| 1. |
- Schmidt, Amand F., et al.
(författare)
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Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9
- 2019
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Ingår i: BMC Cardiovascular Disorders. - : BMC. - 1471-2261 .- 1471-2261. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
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| 2. |
- Adam, Meike, et al.
(författare)
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Functional Outcomes and Quality of Life After Radical Prostatectomy Only Versus a Combination of Prostatectomy with Radiation and Hormonal Therapy
- 2017
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Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 71:3, s. 330-336
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Tidskriftsartikel (refereegranskat)abstract
- Background: While the optimal use and timing of secondary therapy after radical prostatectomy (RP) remain controversial, there are limited data on patient-reported outcomes following multimodal therapy.Objective: To assess the impact of additional radiation therapy (RT) and/or androgen deprivation therapy (ADT) on urinary continence, potency, and quality of life (QoL) after RP.Design, setting, and participants: Among 13 150 men who underwent RP from 1992 to 2013, 905 received RP + RT, 407 RP + ADT and 688 RP + RT + ADT.Outcome measurements and statistical analyses: Urinary function, sexual function, and overall QoL were evaluated annually using self-administered validated questionnaires. Propensity score-matched and bootstrap analyses were performed, and the distributions for all functional outcomes were analyzed as a function of time after RP.Results and limitations: Patients who received RP + RT had a 4% higher overall incontinence rate 3 yr after surgery, and 1% higher rate for severe incontinence (> 3 pads/24 h) compared to matched RP-only patients. ADT further increased the overall and severe incontinence rates by 4% and 3%, respectively, compared to matched RP + RT patients. RP + RT was associated with an 18% lower rate of potency compared to RP alone, while RP + RT + ADT was associated with a further 17% reduction compared to RP + RT. Additional RT reduced QoL by 10% and additional ADT by a further 12% compared to RP only and RP + RT, respectively. The timing of RT after RP had no influence on continence, but adjuvant compared to salvage RT was associated with significantly lower potency (37% vs 45%), but higher QoL (60% vs 56%). Limitations of our study include the observational study design and potential for selection bias in the treatments received.Conclusions: Secondary RT and ADT after RP have an additive negative influence on urinary function, potency, and QoL. Patients with high-risk disease should be counseled before RP on the potential net impairment of functional outcomes due to multimodal treatment.Patient summary: Men with high-risk disease choosing surgery upfront should be counseled on the potential need for additional radiation and or androgen deprivation, and the potential net impairment of functional outcomes arising from multimodal treatment.
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| 3. |
- Andersen, Kasper Winther, et al.
(författare)
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Disentangling white-matter damage from physiological fibre orientation dispersion in multiple sclerosis
- 2020
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Ingår i: Brain Communications. - : Oxford University Press (OUP). - 2632-1297. ; 2:2, s. 1-14
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis leads to diffuse damage of the central nervous system, affecting also the normal-appearing white matter. Demyelination and axonal degeneration reduce regional fractional anisotropy in normal-appearing white matter, which can be routinely mapped with diffusion tensor imaging. However, the standard fractional anisotropy metric is also sensitive to physiological variations in orientation dispersion of white matter fibres. This complicates the detection of disease-related damage in large parts of cerebral white matter where microstructure physiologically displays a high degree of fibre dispersion. To resolve this ambiguity, we employed a novel tensor-valued encoding method for diffusion MRI, which yields a microscopic fractional anisotropy metric that is unaffected by regional variations in orientation dispersion. In 26 patients with relapsing-remitting multiple sclerosis, 14 patients with primary-progressive multiple sclerosis and 27 age-matched healthy controls, we compared standard fractional anisotropy mapping with the novel microscopic fractional anisotropy mapping method, focusing on normal-appearing white matter. Mean microscopic fractional anisotropy and standard fractional anisotropy of normal-appearing white matter were significantly reduced in both patient groups relative to healthy controls, but microscopic fractional anisotropy yielded a better reflection of disease-related white-matter alterations. The reduction in mean microscopic fractional anisotropy showed a significant positive linear relationship with physical disability, as reflected by the expanded disability status scale. Mean reduction of microscopic fractional anisotropy in normal-appearing white matter also scaled positively with individual cognitive dysfunction, as measured with the symbol digit modality test. Mean microscopic fractional anisotropy reduction in normal-appearing white matter also showed a positive relationship with total white-matter lesion load as well as lesion load in specific tract systems. None of these relationships between normal-appearing white-matter microstructure and clinical, cognitive or structural measures emerged when using mean fractional anisotropy. Together, the results provide converging evidence that microscopic fractional anisotropy mapping substantially advances the assessment of cerebral white matter in multiple sclerosis by disentangling microstructure damage from variations in physiological fibre orientation dispersion at the stage of data acquisition. Since tensor-valued encoding can be implemented in routine diffusion MRI, microscopic fractional anisotropy mapping bears considerable potential for the future assessment of disease progression in normal-appearing white matter in both relapsing-remitting and progressive forms of multiple sclerosis as well as other white-matter-related brain diseases.
