| 1. |
- Gennemark, Peter, et al.
(författare)
-
An oral antisense oligonucleotide for PCSK9 inhibition
- 2021
-
Ingår i: Science Translational Medicine. - : AMER ASSOC ADVANCEMENT SCIENCE. - 1946-6234 .- 1946-6242. ; 13:593
-
Tidskriftsartikel (refereegranskat)abstract
- Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein (LDL) cholesterol and are used for treatment of dyslipidemia. Current PCSK9 inhibitors are administered via subcutaneous injection. We present a highly potent, chemically modified PCSK9 antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at oral delivery using earlier-generation ASO chemistries and transient permeation enhancers provided encouraging data, suggesting that improving potency of the ASO could make oral delivery a reality. The constrained ethyl chemistry and liver targeting enabled by N-acetylgalactosamine conjugation make this ASO highly potent. A single subcutaneous dose of 90 mg reduced PCSK9 by >90% in humans with elevated LDL cholesterol and a monthly subcutaneous dose of around 25 mg is predicted to reduce PCSK9 by 80% at steady state. To investigate the feasibility of oral administration, the ASO was coformulated in a tablet with sodium caprate as permeation enhancer. Repeated oral daily dosing in dogs resulted in a bioavailability of 7% in the liver (target organ), about fivefold greater than the plasma bioavailability. Target engagement after oral administration was confirmed by intrajejunal administration of a rat-specific surrogate ASO in solution with the enhancer to rats and by plasma PCSK9 and LDL cholesterol lowering in cynomolgus monkey after tablet administration. On the basis of an assumption of 5% liver bioavailability after oral administration in humans, a daily dose of 15 mg is predicted to reduce circulating PCSK9 by 80% at steady state, supporting the development of the compound for oral administration to treat dyslipidemia.
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
- Jerrhag, Daniel, et al.
(författare)
-
Epidemiology and time trends of distal forearm fractures in adults - a study of 11.2 million person-years in Sweden
- 2017
-
Ingår i: BMC Musculoskeletal Disorders. - : Springer Science and Business Media LLC. - 1471-2474. ; 18:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: A distal forearm fracture is a very common injury causing both suffering and substantial health care costs. The incidence of this fracture type seemed to increase worldwide until the middle 1980’s, but thereafter most reports have shown stable or decreasing rates. As few large studies have been presented lately we aimed to describe recent epidemiology and time trends of distal forearm fractures in adults. We paid special attention to fractures in working ages as they present challenges in terms of treatment and costs for sick-leave, and have not previously been thoroughly investigated. Methods: By use of population data from Statistics Sweden and official in- and out-patient register data of men and women (≥17 years) in Sweden (Skåne region), we ascertained distal forearm fractures and estimated age- and sex-specific rates and time-trends from year 1999 to 2010 (11.2 million person-years (py)). Results: The total incidence rate was 278 per 100,000 py (31,233 fractures) with 23% higher annual numbers 2010 compared with 1999. An increase in the annual age standardized incidence was found in men, +0.7% per annum (95% confidence interval (CI) 0.1, 1.4), and women, +0.9% (95% CI 0.5, 1.3), driven mainly by an increasing incidence in working ages (17-64 years). Also, expected demographic changes including a 25% population increase may result in 38% more fractures until 2050, compared to 2017. Conclusions: The incidence of distal forearm fractures in adults in southern Sweden is increasing, mainly driven by an increase in working ages. In combination with expected demographic changes these findings may present substantial challenges for the future.
|
|
| 5. |
- Rawshani, Aidin, et al.
