Dysbetalipoproteinaemia : clinical and laboratory aspects, changes in lipoprotein composition and remnant metabolism associated with lipid lowering drugs

Includes bibliographical references (p. 483-539).This thesis examines and reviews multiple aspects of dysbetalipoproteinaemia. Dysbetalipoproteinaemia is a severe, highly atherogenic mixed hyperlipidaernia characterized by the accumulation of remnants of triglyceride-rich lipoproteins. Genetic susceptibility is conferred by mutations in apolipoproteinE, but manifest hyperlipidaemia often only occurs in the presence of metabolic abnormalities that influence lipoprotein production or clearance. Normal lipid metabolism is briefly reviewed to enable a better understanding of the pathophysiology of dysbetalipoproteinaernia. Hepatic remnant clearance is reviewed in detail with particular emphasis on the roles of all hepatic lipoprotein receptors. The importance of differential hepatic lipoprotein receptor binding affinities according to apoE mutation is emphasized

Severe Sleep Deprivation Causes Hallucinations and a Gradual Progression Toward Psychosis With Increasing Time Awake

Background: Going without sleep for long periods of time can produce a range of experiences, including perceptual distortions and hallucinations. Many questions, however, remain unanswered regarding the types of symptoms which are most reliably elicited, the time of symptom onset, and whether symptoms worsen over time toward psychotic decompensation. Since sleep deprivation exceeding 48 h is considered unethical today, an examination of historical studies with extreme sleep-loss duration is needed to obtain information about what happens during prolonged sleep loss.Methods: A systematic-review approach was used to identify experimental and observational studies of sleep deprivation in healthy people which describe the effects of prolonged sleep loss on psychopathological symptoms, without any date restriction.Results: A total of 476 articles were identified. Of these, 21 were eligible for inclusion. Duration of sleep loss ranged between 24 h and 11 nights (total 760 participants; average 72–92 h without sleep). All studies except one reported perceptual changes, including visual distortions (i.e., metamorphopsias), illusions, somatosensory changes and, in some cases, frank hallucinations. The visual modality was the most consistently affected (in 90% of the studies), followed by the somatosensory (52%) and auditory (33%) modalities. Symptoms rapidly developed after one night without sleep, progressing in an almost fixed time-dependent way. Perceptual distortions, anxiety, irritability, depersonalization, and temporal disorientation started within 24–48 h of sleep loss, followed by complex hallucinations and disordered thinking after 48–90 h, and delusions after 72 h, after which time the clinical picture resembled that of acute psychosis or toxic delirium. By the third day without sleep, hallucinations in all three sensory modalities were reported. A period of normal sleep served to resolve psychotic symptoms in many—although not all—cases.Conclusions: Psychotic symptoms develop with increasing time awake, from simple visual/somatosensory misperceptions to hallucinations and delusions, ending in a condition resembling acute psychosis. These experiences are likely to resolve after a period of sleep, although more information is required to identify factors which can contribute to the prevention of persistent symptoms

Effect of the proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab on glycemia, body weight, and new-onset diabetes mellitus

Statin therapy modestly increases new-onset diabetes risk. The effect of proprotein convertase subtilisin/kexin type 9 inhibition on new-onset diabetes, glycemia, and weight remains unclear. We studied the effects of the proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab on fasting plasma glucose, glycated hemoglobin, weight, and new-onset diabetes mellitus. We pooled 1-year (48-week) data for participants who had completed an evolocumab parent study before entering an open-label extension (OLE) trial. Data were available for 4,802 participants (1,602 on standard of care [SOC]; 3,200 on evolocumab plus SOC) in 2 OLE trials. Evolocumab lowered low-density lipoprotein cholesterol by approximately 60% compared with SOC alone. Over the first year of the OLE trials, there was no difference in median (Q1, Q3) change in glycated hemoglobin (0.1% [-0.1, 0.2] for both SOC and evolocumab plus SOC) and fasting plasma glucose (0.06 mmol/L [-0.28, 0.38 mmol/L] for SOC and 0.06 mmol/L [-0.28, 0.44 mmol/L] for evolocumab plus SOC). Mean weight change (standard error) at 1 year was -0.1 kg (0.2) on SOC compared with 0.3 kg (0.1) on evolocumab plus SOC. The exposure-adjusted incidence rate (95% confidence intervals) for new-onset diabetes per 100 patient years was 3.7 (2.9 to 4.7) on control/SOC alone and 3.9 (3.2 to 4.6) on evolocumab/evolocumab plus SOC treatment. Glycemic changes observed in 6,430 participants at week 12 in the parent studies were comparable with OLE trial findings. In conclusion, evolocumab therapy has no effect on glucose homeostasis over 1 year of open-label treatment

Sexual Hallucinations in Schizophrenia Spectrum Disorders and Their Relation With Childhood Trauma

