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- Jefferson, A. L., et al.
(författare)
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The Vanderbilt Memory & Aging Project: Study Design and Baseline Cohort Overview
- 2016
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Ingår i: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 52:2, s. 539-559
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Tidskriftsartikel (refereegranskat)abstract
- Background: Vascular health factors frequently co-occur with Alzheimer's disease (AD). A better understanding of how systemic vascular and cerebrovascular health intersects with clinical and pathological AD may inform prevention and treatment opportunities. Objective: To establish the Vanderbilt Memory & Aging Project, a case-control longitudinal study investigating vascular health and brain aging, and describe baseline methodology and participant characteristics. Methods: From September 2012 to November 2014, 335 participants age 60-92 were enrolled, including 168 individuals with mild cognitive impairment (MCI, 73 +/- 8 years, 41% female) and 167 age-, sex-, and race-matched cognitively normal controls (NC, 72 +/- 7 years, 41% female). At baseline, participants completed a physical and frailty examination, fasting blood draw, neuropsychological assessment, echocardiogram, cardiac MRI, and brain MRI. A subset underwent 24-hour ambulatory blood pressure monitoring and lumbar puncture for cerebrospinal fluid (CSF) collection. Results: As designed, participant groups were comparable for age (p = 0.31), sex (p = 0.95), and race (p = 0.65). MCI participants had greater Framingham Stroke Risk Profile scores (p = 0.008), systolic blood pressure values (p = 0.008), and history of left ventricular hypertrophy (p = 0.04) than NC participants. As expected, MCI participants performed worse on all neuropsychological measures (p-values <0.001), were more likely to be APOE epsilon 4 carriers (p = 0.02), and had enhanced CSF biomarkers, including lower A beta(42) (p = 0.02), higher total tau (p = 0.004), and higher p-tau (p = 0.02) compared to NC participants. Conclusion: Diverse sources of baseline and longitudinal data will provide rich opportunities to investigate pathways linking vascular and cerebrovascular health, clinical and pathological AD, and neurodegeneration contributing to novel strategies to delay or prevent cognitive decline.
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- Horne, B D, et al.
(författare)
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Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy
- 2012
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Ingår i: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 107:2, s. 232-240
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Tidskriftsartikel (refereegranskat)abstract
- By guiding initial warfarin dose, pharmacogenetic (PGx) algorithms may improve the safety of warfarin initiation. However, once international normalised ratio (INR) response is known, the contribution of PGx to dose refinements is uncertain. This study sought to develop and validate clinical and PGx dosing algorithms for warfarin dose refinement on days 6-11 after therapy initiation. An international sample of 2,022 patients at 13 medical centres on three continents provided clinical, INR, and genetic data at treatment days 6-11 to predict therapeutic warfarin dose. Independent derivation and retrospective validation samples were composed by randomly dividing the population (80%/20%). Prior warfarin doses were weighted by their expected effect on S-warfarin concentrations using an exponential-decay pharmacokinetic model. The INR divided by that "effective" dose constituted a treatment response index . Treatment response index, age, amiodarone, body surface area, warfarin indication, and target INR were associated with dose in the derivation sample. A clinical algorithm based on these factors was remarkably accurate: in the retrospective validation cohort its R2 was 61.2% and median absolute error (MAE) was 5.0 mg/week. Accuracy and safety was confirmed in a prospective cohort (N=43). CYP2C9 variants and VKORC1-1639 G→A were significant dose predictors in both the derivation and validation samples. In the retrospective validation cohort, the PGx algorithm had: R2= 69.1% (p<0.05 vs. clinical algorithm), MAE= 4.7 mg/week. In conclusion, a pharmacogenetic warfarin dose-refinement algorithm based on clinical, INR, and genetic factors can explain at least 69.1% of therapeutic warfarin dose variability after about one week of therapy.
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- Lenzini, P., et al.
(författare)
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Integration of genetic, clinical, and INR data to refine warfarin dosing
- 2010
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Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 87:5, s. 572-578
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Tidskriftsartikel (refereegranskat)abstract
- Well-characterized genes that affect warfarin metabolism (cytochrome P450 (CYP) 2C9) and sensitivity (vitamin K epoxide reductase complex 1 (VKORC1)) explain one-third of the variability in therapeutic dose before the international normalized ratio (INR) is measured. To determine genotypic relevance after INR becomes available, we derived clinical and pharmacogenetic refinement algorithms on the basis of INR values (on day 4 or 5 of therapy), clinical factors, and genotype. After adjusting for INR, CYP2C9 and VKORC1 genotypes remained significant predictors (P < 0.001) of warfarin dose. The clinical algorithm had an R(2) of 48% (median absolute error (MAE): 7.0 mg/week) and the pharmacogenetic algorithm had an R(2) of 63% (MAE: 5.5 mg/week) in the derivation set (N = 969). In independent validation sets, the R(2) was 26-43% with the clinical algorithm and 42-58% when genotype was added (P = 0.002). After several days of therapy, a pharmacogenetic algorithm estimates the therapeutic warfarin dose more accurately than one using clinical factors and INR response alone.
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- Vrablik, M., et al.
