of unbound AUC(0-24) based on total AUC(0-24) resulted in a bias of -0.05% and an imprecision of 13.2%. Conclusions Plasma protein binding of rifampicin can become saturated, but exposures after high-dose rifampicin are not high enough to increase the free fraction in TB patients with normal albumin values. Unbound rifampicin exposures can be predicted from total exposures, even in the higher dose range.
|
|
| 25. |
- Martial, Lisa C, et al.
(författare)
-
Dose Reduction of Caspofungin in Intensive Care Unit Patients with Child Pugh B Will Result in Suboptimal Exposure.
- 2016
-
Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 55:6, s. 723-733
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVES: Caspofungin is an echinocandin antifungal agent used as first-line therapy for the treatment of invasive candidiasis. The maintenance dose is adapted to body weight (BW) or liver function (Child-Pugh score B or C). We aimed to study the pharmacokinetics of caspofungin and assess pharmacokinetic target attainment for various dosing strategies.METHODS: Caspofungin pharmacokinetic data from 21 intensive care unit (ICU) patients was available. A population pharmacokinetic model was developed. Various dosing regimens (loading dose/maintenance dose) were simulated: licensed regimens (I) 70/50 mg (for BW <80 kg) or 70/70 mg (for BW >80 kg); and (II) 70/35 mg (for Child-Pugh score B); and adapted regimens (III) 100/50 mg (for Child-Pugh score B); (IV) 100/70 mg; and (V) 100/100 mg. Target attainment based on a preclinical pharmacokinetic target for Candida albicans was assessed for relevant minimal inhibitory concentrations (MICs).RESULTS: A two-compartment model best fitted the data. Clearance was 0.55 L/h and the apparent volumes of distribution in the central and peripheral compartments were 8.9 and 5.0 L, respectively. The median area under the plasma concentration-time curve from time zero to 24 h on day 14 for regimens I-V were 105, 65, 93, 130, and 186 mg·h/L, respectively. Pharmacokinetic target attainment was 100 % (MIC 0.03 µg/mL) irrespective of dosing regimen but decreased to (I) 47 %, (II) 14 %, (III) 36 %, (IV) 69 %, and (V) 94 % for MIC 0.125 µg/mL.CONCLUSION: The caspofungin maintenance dose should not be reduced in non-cirrhotic ICU patients based on the Child-Pugh score if this classification is driven by hypoalbuminemia as it results in significantly lower exposure. A higher maintenance dose of 70 mg in ICU patients results in target attainment of >90 % of the ICU patients with species with an MIC of up to 0.125 µg/mL.
|
|
| 26. |
|
|
| 27. |
- Nag, Somnath, et al.
(författare)
-
Observation of high-spin bands with large moments of inertia in Xe 124
- 2016
-
Ingår i: Physical Review C - Nuclear Physics. - 0556-2813. ; 94:3
-
Tidskriftsartikel (refereegranskat)abstract
- High-spin states in Xe124 have been populated using the Se80(Ca48,4n) reaction at a beam energy of 207 MeV and high-multiplicity, γ-ray coincidence events were measured using the Gammasphere spectrometer. Six high-spin bands with large moments of inertia, similar to those observed in neighboring nuclei, have been observed. The experimental results are compared with calculations within the framework of the cranked Nilsson-Strutinsky model. It is suggested that the configurations of the bands involve excitations of protons across the Z=50 shell gap coupled to neutrons within the N=50-82 shell or excited across the N=82 shell closure.
|
|
| 28. |
|
|
| 29. |
- Postema, Sietke G., et al.
