| 1. |
- Walters, R G, et al.
(författare)
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A new highly penetrant form of obesity due to deletions on chromosome 16p11.2.
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 463:7281, s. 671-5
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Tidskriftsartikel (refereegranskat)abstract
- Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.
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| 2. |
- Heerspink, Hiddo J L, et al.
(författare)
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Effects of dapagliflozin on mortality in patients with chronic kidney disease : a pre-specified analysis from the DAPA-CKD randomized controlled trial.
- 2021
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Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 42:13, s. 1216-1227
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Mortality rates from chronic kidney disease (CKD) have increased in the last decade. In this pre-specified analysis of the DAPA-CKD trial, we determined the effects of dapagliflozin on cardiovascular and non-cardiovascular causes of death.METHODS AND RESULTS: DAPA-CKD was an international, randomized, placebo-controlled trial with a median of 2.4 years of follow-up. Eligible participants were adult patients with CKD, defined as a urinary albumin-to-creatinine ratio (UACR) 200-5000 mg/g and an estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m2. All-cause mortality was a key secondary endpoint. Cardiovascular and non-cardiovascular death was adjudicated by an independent clinical events committee. The DAPA-CKD trial randomized participants to dapagliflozin 10 mg/day (n = 2152) or placebo (n = 2152). The mean age was 62 years, 33% were women, the mean eGFR was 43.1 mL/min/1.73 m2, and the median UACR was 949 mg/g. During follow-up, 247 (5.7%) patients died, of whom 91 (36.8%) died due to cardiovascular causes, 102 (41.3%) due to non-cardiovascular causes, and in 54 (21.9%) patients, the cause of death was undetermined. The relative risk reduction for all-cause mortality with dapagliflozin (31%, hazard ratio [HR] [95% confidence interval (CI)] 0.69 [0.53, 0.88]; P = 0.003) was consistent across pre-specified subgroups. The effect on all-cause mortality was driven largely by a 46% relative risk reduction of non-cardiovascular death (HR [95% CI] 0.54 [0.36, 0.82]). Deaths due to infections and malignancies were the most frequently occurring causes of non-cardiovascular deaths and were reduced with dapagliflozin vs. placebo.CONCLUSION: In patients with CKD, dapagliflozin prolonged survival irrespective of baseline patient characteristics. The benefits were driven largely by reductions in non-cardiovascular death.
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| 3. |
- McMurray, John J. V., et al.
(författare)
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Effect of Dapagliflozin on Clinical Outcomes in Patients with Chronic Kidney Disease, With and Without Cardiovascular Disease
- 2021
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Ingår i: Circulation. - : Wolters Kluwer. - 0009-7322 .- 1524-4539. ; 143:5, s. 438-448
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Tidskriftsartikel (refereegranskat)abstract
- Background:Dapagliflozin reduces the risk of end-stage renal disease in patients with chronic kidney disease. We examined the relative risk of cardiovascular and renal events in these patients and the effect of dapagliflozin on either type of event, taking account of history of cardiovascular disease.Methods:In the DAPA-CKD trial (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease), 4304 participants with chronic kidney disease were randomly assigned to dapagliflozin 10 mg once daily or placebo. The primary end point was a composite of sustained decline in estimated glomerular filtration rate ≥50%, end-stage kidney disease, or kidney or cardiovascular death. The secondary end points were a kidney composite outcome (primary end point, minus cardiovascular death), the composite of hospitalization for heart failure or cardiovascular death, and all-cause death. In a prespecified subgroup analysis, we divided patients into primary and secondary prevention subgroups according to history of cardiovascular disease.Results:Secondary prevention patients (n=1610; 37.4%) were older, were more often male, had a higher blood pressure and body mass index, and were more likely to have diabetes. Mean estimated glomerular filtration rate and median urinary albumin-to-creatinine ratio were similar in the primary and secondary prevention groups. The rates of adverse cardiovascular outcomes were higher in the secondary prevention group, but kidney failure occurred at the same rate in the primary and secondary prevention groups. Dapagliflozin reduced the risk of the primary composite outcome to a similar extent in both the primary (hazard ratio, 0.61 [95% CI, 0.48–0.78]) and secondary (0.61 [0.47–0.79]) prevention groups (P-interaction=0.90). This was also true for the composite of heart failure hospitalization or cardiovascular death (0.67 [0.40–1.13] versus 0.70 [0.52–0.94], respectively; P-interaction=0.88), and all-cause mortality (0.63 [0.41–0.98] versus 0.70 [0.51–0.95], respectively; P-interaction=0.71). Rates of adverse events were low overall and did not differ between patients with and without cardiovascular disease.Conclusions:Dapagliflozin reduced the risk of kidney failure, death from cardiovascular causes or hospitalization for heart failure, and prolonged survival in people with chronic kidney disease, with or without type 2 diabetes, independently of the presence of concomitant cardiovascular disease.Registration:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036150.