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| 4. |
- Haese, Alexander, et al.
(författare)
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Human glandular kallikrein 2 levels in serum for discrimination of pathologically organ-confined from locally-advanced prostate cancer in total PSA-levels below 10 ng/ml
- 2001
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Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 49:2, s. 101-109
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: We measured serum levels of human glandular kallikrein 2 (hK2) in patients treated with radical retropubic prostatectomy (rrP) for clinically localized prostate cancer (PCa) with a total PSA (tPSA)-level below 10 ng/ml to investigate whether hK2 can be applied to preoperatively distinguish organ-confined (pT2a/b) from nonorgan-confined (> or = pT3a)-PCa more accurately than total PSA. Further, we evaluated hK2, free- and tPSA-concentrations in all pathologic stages of PCa. METHODS: 161 serum samples from men scheduled for rrP were collected 1 day before surgery prior to any prostatic manipulation. Pathologic work-up revealed > or = pT3a-PCa in 48 and pT2a/b-PCa in 113 patients. HK2-levels in serum were measured using an immunofluorometric assay with an analytical sensitivity of 0.5 pg/ml, a functional sensitivity of 5 pg/ml and insignificant cross-reactivity with PSA (< 0.005%). Total (tPSA) and free PSA (fPSA) levels were measured using a commercially available assay from which we calculated %fPSA and an algorithm that combined hK2 and PSA-levels [hK2] x [tPSA/fPSA]. Means, medians, and ranges were calculated for pT2a/b vs. >/= pT3a-PCa and for all pathologic stages. Statistical significance of differences was calculated using Mann-Whitney-U and Kruskal-Wallis tests. Calculation of receiver-operator-characteristic (ROC) curves were performed for hK2, [hK2] x [tPSA/fPSA] and tPSA to compare diagnostic performance. RESULTS: A mean tPSA level in serum of 6.12 ng/ml in > or = pT3a-PCa was not significantly different (P = 0.366) from 5.78 ng/ml in pT2a/b-PCa. Also, there were no statistically significantly different levels of fPSA (P = 0.947) or %fPSA (0.292) for these two groups. By contrast, mean hK2-level in pT2a/b-PCa of 80 pg/ml was significantly different (P = 0.004) from a mean hK2 level of 120 pg/ml in > or = pT3a-PCa as shown by Mann-Whitney-analysis Moreover, the algorithm of [hK2] x [tPSA/fPSA] was significantly lower (P = 0.0004) in pT2a/b-PCa vs. > or = pT3a-PCa. Calculation of areas under curve (AUC) by receiver-operator-characteristics (ROC) demonstrated that the AUC for hK2 (0.64) was larger and the AUC for [hK2] x [tPSA/fPSA] (=0.68) significantly larger (P = 0.007) compared to the AUC of tPSA (0.55). Furthermore, Kruskal-Wallis Test revealed a highly significant correlation to pathologic stage using hK2 (P = 0.008) and [hK2] x [tPSA/fPSA] (P = 0.0015) compared to no significant differences in serum concentration of tPSA (P = 0.296). Also at tPSA-levels from 10-20 ng/ml, the hK2-levels in pT2a/b-PCa were close to significantly different (P = 0.051) from those in men with >/= pT3a-PCa, while the algorithm of [hK2] x [tPSA/fPSA] in that tPSA-range was significantly lower (P = 0.002) in pT2a/b-PCa compared to > or = pT3a0-PCa. CONCLUSIONS: Highly significant differences in serum concentration enable hK2 to be a powerful predictor of organ-confined disease and pathologic stage of clinically localized prostate cancer, especially in the PSA-range below 10 ng/ml. As such, there are important clinical consequences for the application of hK2 for the adequate treatment of prostate cancer patients, i.e., the option of nerve-sparing surgery.
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| 5. |
- Hartwig, Markus
(författare)
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Authority allocation and alignment of interest
- 2014
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- This paper is the first one to show how delegation of power and interest alignment need to go hand in order for employees to exert effort and thus increase company performance. The experiment is based on the partial restructuring of an electricity grid operator in Scandinavia where identification strategy is based on using a subset of teams that were not affected by the reorganisation.