(författare)
-
Musculoskeletal Complaints in Transverse Upper Limb Reduction Deficiency and Amputation in The Netherlands : Prevalence, Predictors, and Effect on Health
- 2016
-
Ingår i: Archives of Physical Medicine and Rehabilitation. - Philadelphia, USA : Saunders Elsevier. - 0003-9993 .- 1532-821X. ; 97:7, s. 1137-1145
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: (1) To determine the prevalence of musculoskeletal complaints (MSCs) in individuals with upper limb absence in The Netherlands, (2) to assess the health status of individuals with upper limb absence in general and in relation to the presence of MSCs, and (3) to explore the predictors of development of MSCs and MSC-related disability in this population.Design: Cross-sectional study: national survey.Setting: Twelve rehabilitation centers and orthopedic workshops.Partiscipants: Individuals (n=263; mean age, 50.7±16.7y; 60% men) ≥18 years old, with transverse upper limb reduction deficiency (42%) or amputation (58%) at or proximal to the carpal level (response, 45%) and 108 individuals without upper limb reduction deficiency or amputation (n=108; mean age, 50.6±15.7y; 65% men) (N=371).Interventions: Not applicable.Main outcome measures: Point and year prevalence of MSCs, MSC-related disability (Pain Disability Index), and general health perception and mental health (RAND-36 subscales).Results: Point and year prevalence of MSCs were almost twice as high in individuals with upper limb absence (57% and 65%, respectively) compared with individuals without upper limb absence (27% and 34%, respectively) and were most often located in the nonaffected limb and upper back/neck. MSCs were associated with decreased general health perception and mental health and higher perceived upper extremity work demands. Prosthesis use was not related to presence of MSCs. Clinically relevant predictors of MSCs were middle age, being divorced/widowed, and lower mental health. Individuals with upper limb absence experienced more MSC-related disability than individuals without upper limb absence. Higher age, more pain, lower general and mental health, and not using a prosthesis were related to higher disability.Conclusions: Presence of MSCs is a frequent problem in individuals with upper limb absence and is associated with decreased general and mental health. Mental health and physical work demands should be taken into account when assessing such a patient. Clinicians should note that MSC-related disability increases with age.
|
|
| 30. |
- Postema, Sietke, et al.
(författare)
-
Upper limb absence : predictors of work participation and work productivity
- 2016
-
Ingår i: Archives of Physical Medicine and Rehabilitation. - Philadelphia, USA : Elsevier. - 0003-9993 .- 1532-821X. ; 97:6, s. 892-899
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: to analyze work participation, work productivity and contributing factors, as well as physical work demands, in individuals with an upper limb defect (ULD).Design: cross-sectional study: postal survey (response rate: 53%).Setting: patients of twelve rehabilitation centers and orthopedic workshops in the Netherlands.Participants: 207 individuals with unilateral transversal upper limb reduction deficiency (ULRD) or amputation (ULA), at or proximal to the carpal level, between the ages of 18 and 65 years, and a convenience sample of 90 controls (matched on age and gender).Interventions: not applicable.Main outcome measures: employment status, self-reported work productivity and self-reported upper extremity work demands.Results: 74% of individuals with ULRD and 57% of the individuals with ULA were employed. Males, using a prosthesis, with medium or higher level of education and good general health were most often employed. Work productivity was similar to the control group. Higher work productivity was related to predominantly mentally demanding type of work and less MSC related pain. Upper extremity work demands were higher in individuals with ULD with predominantly mentally demanding work, compared to controls with this type of work. Conclusions: the outcome of work participation of individuals with ULRD is comparable to the general population in the Netherlands. Individuals with ULA had lower rates of employment. Work productivity was not associated to one-handedness.
|
|
| 31. |
|
|
| 32. |
|
|
| 33. |
|
|
| 34. |
|
|
| 35. |
|
|
| 36. |
- Broushaki, Farnaz, et al.
(författare)
-
Early Neolithic genomes from the eastern Fertile Crescent.
- 2016
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 353:6298
-
Tidskriftsartikel (refereegranskat)abstract
- We sequenced Early Neolithic genomes from the Zagros region of Iran (eastern Fertile Crescent), where some of the earliest evidence for farming is found, and identify a previously uncharacterized population that is neither ancestral to the first European farmers nor has contributed substantially to the ancestry of modern Europeans. These people are estimated to have separated from Early Neolithic farmers in Anatolia some 46,000 to 77,000 years ago and show affinities to modern-day Pakistani and Afghan populations, but particularly to Iranian Zoroastrians. We conclude that multiple, genetically differentiated hunter-gatherer populations adopted farming in southwestern Asia, that components of pre-Neolithic population structure were preserved as farming spread into neighboring regions, and that the Zagros region was the cradle of eastward expansion.
|
|
| 37. |
- Burger, Antoinette, et al.
