1.
Impact of LDL Cholesterol on Microvascular Versus Macrovascular Disease: A Mendelian Randomization Study.
Emanuelsson, F, Nordestgaard, BG, Tybjærg-Hansen, A, Benn, M
Journal of the American College of Cardiology. 2019;(11):1465-1476
Abstract
BACKGROUND Low-density lipoprotein cholesterol (LDL-C) is causally associated with a high risk of coronary artery disease. Whether this also holds for a spectrum of peripheral vascular diseases is unknown. OBJECTIVES The purpose of this study was to determine whether high LDL-C causally relates to risk of retinopathy, neuropathy, chronic kidney disease (CKD), and peripheral arterial disease (PAD) in the general population. METHODS One-sample Mendelian randomization (MR) of 116,419 Danish individuals, 2-sample MR on summary-level data from the Global Lipid Genetics Consortium (GLGC) (n = 94,595) and the UK Biobank (n = 408,455), and meta-analysis of randomized statin trials (n = 64,134) were performed. RESULTS Observationally, high LDL-C did not associate with high risk of retinopathy or neuropathy. There were stepwise increases in risk of CKD and PAD with higher LDL-C (both p for trend <0.001), with hazard ratios of 1.05 (95% confidence interval [CI]: 0.97 to 1.13) for CKD, and 1.41 (95% CI: 1.23 to 1.62) for PAD in individuals with LDL-C above the 95th percentile versus below the 50th percentile. In genetic, causal analyses in the Copenhagen studies, the risk ratio of disease for a 1 mmol/l higher LDL-C was 1.06 (95% CI: 0.24 to 4.58) for retinopathy, 1.05 (95% CI: 0.64 to 1.72) for neuropathy, 3.83 (95% CI: 2.00 to 7.34) for CKD, and 2.09 (95% CI: 1.30 to 2.38) for PAD. Summary-level data from the GLGC and the UK Biobank for retinopathy, neuropathy, and PAD gave similar results. For CKD, a 1-mmol/l lower LDL-C conferred a higher eGFR of 1.95 ml/min/1.73 m2 (95% CI: 1.88 to 2.02 ml/min/1.73 m2) observationally, 5.92 ml/min/1.73 m2 (95% CI: 4.97 to 6.86 ml/min/1.73 m2) genetically, and 2.69 ml/min/1.73 m2 (95% CI: 1.48 to 3.94 ml/min/1.73 m2) through statin therapy. CONCLUSIONS High LDL-C was not causally associated with risk of retinopathy and neuropathy; however, high LDL-C was observationally and genetically associated with high risks of PAD and CKD, suggesting that LDL-C is causally involved in the pathogenesis of these diseases.
2.
Stressful life events and maltreatment in conversion (functional neurological) disorder: systematic review and meta-analysis of case-control studies.
Ludwig, L, Pasman, JA, Nicholson, T, Aybek, S, David, AS, Tuck, S, Kanaan, RA, Roelofs, K, Carson, A, Stone, J
The lancet. Psychiatry. 2018;(4):307-320
Abstract
BACKGROUND Stressful life events and maltreatment have traditionally been considered crucial in the development of conversion (functional neurological) disorder, but the evidence underpinning this association is not clear. We aimed to assess the association between stressors and functional neurological disorder. METHODS We systematically reviewed controlled studies reporting stressors occurring in childhood or adulthood, such as stressful life events and maltreatment (including sexual, physical abuse, and emotional neglect) and functional neurological disorder. We did a meta-analysis, with assessments of methodology, sources of bias, and sensitivity analyses. FINDINGS 34 case-control studies, with 1405 patients, were eligible. Studies were of moderate-to-low quality. The frequency of childhood and adulthood stressors was increased in cases compared with controls. Odds ratios (OR) were higher for emotional neglect in childhood (49% for cases vs 20% for controls; OR 5·6, 95% CI 2·4-13·1) compared with sexual abuse (24% vs 10%; 3·3, 2·2-4·8) or physical abuse (30% vs 12%; 3·9, 2·2-7·2). An association with stressful life events preceding onset (OR 2·8, 95% CI 1·4-6·0) was stronger in studies with better methods (interviews; 4·3, 1·4-13·2). Heterogeneity was significant between studies (I2 21·1-90·7%). 13 studies that specifically ascertained that the participants had not had either severe life events or any subtype of maltreatment all found a proportion of patients with functional neurological disorder reporting no stressor. INTERPRETATION Stressful life events and maltreatment are substantially more common in people with functional neurological disorder than in healthy controls and patient controls. Emotional neglect had a higher risk than traditionally emphasised sexual and physical abuse, but many cases report no stressors. This outcome supports changes to diagnostic criteria in DSM-5; stressors, although relevant to the cause in many patients, are not a core diagnostic feature. This result has implications for ICD-11. FUNDING None.