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| 4. |
- Moberg, Christina, et al.
(författare)
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De unga gör helt rätt när de stämmer staten
- 2022
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Ingår i: Aftonbladet. - 1103-9000.
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Tidskriftsartikel (populärvet., debatt m.m.)abstract
- 1 620 forskare och lärare i forskarvärlden: Vi ställer oss bakom Auroras klimatkrav
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| 5. |
- Stefánsson, Bergur V., et al.
(författare)
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Correction of anemia by dapagliflozin in patients with type 2 diabetes
- 2020
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Ingår i: Journal of diabetes and its complications. - : Elsevier. - 1056-8727 .- 1873-460X. ; 34:12
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Anemia is common in type 2 diabetes (T2D), particularly in patients with kidney impairment, and often goes unrecognized. Dapagliflozin treatment increases hemoglobin and serum erythropoietin levels. We investigated the effect of dapagliflozin 10-mg/day on hemoglobin in T2D patients with and without anemia. Methods: Data from 5325 patients from 14 placebo-controlled, dapagliflozin-treatment studies of at least 24-weeks duration were pooled. Dapagliflozin's effects (vs. placebo) on hemoglobin, serum albumin, estimated glomerular filtration rate (eGFR), systolic blood pressure, body weight, and safety in patients with and without anemia were evaluated. Results: At baseline, 13% of all T2D patients and 28% of those with chronic kidney disease (eGFR <60 mL/min/1.73 m2) had anemia. Hemoglobin increased continuously to at least week 8 and was sustained throughout 24-weeks follow-up in dapagliflozin-treated patients. Serum albumin increased in dapagliflozin-treated patients at week 4 and remained stable thereafter. Dapagliflozin was well tolerated and corrected anemia in 52% of patients with anemia at baseline (placebo: 26%). Incidences of new-onset anemia were lower in dapagliflozin-treated (2.3%) versus placebo-treated (6.5%) patients. Conclusions: Treatment with dapagliflozin can correct and prevent anemia in T2D patients. A gradual increase in hemoglobin beyond week 4 may indicate an erythropoiesis-stimulating effect of sodium-glucose cotransporter 2 inhibition.
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| 6. |
- Stefánsson, Bergur V., et al.