(författare)
-
The impact of acute and short-term methamphetamine abstinence on brain metabolites : A proton magnetic resonance spectroscopy chemical shift imaging study
- 2018
-
Ingår i: Drug And Alcohol Dependence. - : Elsevier BV. - 0376-8716 .- 1879-0046. ; 185, s. 226-237
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundAbuse of methamphetamine (MA) is a global health concern. Previous H-1-MRS studies have found that, with methamphetamine abstinence (MAA), there are changes in n-acetyl-aspartate (NAA/Cr), myo-inositol (mI/Cr), choline (Cho/Cr and Cho/NAA), and glutamate with glutamine (Glx) metabolites. Limited studies have investigated the effect of acute MAA, and acute-to-short-term MAA on brain metabolites.MethodsAdults with chronic MA dependence (n = 31) and healthy controls (n = 22) were recruited. Two-dimensional chemical shift H-1-MRS imaging (TR2000 ms, TE30 ms) slice was performed and included voxels in bilateral anterior-cingulate (ACC), frontal-white-matter (FWM), and dorsolateral-prefrontal-cortices (DLPFC). Control participants were scanned once. The MA group was scanned twice, with acute (1.5 +/- 0.6 weeks, n = 31) and short-term MAA (5.1 +/- 0.8 weeks, n = 22). The change in H-1-MRS metabolites over time (n = 19) was also investigated. Standard H-1-MRS metabolites are reported relative to Cr + PCr.ResultsAcute MAA showed lower n-acetyl-aspartate (NAA) and n-acetyl-aspartate with n-acetyl-aspartyl-glutamate (NAA + NAAG) in left DLPFC, and glycerophosphocholine with phosphocholine (GPC + PCh) in left FWM. Short-term MAA showed lower NAA + NAAG and higher myo-inositol (mI) in right ACC, lower NAA and NAA + NAAG in the left DLPFC, and lower GPC + PCh in left FWM. Over time, MAA showed decreased NAA and NAA + NAAG and increased mI in right ACC, decreased NAA and NAA + NAAG in right FWM, and decreased in mI in left FWM.ConclusionIn acute MAA, there was damage to the integrity of neuronal tissue, which was enhanced with short-term MAA. From acute to short-term MAA, activation of neuroinflammatory processes are suggested. This is the first H-1-MRS study to report the development of neuroinflammation with loss of neuronal integrity in MAA.
|
|
| 38. |
- Bürger, Christoff, et al.
(författare)
-
fUML Activity Diagrams with RAG-controlled Rewriting: A RACR Solution of The TTC 2015 Model Execution Case
- 2015
-
Ingår i: CEUR Workshop Proceedings. - 1613-0073. ; 1524, s. 27-36
-
Konferensbidrag (refereegranskat)abstract
- This paper summarises a RACR solution of The TTC 2015 Model Execution Case. RACR is a metacompiler library for Scheme. Its most distinguished feature is the seamless combination of reference attribute grammars and graph rewriting combined with incremental evaluation semantics. The presented solution sketches how these integrated analyses and rewriting facilities are used to transform fUML Activity Diagrams to executable Petri nets. Of particular interest are (1) the exploitation of reference attribute grammar analyses for Petri net generation and (2) the efficient execution of generated nets based on the incremental evaluation semantics of RACR.
|
|
| 39. |
- Burger, Gregor, et al.
(författare)
-
Designing and implementing a multi-core capable integrated urban drainage modelling Toolkit : Lessons from CityDrain3
- 2016
-
Ingår i: Advances in Engineering Software. - : Elsevier BV. - 0965-9978 .- 1873-5339. ; 100, s. 277-289
-
Tidskriftsartikel (refereegranskat)abstract
- Integrated urban drainage modelling combines different aspects of the urban water system into a common framework. With increasing pressures of a changing climate, urban growth and economic constraints, the need for wider spread integration is necessary in the interest of a sustainable future. Greater complexity results in greater computational burden but modelling packages will, likewise, need to be flexible enough to allow incorporation of new algorithms. With advancements in modern information technology, a parallel implementation of such a modelling toolkit is mandatory while still leaving its users the flexibility of extensions. The design and implementation of the integrated modelling framework CityDrain3 shows that it is possible to write research code that is high-performance and extensible by many research projects. Three use case scenarios are presented to showcase the application of CityDrain3. The performance advantage of parallelization (up to 40 times compared to its predecessor) and the scalability of the framework are also demonstrated.
|
|
| 40. |
|
|
| 41. |
- Burger, Raimund, et al.