3.
Metabolic and neurological complications of second-generation antipsychotic use in children: a systematic review and meta-analysis of randomized controlled trials.
Pringsheim, T, Lam, D, Ching, H, Patten, S
Drug safety. 2011;(8):651-68
Abstract
BACKGROUND Available evidence indicates that the use of antipsychotics, especially second-generation antipsychotics (SGAs), for children with mental health disorders has increased dramatically. Given the demonstrated metabolic and neurological adverse effects seen in adult patients on these medications, detailed evaluation of the risk for these adverse effects in children is appropriate. OBJECTIVE The aim of the study was to assess the evidence for specific metabolic and neurological adverse effects associated with the use of SGAs in children. DATA SOURCES MEDLINE (1996-May 2010) and EMBASE (1996-May 2010) databases were searched using highly sensitive search strategies for clinical trials in a paediatric population (children up to age 18 years). STUDY SELECTION We included any double-blind, randomized controlled trial (RCT) of SGA medications conducted specifically in a paediatric population for the treatment of a mental health disorder. This included the medications risperidone, olanzapine, quetiapine, aripiprazole, clozapine, ziprasidone and paliperidone. The primary outcomes assessed for this review were metabolic and neurological adverse effects, as measured using physical examination manoeuvres, rating scales or laboratory tests. A total of 35 RCTs were included in the analysis, but not all studies had data that could be used in the meta-analysis. DATA EXTRACTION Abstracts retrieved from the searches were reviewed independently by two different reviewers for potential relevant articles. Full-text articles were then read in detail independently by two different reviewers to see if inclusion criteria were fulfilled. Data were extracted independently by two review authors from included studies and entered onto pre-designed summary forms. Clinical trials were evaluated for methodological quality using quality criteria developed by the US Preventive Services Task Force. Based on the fulfilment of quality criteria, studies were rated as good, fair or poor. DATA SYNTHESIS Meta-analysis was performed on the data for synthesis, and was carried out for commonly reported outcomes for each medication individually, in comparison with placebo or another drug. Odds ratios (ORs) with 95% confidence intervals for binary outcomes were used. For continuous outcomes, mean differences were used to analyze the data. Meta-analysis revealed that mean weight gain compared with placebo was highest for olanzapine at 3.47 kg (95% CI 2.94, 3.99) followed by risperidone at 1.72 kg (95% CI 1.17, 2.26), quetiapine at 1.41 kg (95% CI 1.10, 1.81) and aripiprazole at 0.85 kg (95% CI 0.58, 1.13). Olanzapine and clozapine treatment were associated with the highest rate of metabolic laboratory abnormalities in cholesterol and triglycerides. Prolactin elevation occurred with risperidone and olanzapine therapy. Higher odds of extrapyramidal symptoms compared with placebo were seen in children treated with risperidone (OR 3.55; 95% CI 2.04, 5.48) and aripiprazole (OR 3.70; 95% CI 2.37, 5.77). Elevated rates of extrapyramidal symptoms were also experienced with olanzapine use. CONCLUSIONS There is good evidence to support the existence of both metabolic and neurological adverse effects in children treated with these medications. Proper attention and vigilance to potential metabolic and neurological adverse effects is necessary, and should be considered part of the standard of care.