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- Ruilope, LM, et al.
(författare)
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Design and Baseline Characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial
- 2019
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Ingår i: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 50:5, s. 345-356
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Background:</i></b> Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. <b><i>Patients and</i></b> <b><i>Methods:</i></b> The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m<sup>2</sup> and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. <b><i>Conclusions:</i></b> FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.
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| 9. |
- Cools, M, et al.
(författare)
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Caring for individuals with a difference of sex development (DSD): a Consensus Statement
- 2018
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Ingår i: Nature reviews. Endocrinology. - : Springer Science and Business Media LLC. - 1759-5037 .- 1759-5029. ; 14:7, s. 415-429
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Tidskriftsartikel (refereegranskat)abstract
- The term differences of sex development (DSDs; also known as disorders of sex development) refers to a heterogeneous group of congenital conditions affecting human sex determination and differentiation. Several reports highlighting suboptimal physical and psychosexual outcomes in individuals who have a DSD led to a radical revision of nomenclature and management a decade ago. Whereas the resulting recommendations for holistic, multidisciplinary care seem to have been implemented rapidly in specialized paediatric services around the world, adolescents often experience difficulties in finding access to expert adult care and gradually or abruptly cease medical follow-up. Many adults with a DSD have health-related questions that remain unanswered owing to a lack of evidence pertaining to the natural evolution of the various conditions in later life stages. This Consensus Statement, developed by a European multidisciplinary group of experts, including patient representatives, summarizes evidence-based and experience-based recommendations for lifelong care and data collection in individuals with a DSD across ages and highlights clinical research priorities. By doing so, we hope to contribute to improving understanding and management of these conditions by involved medical professionals. In addition, we hope to give impetus to multicentre studies that will shed light on outcomes and comorbidities of DSD conditions across the lifespan.
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| 11. |
- Lundby, Carsten, et al.
(författare)
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Physiological, biochemical, anthropometric, and biomechanical influences on exercise economy in humans
- 2017
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Ingår i: Scandinavian Journal of Medicine & Science in Sports. - : Wiley. - 0905-7188. ; 27:12, s. 1627-1637
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Tidskriftsartikel (refereegranskat)abstract
- Interindividual variation in running and cycling exercise economy (EE) remains unexplained although studied for more than a century. This study is the first to comprehensively evaluate the importance of biochemical, structural, physiological, anthropometric, and biomechanical influences on running and cycling EE within a single study. In 22 healthy males (VO(2)max range 45.5-72.1mLmin-1kg-1), no factor related to skeletal muscle structure (% slow-twitch fiber content, number of capillaries per fiber), mitochondrial properties (volume density, oxidative capacity, or mitochondrial efficiency), or protein content (UCP3 and MFN2 expression) explained variation in cycling and running EE among subjects. In contrast, biomechanical variables related to vertical displacement correlated well with running EE, but were not significant when taking body weight into account. Thus, running EE and body weight were correlated (R-2=.94; P<.001), but was lower for cycling EE (R-2=.23; P<.023). To separate biomechanical determinants of running EE, we contrasted individual running and cycling EE considering that during cycle ergometer exercise, the biomechanical influence on EE would be small because of the fixed movement pattern. Differences in cycling and running exercise protocols, for example, related to biomechanics, play however only a secondary role in determining EE. There was no evidence for an impact of structural or functional skeletal muscle variables on EE. Body weight was the main determinant of EE explaining 94% of variance in running EE, although more than 50% of the variability of cycling EE remains unexplained.
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| 12. |
- Tack, LJW, et al.
(författare)
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Management of Gonads in Adults with Androgen Insensitivity: An International Survey
- 2018
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Ingår i: Hormone research in paediatrics. - : S. Karger AG. - 1663-2826 .- 1663-2818. ; 90:4, s. 236-246
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Background:</i></b> Complete and partial androgen insensitivity syndrome (CAIS, PAIS) are associated with an increased risk of gonadal germ cell cancer (GGCC). Recent guidelines recommend gonadectomy in women with CAIS in late adolescence. Nevertheless, many adult women prefer to retain their gonads. <b><i>Aims:</i></b> This study aims to explore attitudes towards gonadectomy in AIS in centres around the world, estimate the proportion of adults with retained gonads and/or who developed GGCC, and explore reasons for declining gonadectomy. <b><i>Methods:</i></b> A survey was performed among health care professionals who use the International DSD Registry (I-DSD). <b><i>Results:</i></b> Data were provided from 22 centres in 16 countries on 166 women (CAIS) and 26 men (PAIS). In CAIS, gonadectomy was recommended in early adulthood in 67% of centres; 19/166 (11.4%) women refused gonadectomy. Among 142 women who had gonadectomy, evidence of germ cell neoplasm in situ (GCNIS), the precursor of GGCC, was reported in 2 (1.4%) out of 8 from whom pathology results were formally provided. Nine out of 26 men with PAIS (34.6%) had retained gonads; 11% of centres recommended routine gonadectomy in PAIS. <b><i>Conclusion:</i></b> Although development of GGCC seems rare, gonadectomy after puberty is broadly recommended in CAIS; in PAIS this is more variable. Overall, our data reflect the need for evidence-based guidelines regarding prophylactic gonadectomy in AIS.