(författare)
-
Convection-diffusion-reaction and transport-flow problems motivated by models of sedimentation: some recent advances
- 2018
-
Ingår i: Proceedings of the International Congress of Mathematicians 2018. - 9789813272873 ; Vol. IV: Invited Lectures, s. 3489-3514
-
Konferensbidrag (refereegranskat)abstract
- The sedimentation of a suspension is a unit operation widely used in mineral processing, chemical engineering,wastewater treatment, and other industrial applications. Mathematical models that describe these processes and may be employed for simulation, design and control are usually given as nonlinear, time-dependent partial differential equations that in one space dimension include strongly degenerate convection-diffusion-reaction equations with discontinuous coefficients, and in two or more dimensions, coupled flowtransport problems. These models incorporate non-standardproperties that have motivated original research in applied mathematics and numerical analysis. This contribution summarizes recent advances, and presents original numerical results, for three different topics of research: a novel method of fluxidentification for a scalar conservation law from observation of curved shock trajectories that can be observed in sedimentation in a cone; a new description of continuous sedimentation with reactions including transport and reactions of biological components; and the numerical solution of a multi-dimensional sedimentation-consolidation system by an augmented mixed-primal method, including an a posteriori error estimation.
|
|
| 42. |
- Bürger, Raimund, et al.
(författare)
-
Numerical solution of a multi-class model for batch settling in water resource recovery facilities
- 2017
-
Ingår i: Applied Mathematical Modelling. - : Elsevier BV. - 0307-904X. ; 49, s. 415-436
-
Tidskriftsartikel (refereegranskat)abstract
- In Torfs et al. (2017) a new unified framework to model settling tanks in water resource recovery facilities was proposed providing a set of partial differential equations (PDEs) modelling different settling unit processes in wastewater treatment such as primary and secondary settling tanks (PSTs and SSTs). The extension to a multi-class framework to deal with the distributed properties of the settling particles leads to a system of non-linear hyperbolic-parabolic PDEs whose solutions may contain very sharp transitions. This necessitates the use of a consistent and robust numerical method to obtain well-resolved and reliable approximations to the PDE solutions. The use of implicit–explicit Runge–Kutta (IMEX-RK) schemes, along with the weighted essentially non-oscillatory (WENO) shock-capturing technology for the discretization of the set of equations, is advocated in this work. The versatility of the proposed unified framework is demonstrated through a set of numerical examples for batch settling occurring in both PSTs and SSTs, along with the efficiency and reliability of the numerical scheme.
|
|
| 43. |
|
|
| 44. |
|
|
| 45. |
- Karyotaki, Eirini, et al.
(författare)
-
Do guided internet-based interventions result in clinically relevant changes for patients with depression? : An individual participant data meta-analysis
- 2018
-
Ingår i: Clinical Psychology Review. - : Elsevier. - 0272-7358 .- 1873-7811. ; 63, s. 80-92
-
Forskningsöversikt (refereegranskat)abstract
- Little is known about clinically relevant changes in guided Internet-based interventions for depression. Moreover, methodological and power limitations preclude the identification of patients' groups that may benefit more from these interventions. This study aimed to investigate response rates, remission rates, and their moderators in randomized controlled trials (RCTs) comparing the effect of guided Internet-based interventions for adult depression to control groups using an individual patient data meta-analysis approach. Literature searches in PubMed, Embase, PsycINFO and Cochrane Library resulted in 13,384 abstracts from database inception to January 1, 2016. Twenty-four RCTs (4889 participants) comparing a guided Internet-based intervention with a control group contributed data to the analysis. Missing data were multiply imputed. To examine treatment outcome on response and remission, mixed-effects models with participants nested within studies were used. Response and remission rates were calculated using the Reliable Change Index. The intervention group obtained significantly higher response rates (OR = 2.49, 95% CI 2.17-2.85) and remission rates compared to controls (OR = 2.41, 95% CI 2.07-2.79). The moderator analysis indicated that older participants (OR = 1.01) and native-born participants (1.66) were more likely to respond to treatment compared to younger participants and ethnic minorities respectively. Age (OR = 1.01) and ethnicity (1.73) also moderated the effects of treatment on remission.Moreover, adults with more severe depressive symptoms at baseline were more likely to remit after receiving intemet-based treatment (OR = 1.19). Guided Internet-based interventions lead to substantial positive treatment effects on treatment response and remission at post-treatment. Thus, such interventions may complement existing services for depression and potentially reduce the gap between the need and provision of evidence-based treatments.