(författare)
-
Relative Prognostic Importance and Optimal Levels of Risk Factors for Mortality and Cardiovascular Outcomes in Type 1 Diabetes Mellitus
- 2019
-
Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 139:16, s. 1900-1912
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The strength of association and optimal levels for risk factors related to excess risk of death and cardiovascular outcomes in type 1 diabetes mellitus have been sparsely studied. METHODS: In a national observational cohort study from the Swedish National Diabetes Register from 1998 to 2014, we assessed relative prognostic importance of 17 risk factors for death and cardiovascular outcomes in individuals with type 1 diabetes mellitus. We used Cox regression and machine learning analyses. In addition, we examined optimal cut point levels for glycohemoglobin, systolic blood pressure, and low-density lipoprotein cholesterol. Patients with type 1 diabetes mellitus were followed up until death or study end on December 31, 2013. The primary outcomes were death resulting from all causes, fatal/nonfatal acute myocardial infarction, fatal/nonfatal stroke, and hospitalization for heart failure. RESULTS: Of 32 611 patients with type 1 diabetes mellitus, 1809 (5.5%) died during follow-up over 10.4 years. The strongest predictors for death and cardiovascular outcomes were glycohemoglobin, albuminuria, duration of diabetes mellitus, systolic blood pressure, and low-density lipoprotein cholesterol. Glycohemoglobin displayed approximate to 2% higher risk for each 1-mmol/mol increase (equating to approximate to 22% per 1% glycohemoglobin difference), whereas low-density lipoprotein cholesterol was associated with 35% to 50% greater risk for each 1-mmol/L increase. Microalbuminuria or macroalbuminuria was associated with 2 to 4 times greater risk for cardiovascular complications and death. Glycohemoglobin <53 mmol/mol (7.0%), systolic blood pressure <140 mm Hg, and low-density lipoprotein cholesterol <2.5 mmol/L were associated with significantly lower risk for outcomes observed. CONCLUSIONS: Glycohemoglobin, albuminuria, duration of diabetes mellitus, systolic blood pressure, and low-density lipoprotein cholesterol appear to be the most important predictors for mortality and cardiovascular outcomes in patients with type 1 diabetes mellitus. Lower levels for glycohemoglobin, systolic blood pressure, and low-density lipoprotein cholesterol than contemporary guideline target levels appear to be associated with significantly lower risk for outcomes.
|
|
| 6. |
- Sun, Jiangwei, et al.
(författare)
-
Long-term risk of myocarditis in patients with inflammatory bowel disease : a nationwide cohort study in Sweden
- 2024
-
Ingår i: American Journal of Gastroenterology. - : Wolters Kluwer. - 0002-9270 .- 1572-0241.
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Despite a suggested link between inflammatory bowel disease (IBD) and myocarditis, the association has not been well-established. This study aimed to investigate the long-term risk of myocarditis in patients with IBD.METHODS: This nationwide cohort involved all patients with biopsy-confirmed IBD in Sweden (1969-2017) (n=83,264, Crohn's disease [CD, n=24,738], ulcerative colitis [UC, n=46,409], and IBD-unclassified [IBD-U, n=12,117]), general population reference individuals (n=391,344), and IBD-free full siblings (n=96,149), and followed until 2019. Primary outcome was incident myocarditis and secondary outcome was severe myocarditis (complicated with heart failure, death, or readmission). Flexible parametric survival models were used to estimate adjusted hazard ratios (aHR) and cumulative incidence of outcomes, along with 95% confidence intervals (CIs).RESULTS: During a median follow-up of 12 years, there were 256 myocarditis cases in IBD patients (incidence rate [IR]=22.6/100,000 person-years) and 710 in reference individuals (IR=12.9), with an aHR of 1.55 (95%CI: 1.33 to 1.81). The increased risk persisted through 20 years after IBD diagnosis, corresponding to one extra myocarditis case in 735 IBD patients until then. This increased risk was observed in CD (aHR=1.48 [1.11 to 1.97]) and UC (aHR=1.58 [1.30 to 1.93]). IBD was also associated with severe myocarditis (IR: 10.1 vs. 3.5; aHR=2.44 [1.89 to 3.15]), irrespective of IBD subtypes (CD: aHR=2.39 [1.43 to 4.01], UC: aHR=2.82 [1.99 to 4.00], and IBD-U: aHR=3.14 [1.55 to 6.33]). Sibling comparison analyses yielded similar results.CONCLUSIONS: Patients with IBD had an increased risk of myocarditis, especially severe myocarditis, for ≥20 years after diagnosis, but absolute risks were low.
|
|
| 7. |
|
|