(författare)
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Data from a pooled post hoc analysis of 14 placebo-controlled, dapagliflozin treatment studies in patients with type 2 diabetes with and without anemia at baseline
- 2021
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Ingår i: Data in Brief. - : Elsevier. - 2352-3409. ; 37, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- Dapagliflozin is a highly selective sodium-glucose cotransporter 2 inhibitor associated with stabilization of estimated glomerular filtration rate (eGFR); reductions in glycated hemoglobin (HbA1c), systolic blood pressure, body weight, and albuminuria; and a small and consistent increase in hematocrit [1–4]. This data set is based on the associated article [5] analyzing data from 5325 patients with type 2 diabetes from 14 placebo-controlled, phase 3 (one phase 2/3), double-blind dapagliflozin treatment studies of 24–104 weeks’ duration. Data on dapagliflozin's effects (vs. placebo) on hemoglobin (Hb), hematocrit, serum albumin, serum total protein concentrations, urine albumin/creatinine ratio, eGFR, heart rate, blood pressure, body weight, and safety in patients with type 2 diabetes with and without anemia were pooled and analyzed. Patients were divided into two groups according to baseline Hb levels: anemia (Hb <13 g/dL in men and <12 g/dL in women) and no anemia. Some biomarkers associated with erythropoiesis and the presence of anemia, such as iron, transferrin, ferritin, reticulocytes, and hepcidin, were not included in the original studies and therefore data for these biomarkers were not available. Descriptive statistics were used for baseline characteristics and safety data and a longitudinal repeated-measures mixed model for efficacy data. Changes in Hb concentrations were evaluated, and the proportion of patients with baseline anemia who were no longer anemic at week 24 was determined, as was the occurrence of polycythemia (Hb >16.5 g/dL in men and >16.0 g/dL in women). Because anemia commonly occurs in patients with diabetes and chronic kidney disease [6], the data can be of value to further analyze trends in relevant physiological and pathophysiological parameters.
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| 7. |
- Sjöström, Lars, et al.
(författare)
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Effects of bariatric surgery on cancer incidence in obese patients in Sweden (Swedish Obese Subjects Study): a prospective, controlled intervention trial.
- 2009
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Ingår i: The lancet oncology. - 1474-5488. ; 10:7, s. 653-62
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Obesity is a risk factor for cancer. Intentional weight loss in the obese might protect against malignancy, but evidence is limited. To our knowledge, the Swedish Obese Subjects (SOS) study is the first intervention trial in the obese population to provide prospective, controlled cancer-incidence data. METHODS: The SOS study started in 1987 and involved 2010 obese patients (body-mass index [BMI] >or=34 kg/m(2) in men, and >or=38 kg/m(2) in women) who underwent bariatric surgery and 2037 contemporaneously matched obese controls, who received conventional treatment. While the main endpoint of SOS was overall mortality, the main outcome of this exploratory report was cancer incidence until Dec 31, 2005. Cancer follow-up rate was 99.9% and the median follow-up time was 10.9 years (range 0-18.1 years). FINDINGS: Bariatric surgery resulted in a sustained mean weight reduction of 19.9 kg (SD 15.6 kg) over 10 years, whereas the mean weight change in controls was a gain of 1.3 kg (SD 13.7 kg). The number of first-time cancers after inclusion was lower in the surgery group (n=117) than in the control group (n=169; HR 0.67, 95% CI 0.53-0.85, p=0.0009). The sex-treatment interaction p value was 0.054. In women, the number of first-time cancers after inclusion was lower in the surgery group (n=79) than in the control group (n=130; HR 0.58, 0.44-0.77; p=0.0001), whereas there was no effect of surgery in men (38 in the surgery group vs 39 in the control group; HR 0.97, 0.62-1.52; p=0.90). Similar results were obtained after exclusion of all cancer cases during the first 3 years of the intervention. INTERPRETATION: Bariatric surgery was associated with reduced cancer incidence in obese women but not in obese men. FUNDING: Swedish Research Council, Swedish Foundation for Strategic Research, Swedish Federal Government under the LUA/ALF agreement, Hoffmann La Roche, Cederoths, AstraZeneca, Sanofi-Aventis, Ethicon Endosurgery.
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| 8. |
- Sjöström, Lars, et al.
(författare)
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Effects of bariatric surgery on mortality in Swedish obese subjects.