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| 13. |
- Flück, D., et al.
(författare)
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Age, aerobic fitness, and cerebral perfusion during exercise: Role of carbon dioxide
- 2014
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Ingår i: American Journal of Physiology - Heart and Circulatory Physiology. - : American Physiological Society. - 0363-6135 .- 1522-1539. ; 307:4
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Tidskriftsartikel (refereegranskat)abstract
- Middle cerebral artery mean velocity (MCAvmean) is attenuated with increasing age both at rest and during exercise. The aim of this study was to determine the influence of the age-dependent reduction in arterial PCO2 (PaCO2) and physical fitness herein. We administered supplemental CO2 (CO2 trial) or no additional gas (control trial) to the inspired air in a blinded and randomized manner, and assessed middle cerebral artery mean flow velocity during graded exercise in 1) 21 young [Y; age 24 ± 3 yr (±SD)] volunteers of whom 11 were trained (YT) and 10 considered untrained (YUT), and 2) 17 old (O; 66 ± 4 yr) volunteers of whom 8 and 9 were considered trained (OT) and untrained (OUT), respectively. A resting hypercapnic reactivity test was also performed. MCAvmean and PaCO2 were lower in O [44.9 ± 3.1 cm/s and 30 ± 1 mmHg (±SE)] compared with Y (59.3 ± 2.3 cm/s and 34 ± 1 mmHg, P < 0.01) at rest, independent of aerobic fitness level. The age-related decreases in MCAvmean and PaCO2 persisted during exercise. Supplemental CO2 reduced the age-associated decline in MCAvmean by 50%, suggesting that PaCO2 is a major component in the decline. On the other hand, relative hypercapnic reactivity was neither influenced by age (P = 0.46) nor aerobic fitness (P = 0.36). Although supplemental CO2 attenuated exercise-induced reduction in cerebral oxygenation (near-infrared spectroscopy), this did not influence exercise performance. In conclusion, PaCO2 contributes to the age-associated decline in MCAvmean at rest and during exercise; however exercise capacity did not diminish this age effect. © 2014 the American Physiological Society.
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| 14. |
- Fluck, M., et al.
(författare)
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Comparison of potential flow-based and measured pressure distributions over upwind sails
- 2010
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Ingår i: Journal of Aircraft. - : American Institute of Aeronautics and Astronautics Inc.. - 0021-8669 .- 1533-3868. ; 47:6, s. 2174-2176
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Tidskriftsartikel (refereegranskat)abstract
- The results of the comparative analysis of potential flow-based and measured pressure distributions over upwind sails were investigated. The sail models were supported by wires inside a frame, rather than being set on a yacht model that allowed trimming the models to several predefined positions very precisely and with good repeatability. The freestream dynamic pressure was q = 32.5 Pa, with a variation of ±1 Pa in the vicinity of the sails. The headsail and its image were considered to be one sail with a continuous deck-symmetrical circulation distribution. The vortex-lattice method (VLM) code uses mirror images of the sails to model the influence of the sea surface. The results indicated that the mast and hull, which are ignored in the theoretical analysis, lead to only a 3% reduction in lift of the headsail, but to a 7% reduction for the mainsail.
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| 15. |
- Fluck, Martin, et al.
(författare)
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Early Changes in Costameric and Mitochondrial Protein Expression with Unloading Are Muscle Specific
- 2014
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Ingår i: BioMed Research International. - : Hindawi Limited. - 2314-6133 .- 2314-6141.
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Tidskriftsartikel (refereegranskat)abstract
- We hypothesised that load-sensitive expression of costameric proteins, which hold the sarcomere in place and position the mitochondria, contributes to the early adaptations of antigravity muscle to unloading and would depend on muscle fibre composition and chymotrypsin activity of the proteasome. Biopsies were obtained from vastus lateralis (VL) and soleus (SOL) muscles of eight men before and after 3 days of unilateral lower limb suspension (ULLS) and subjected to fibre typing and measures for costameric (FAK and FRNK), mitochondrial (NDUFA9, SDHA, UQCRC1, UCP3, and ATP5A1), and MHCI protein and RNA content. Mean cross-sectional area (MCSA) of types I and II muscle fibres in VL and type I fibres in SOL demonstrated a trend for a reduction after ULLS (0.05 <= P < 0.10). FAK phosphorylation at tyrosine 397 showed a 20% reduction in VL muscle (P = 0.029). SOL muscle demonstrated a specific reduction in UCP3 content (-23%; P = 0.012). Muscle-specific effects of ULLS were identified for linear relationships between measured proteins, chymotrypsin activity and fibre MCSA. The molecular modifications in costamere turnover and energy homoeostasis identify that aspects of atrophy and fibre transformation are detectable at the protein level in weight-bearing muscles within 3 days of unloading.