|
|
| 46. |
|
|
| 47. |
- Ron-Doitch, Sapir, et al.
(författare)
-
Reduced cytotoxicity and enhanced bioactivity of cationic antimicrobial peptides liposomes in cell cultures and 3D epidermis model against HSV
- 2016
-
Ingår i: Journal of Controlled Release. - : ELSEVIER SCIENCE BV. - 0168-3659 .- 1873-4995. ; 229, s. 163-171
-
Tidskriftsartikel (refereegranskat)abstract
- Cationic antimicrobial peptides (AMPs) are part of the innate immunity, and act against a wide variety of pathogenic microorganisms by perturbation of the microorganisms plasma membrane. Although attractive for clinical applications, these agents suffer from limited stability and activity in vivo, as well as non-specific interaction with host biological membranes, leading to cytotoxic adverse effects. We hypothesized that encapsulation of AMPs within liposomes could result in reduced cytotoxicity, and with enhanced stability as well as bioactivity against herpes simplex virus 1 (HSV-1). We formulated nano-sized liposomal formulations of LL-37 and indolicidin, and their physicochemical properties, cellular uptake, in vitro cytotoxicity and antiviral efficacy have been determined. Lower cytotoxicity of LL-37 liposomes was found in comparison to indolicidin liposomes attributed to the superior physicochemical properties, and to the different degree of interaction with the liposomal membrane. The disc-like shaped LL-37 liposomes (106.8 +/- 10.1 nm, shelf-life stability of N1 year) were taken up more rapidly and to a significantly higher extent than the free peptide by human keratinocyte cell line (HaCaT), remained intact within the cells, followed by release of the active peptide within the cytoplasm and migration of the vesicles lipids to the plasma membrane. LL-37 liposomes were found significantly less toxic than both the free agent and liposomal indolicidin. In the new 3D epidermis model (immortalized primary keratinocytes) liposomal LL-37 treatment (N20 mu M), but not free LL-37, efficiently protected the epidermis, inhibiting HSV-1 infection. This positive antiviral effect was obtained with no cytotoxicity even at very high concentrations (400 mu M). Thus, the antiviral activity of encapsulated LL-37 was significantly improved, expanding its therapeutic window. Liposomal LL-37 appears to be a promising delivery system for HSV therapy. (C) 2016 Elsevier B.V. All rights reserved.
|
|
| 48. |
|
|
| 49. |
- Torfs, Elena, et al.
(författare)
-
Concentration-driven models revisited : Towards a unified framework to model settling tanks in water resource recovery facilities
- 2017
-
Ingår i: Water Science and Technology. - : IWA Publishing. - 0273-1223 .- 1996-9732. ; 75:3, s. 539-551
-
Tidskriftsartikel (refereegranskat)abstract
- A new perspective on the modelling of settling behaviour in water resource recovery facilities is introduced. The ultimate goal is to describe in a unified way the processes taking place both in primary settling tanks (PSTs) and secondary settling tanks (SSTs) for a more detailed operation and control. First, experimental evidence is provided, pointing out distributed particle properties (such as size, shape, density, porosity, and flocculation state) as an important common source of distributed settling behaviour in different settling unit processes and throughout different settling regimes (discrete, hindered and compression settling). Subsequently, a unified model framework that considers several particle classes is proposed in order to describe distributions in settling behaviour as well as the effect of variations in particle properties on the settling process. The result is a set of partial differential equations (PDEs) that are valid from dilute concentrations, where they correspond to discrete settling, to concentrated suspensions, where they correspond to compression settling. Consequently, these PDEs model both PSTs and SSTs.
|
|
| 50. |
|
|