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| 6. |
- Hartwig, Markus
(författare)
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Authority allocation and geographic dispersion
- 2014
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- This paper shows empirically that proximity or ease of access from divisions to headquarters can affect the allocation of authority and company performance. I find that managers that are selected via a centralized process have significantly higher probability of being selected if they work in relative proximity to the head quarters. I also show that authority is more easily delegated to geographically accessible units and that these tend to show higher effort levels.
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| 7. |
- Hartwig, Markus
(författare)
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Authority allocation in hierarchies, a literature overview
- 2014
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- This paper gives an overview on how different branches of research derive concepts of optimal authority allocation taking into account human behaviour. The paper spans a bow from game theory and the focus on the strategic behaviour of the individual over operations research and the relevance of market mechanisms in organisations to organizational and contingency theorists that searched for an organisational set up that would gurantee certain outcomes and finally behavioural sciences that see hierarchies as a way to manage social conflicts.
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| 8. |
- Hartwig, Markus
(författare)
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Do utilities in the German electricity market extract economic rent?
- 2014
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The market liberalization of the European electricity sector aimed for a more efficient allocation of resources and lower overall lower wholesale price levels. This paper uses a two-step game developed by Kreps and Scheinkman [1983] to assess if the German integrated network- energysupply companies may have succeeded to use their market position in order to extract economic rent. I use an IV regression model to show that this may indeed have been the case. Protected by high barriers to enter, the network energy companies seemed to have managed strategic retirement of assets in such a way, that they may have been able to extract economic rent of approximately 22 billion Euros in gross margin annually.
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| 9. |
- Hartwig, Markus, et al.
(författare)
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Factors Associated with Increased Experience of Postoperative Pain after Laparoscopic Gastric Bypass Surgery
- 2017
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Ingår i: Obesity Surgery. - New York, USA : Springer. - 0960-8923 .- 1708-0428. ; 27:7, s. 1854-1858
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Patients with high body mass index (BMI), pre-existing pain and young age and women seem to experience more postoperative pain. Few studies have, however, addressed these risk factors amongst obese patients undergoing bariatric surgery. The aim of the present study was to evaluate risk factors for postoperative pain following laparoscopic gastric bypass surgery.Methods: In this cohort study, we used data from the PAIN OUT register for postoperative pain during the first 24 h after surgery. Primary outcome measure was severity of pain after surgery. Multivariate analyses were conducted to evaluate BMI, young age, gender and pre-existing pain as independent risk factors for postoperative pain.Results: We included 192 patients in this study. Younger age (B -0.08, 95%CI -0.11 to -0.05/year; p < 0.001), female gender (B 0.92, 95%CI 0.10-1.75; p = 0.029) and pre-existing pain (B 1.06, 95%CI 0.03-2.09; p = 0.044) were all associated with an increased risk for postoperative pain. In the multivariate analyses, only young age ((adjusted OR 0.95, 95%CI 0.92-0.97/year; p < 0.001) and pre-existing pain (adjusted OR 2.56, 95%CI 1.09-6.00; p = 0.031) remained as independent risk factors for severe postoperative pain.Conclusion: Younger age and pre-existing pain are associated with severe postoperative pain during the first 24 h after laparoscopic gastric bypass surgery, whereas female gender and high BMI are not.
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| 10. |
- Hartwig, Markus
(författare)
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Interest Alignment, Delegation of Authority and Economic Rent : A Collection of Empirical Papers
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- “Authority allocation in hierarchies, a literature overview”: This paper gives an overview of literature dealing with authority allocation in hierarchies. It gives an overview on how different branches of research derive concepts of optimal authority allocation taking into account human behaviour. “Authority allocation and alignment of interest”: This paper is the first one to show how delegation of power and interest alignment needs to go hand in hand in order for employees to exert effort and thus increase company performance. The experiment is based on the partial restructuring of an electricity grid operator in Scandinavia where identification strategy is based on using a subset of teams that were not affected by the reorganization. “Authority allocation and geographic dispersion”: This paper shows empirically that proximity or ease of access from divisions to headquarters can affect the allocation of authority and company performance. I find that managers that are selected via a centralized process have significantly higher probability of being selected if they work in relative proximity to the head quarters. I also show that authority is more easily delegated to geographically accessible units and that these tend to show higher effort levels. “Do utilities in the German electricity market extract economic rent?” This paper uses a framework developed by Kreps and Scheinkman [1983] to show there is significant evidence that the integrated network- energy- supply companies in Germany may have succeeded to use their dominating market position in order to extract economic rent, by engaging in a strategic retirement of power plants, thus counteracting the aim of lower energy prices through competition in a liberalized market.
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