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| 17. |
- Hermann, Robert, et al.
(författare)
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The Clinical Pharmacology of Cladribine Tablets for the Treatment of Relapsing Multiple Sclerosis
- 2019
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Ingår i: Clinical Pharmacokinetics. - : ADIS INT LTD. - 0312-5963 .- 1179-1926. ; 58:3, s. 283-297
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Forskningsöversikt (refereegranskat)abstract
- Cladribine Tablets (MAVENCLAD (R)) are used to treat relapsing multiple sclerosis (MS). The recommended dose is 3.5 mg/kg, consisting of 2 annual courses, each comprising 2 treatment weeks 1 month apart. We reviewed the clinical pharmacology of Cladribine Tablets in patients with MS, including pharmacokinetic and pharmacometric data. Cladribine Tablets are rapidly absorbed, with a median time to reach maximum concentration (T-max) of 0.5 h (range 0.5-1.5 h) in fasted patients. When administered with food, absorption is delayed (median T-max 1.5 h, range 1-3 h), and maximum concentration (C-max) is reduced by 29% (based on geometric mean). Area under the concentration-time curve (AUC) is essentially unchanged. Oral bioavailability of cladribine is approximately 40%, pharmacokinetics are linear and time-independent, and volume of distribution is 480-490 L. Plasma protein binding is 20%, independent of cladribine plasma concentration. Cladribine is rapidly distributed to lymphocytes and retained (either as parent drug or its phosphorylated metabolites), resulting in approximately 30- to 40-fold intracellular accumulation versus extracellular concentrations as early as 1 h after cladribine exposure. Cytochrome P450-mediated biotransformation of cladribine is of minor importance. Cladribine elimination is equally dependent on renal and non-renal routes. In vitro studies indicate that cladribine efflux is minimally P-glycoprotein (P-gp)-related, and clinically relevant interactions with P-gp inhibitors are not expected. Cladribine distribution across membranes is primarily facilitated by equilibrative nucleoside transporter (ENT)1, concentrative nucleoside transporter (CNT)3 and breast cancer resistance protein (BCRP), and there is no evidence of any cladribine-related effect on heart rate, atrioventricular conduction or cardiac repolarisation (QTc interval prolongation). Cladribine Tablets are associated with targeted lymphocyte reduction and durable efficacy, with the exposure-effect relationship showing the recommended dose is appropriate in reducing relapse risk.
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| 18. |
- Keiser, S., et al.
(författare)
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Heat training increases exercise capacity in hot but not in temperate conditions: a mechanistic counter-balanced cross-over study
- 2015
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Ingår i: American Journal of Physiology-Heart and Circulatory Physiology. - : American Physiological Society. - 0363-6135 .- 1522-1539. ; 309:5
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Tidskriftsartikel (refereegranskat)abstract
- The aim was to determine the mechanisms facilitating exercise performance in hot conditions following heat training. In a counter-balanced order, seven males ((V) over dotO(2max) 61.2 +/- 4.4 ml.min(-1).kg(-1)) were assigned to either 10 days of 90-min exercise training in 18 or 38 degrees C ambient temperature (30% relative humidity) applying a cross-over design. Participants were tested for (V) over dotO(2max) and 30-min time trial performance in 18 (T18) and 38 degrees C (T38) before and after training. Blood volume parameters, sweat output, cardiac output ((Q) over dot), cerebral perfusion (i.e., middle cerebral artery velocity [MCAv(mean)]), and other variables were determined. Before one set of exercise tests in T38, blood volume was acutely expanded by 538 +/- 16 ml with an albumin solution (T38A) to determine the role of acclimatization induced hypervolemia on exercise performance. We furthermore hypothesized that heat training would restore MCAv(mean) and thereby limit centrally mediated fatigue. (V) over dotO(2max) and time trial performance were equally reduced in T38 and T38A (7.2 +/- 1.6 and 9.3 +/- 2.5% for (V) over dotO(2max); 12.8 +/- 2.8 and 12.9 +/- 2.8% for time trial). Following heat training both were increased in T38 (9.6 +/- 2.1 and 10.4 +/- 3.1%, respectively), whereas both (V) over dotO(2max) and time trial performance remained unchanged in T18. As expected, heat training augmented plasma volume (6 +/- 2%) and mean sweat output (26 +/- 6%), whereas sweat [Na+] became reduced by 19 +/- 7%. In T38 (Q) over dot(max) remained unchanged before (21.3 +/- 0.6 l/min) to after (21.7 +/- 0.5 l/min) training, whereas MCAv(mean) was increased by 13 +/- 10%. However, none of the observed adaptations correlated with the concomitant observed changes in exercise performance.
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