- 2007
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Ingår i: The New England journal of medicine. - 1533-4406. ; 357:8, s. 741-52
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Obesity is associated with increased mortality. Weight loss improves cardiovascular risk factors, but no prospective interventional studies have reported whether weight loss decreases overall mortality. In fact, many observational studies suggest that weight reduction is associated with increased mortality. METHODS: The prospective, controlled Swedish Obese Subjects study involved 4047 obese subjects. Of these subjects, 2010 underwent bariatric surgery (surgery group) and 2037 received conventional treatment (matched control group). We report on overall mortality during an average of 10.9 years of follow-up. At the time of the analysis (November 1, 2005), vital status was known for all but three subjects (follow-up rate, 99.9%). RESULTS: The average weight change in control subjects was less than +/-2% during the period of up to 15 years during which weights were recorded. Maximum weight losses in the surgical subgroups were observed after 1 to 2 years: gastric bypass, 32%; vertical-banded gastroplasty, 25%; and banding, 20%. After 10 years, the weight losses from baseline were stabilized at 25%, 16%, and 14%, respectively. There were 129 deaths in the control group and 101 deaths in the surgery group. The unadjusted overall hazard ratio was 0.76 in the surgery group (P=0.04), as compared with the control group, and the hazard ratio adjusted for sex, age, and risk factors was 0.71 (P=0.01). The most common causes of death were myocardial infarction (control group, 25 subjects; surgery group, 13 subjects) and cancer (control group, 47; surgery group, 29). CONCLUSIONS: Bariatric surgery for severe obesity is associated with long-term weight loss and decreased overall mortality.
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| 9. |
- Downham, David, et al.
(författare)
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Distribution of different fibre types in human skeletal muscles: A method for the detection of neurogenic disorders
- 1987
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Ingår i: IMA journal of mathematics applied in medicine and biology. - : Oxford University Press (OUP). - 0265-0746 .- 1471-6879. ; 4:1, s. 81-91
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Tidskriftsartikel (refereegranskat)abstract
- Human skeletal muscles are composed of two distinguishable types of fibres, which in healthy muscles appear to be randomly arranged. Large groups of one fibre type are commonly regarded as evidence of a neuropathological process affecting the peripheral nerves or the nerve cells in the spinal cord. An objective method that detects non-random arrangements as a sign of a neurogenic disorder, particularly in its early stages, could improve diagnosis. The randomness, or otherwise, of the fibre type arrangement is here considered in terms of the numbers of fibres surrounded entirely by others of the same type (enclosed fibres). The distribution of the number of enclosed fibres is studied for a free-sampling model using Monte Carlo methods. The negative binomial distribution is shown to fit closely, where the parameters can be expressed in terms of the number of fibres and the fibre type proportion in a sample area. This result permits the calculation of significance levels for a sample area and the combination of information in several sample areas. Finally, the method is applied to whole cross-sections of 24 male human autopsied muscles.
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| 10. |
- Durcik, Martina, et al.
(författare)
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New Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate Staphylococcus aureus
- 2023
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 66:6, s. 3968-3994
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Tidskriftsartikel (refereegranskat)abstract
- A new series of dual low nanomolar benzothiazole inhibitors of bacterial DNA gyrase and topoisomerase IV were developed. The resulting compounds show excellent broad-spectrum antibacterial activities against Gram-positive Enterococcus faecalis, Enterococcus faecium and multidrug resistant (MDR) Staphylococcus aureus strains [best compound minimal inhibitory concentrations (MICs): range, <0.03125–0.25 μg/mL] and against the Gram-negatives Acinetobacter baumannii and Klebsiella pneumoniae (best compound MICs: range, 1–4 μg/mL). Lead compound 7a was identified with favorable solubility and plasma protein binding, good metabolic stability, selectivity for bacterial topoisomerases, and no toxicity issues. The crystal structure of 7a in complex with Pseudomonas aeruginosa GyrB24 revealed its binding mode at the ATP-binding site. Expanded profiling of 7a and 7h showed potent antibacterial activity against over 100 MDR and non-MDR strains of A. baumannii and several other Gram-positive and Gram-negative strains. Ultimately, in vivo efficacy of 7a in a mouse model of vancomycin-intermediate S. aureus thigh infection was also demonstrated.
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