(författare)
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Understanding the Patient Perception of Statin Experience: A Qualitative Study
- 2019
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Ingår i: Advances in Therapy. - : Springer Science and Business Media LLC. - 0741-238X .- 1865-8652. ; 36:10, s. 2723-2743
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Statin intolerance (SI) occurs in patients with dyslipidemia treated with statins. Statin-associated symptoms have been reported, but the overall patient experience is poorly understood. No instruments are available to collect this patient experience. Our aim is to develop a patient survey to define SI from the patient's perspective, inform clinical practice, and identify potential patient characteristics and barriers associated with discontinuing treatment when statin-related difficulties are encountered. Methods We conducted qualitative concept elicitation interviews with 65 patients across 12 European study sites. A semi-structured qualitative interview guide was developed based on literature review and clinician interviews. Concept elicitation interviews with patients were used to describe the patient experience and develop the conceptual framework for the survey. Results Symptoms experienced by patients included muscle and non-muscle-related pain and discomfort; other muscle-related symptoms; gastrointestinal, cardiovascular, cold-like, fatigue-related, and sensory and systems symptoms; mood changes; and cognitive and memory problems. Impacts included limitations on general physical functioning; physical activities; social functioning; emotional impacts; sleep disturbances; decreased productivity; and increased healthcare use. Conceptual framework elements to support survey goals include demographic and clinical characteristics, health information and beliefs, statin side-effect history, symptom severity, and impact severity. Conclusions Symptoms and impacts described by patients showed a wider range of symptoms and impacts than usually discussed clinically. The patient survey is designed to capture information from patients who experience difficulties with statin therapy and may be useful in identifying patients who are at higher risk for giving up or discontinuing their treatment. Funding Amgen Inc.
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- Borjesson, A, et al.
(författare)
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Male Anabolic Androgenic Steroid Users with Personality Disorders Report More Aggressive Feelings, Suicidal Thoughts, and Criminality
- 2020
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Ingår i: Medicina (Kaunas, Lithuania). - : MDPI AG. - 1648-9144. ; 56:6
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Tidskriftsartikel (refereegranskat)abstract
- Background and objectives: Anabolic androgenic steroids (AAS) are mainly used for aesthetic and performance-enhancing reasons. Their use is a growing public health problem and concern for society because of their adverse effects. The primary aim of this study was to identify psychiatric and personality disorders and to measure anxiety and depression in AAS users. Materials and Methods: Fifty-six males who actively contacted the Anti-Doping Hot-Line and wished to stop using AAS were included. Structured Clinical Interviews Diagnosis-I and -II were used to diagnose psychiatric and personality disorders. The Brief Scale for Anxiety and Montgomery Asberg Depression Rating Scale (subscales from the Comprehensive Psychopathological Rating Scale) were used to measure changes in anxiety and depression. Structured Clinical Interviews Diagnosis-I and -II were performed at one time point. Anxiety and depression were measured at inclusion and after six months. Urine samples were collected for an analysis of AAS and drugs of abuse. Results: All participants reported some adverse effects that they associated with AAS use. In total, 56% and 52% of the cohort fulfilled the criteria for Structured Clinical Interviews Diagnosis-I and -II diagnoses, respectively. A significantly increased risk of reporting aggressive feelings/behaviors (Odds Ratio (OR) = 4.9; Confidence Interval (CI) 0.99–25, p = 0.04), suicidal thoughts/attempts (OR = 4.6, CI 95; 0.99–21, p = 0.04) and criminality (OR = 6.5, CI 1–39, p = 0.03) was found among individuals with AAS use fulfilling the criteria for personality disorders compared with those without such AAS use. The Brief Scale for Anxiety score decreased from the median of 15 at inclusion to 10 at the follow-up visit six months later (p = 0.01, n = 19). Conclusions: Our findings indicate that among individuals with AAS use, those with a personality disorder report more aggressive behaviors, suicidal thoughts/suicidal attempts, and criminality than those without a personality disorder.
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- Eriksson, Anna-Lena, 1971, et al.
(författare)
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SHBG gene promoter polymorphisms in men are associated with serum sex hormone-binding globulin, androgen and androgen metabolite levels, and hip bone mineral density.
- 2006
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 91:12, s. 5029-37
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: SHBG regulates free sex steroid levels, which in turn regulate skeletal homeostasis. Twin studies have demonstrated that genetic factors largely account for interindividual variation in SHBG levels. Glucuronidated androgen metabolites have been proposed as markers of androgenic activity. OBJECTIVE: Our objective was to investigate whether polymorphisms in the SHBG gene promoter [(TAAAA)(n) microsatellite and rs1799941 single-nucleotide polymorphism] are associated with serum levels of SHBG, sex steroids, or bone mineral density (BMD) in men. DESIGN AND STUDY SUBJECTS: We conducted a population-based study of two cohorts of Swedish men: elderly men (MrOS Sweden; n congruent with 3000; average age, 75.4 yr) and young adult men (GOOD study; n = 1068; average age, 18.9 yr). MAIN OUTCOME MEASURES: We measured serum levels of SHBG, testosterone, estradiol, dihydrotestosterone, 5alpha-androstane-3alpha,17beta-diol glucuronides, androsterone glucuronide, and BMD determined by dual-energy x-ray absorptiometry. RESULTS: In both cohorts, (TAAAA)(n) and rs1799941 genotypes were associated with serum levels of SHBG (P < 0.001), dihydrotestosterone (P < 0.05), and 5alpha-androstane-3alpha,17beta-diol glucuronides (P < 0.05). In the elderly men, they were also associated with testosterone and BMD at all hip bone sites. The genotype associated with high levels of SHBG was also associated with high BMD. Interestingly, male mice overexpressing human SHBG had increased cortical bone mineral content in the femur, suggesting that elevated SHBG levels may cause increased bone mass. CONCLUSIONS: Our findings demonstrate that polymorphisms in the SHBG promoter predict serum levels of SHBG, androgens, and glucuronidated androgen metabolites, and hip BMD in men.
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