Background : Sexual hallucinations are probably the most neglected types of hallucination, even in psychiatric settings. They are often multimodal in nature, and their prevalence rate is unknown. For other types of hallucination, notably auditory hallucinations, childhood trauma is an important risk factor. However, whether this also applies to sexual hallucinations is unexplored. Objective : To establish the prevalence rate of sexual hallucinations in a clinical sample of patients diagnosed with a schizophrenia spectrum disorder, to describe their phenomenological characteristics, and to estimate their relationship with childhood trauma. Methods : After screening 778 patients diagnosed with a schizophrenia spectrum disorder, 42 were considered eligible for inclusion by their treating physician or psychiatrist. Thirty of these patients were interviewed to assess the presence of sexual hallucinations, using a tailor-made questionnaire and the short form of the Childhood Trauma Questionnaire. Results : Of the 30 patients interviewed, 13 reported sexual hallucinations, yielding a 1-year prevalence rate of 0.017 in this clinical sample. Of the hallucinating patients, 46.2% reported multimodal hallucinations, with involvement of up to five sensory modalities. All patients who experienced sexual hallucinations reported a history of childhood trauma, of which 76.9% involved sexual trauma (OR 8.7). In addition, 61.5% of the patients reported high levels of distress. Conclusion : In patients diagnosed with a schizophrenia spectrum disorder, sexual hallucinations warrant appropriate medical attention. They are not as rare as traditionally thought, and their relationship with childhood trauma is overwhelming. Therefore, we recommend that clinical attention be paid to the psychotic and traumatic symptoms of these patients, as well as to the somatic conditions that may underlie them. For clinical and research purposes, we propose a classification of sexual hallucinations in accordance with the sensory modalities involved. As sexual hallucinations are also experienced in the context of temporal lobe epilepsy, narcolepsy, persistent genital arousal disorder, intoxications and other somatic conditions, further research in transdiagnostic populations seems warranted. In line with the current practice of providing trauma-focused treatment for trauma-related auditory hallucinations, we recommend that future studies explore the effectiveness of this type of treatment for sexual hallucinations

Musical hallucinations, secondary delusions, and lack of insight: results from a cohort study

IntroductionAlthough musical hallucinations do not tend to be accompanied by delusions, occasionally patients persistently accuse others of being responsible for causing the music they perceive, sometimes with severe social consequences such as frequently calling the police or moving house. In this study we seek to broaden our understanding of this rare type of musical hallucination that comes with secondary delusions and lack of insight, and to explore associations, underlying mechanisms, and treatment possibilities.MethodsThe present study is part of a cohort study on musical hallucinations carried out in the Netherlands from 2010 through 2023. Participants underwent testing with the aid of the MuHa Questionnaire, Launay-Slade Hallucinations Scale (LSHS), Schizotypal Personality Questionnaire (SPQ), Hamilton Depression Rating Scale (HDRS), and Mini Mental State Examination (MMSE). Additionally, they underwent a brain MRI, electroencephalogram, and audiological testing.ResultsFive patients out of a group of N = 81 (6%) lacked insight and presented with secondary delusions regarding the perceived music. They were all female, of advanced age, and hearing-impaired, and were diagnosed with cognitive impairment. In three patients (60%), risperidone was started. This had a positive effect on the hallucinations and secondary delusions.ConclusionThe pathophysiological process underlying musical hallucinations is multifactorial in nature. We consider cognitive impairment the most likely contributing factor of the secondary delusions and lack of insight encountered in our patients, and antipsychotics the most beneficial treatment. On the basis of these small numbers, no definite conclusions can be drawn, so further research is needed to elucidate the underlying mechanisms and to develop evidence-based treatment methods for people experiencing this rare and debilitating combination of symptoms. Since the black box warning of risperidone cautions against the use of this drug in elderly persons with dementia, a proper comparison with the efficacy and safety of other antipsychotics for this group is paramount

Similar risk of complete revision for infection with single-dose versus multiple-dose antibiotic prophylaxis in primary arthroplasty of the hip and knee:results of an observational cohort study in the Dutch Arthroplasty Register in 242,179 patients

Background and purpose - The optimal type and duration of antibiotic prophylaxis for primary arthroplasty of the hip and knee are subject to debate. We compared the risk of complete revision (obtained by a 1- or 2-stage procedure) for periprosthetic joint infection (PJI) after primary total hip or knee arthroplasty between patients receiving a single dose of prophylactic antibiotics and patients receiving multiple doses of antibiotics for prevention of PJI. Patients and methods - A cohort of 130,712 primary total hip and 111,467 knee arthroplasties performed between 2011 and 2015 in the Netherlands was analyzed. We linked data from the Dutch arthroplasty register to a survey collected across all Dutch institutions on hospital-level antibiotic prophylaxis policy. We used restricted cubic spline Poisson models adjusted for hospital clustering to compare the risk of revision for infection according to type and duration of antibiotic prophylaxis received. Results - For total hip arthroplasties, the rates of revision for infection were 31/10,000 person-years (95% CI 28-35), 39 (25-59), and 23 (15-34) in the groups that received multiple doses of cefazolin, multiple doses of cefuroxime, and a single dose of cefazolin, respectively. The rates for knee arthroplasties were 27/10,000 person-years (95% CI 24-31), 40 (24-62), and 24 (16-36). Similar risk of complete revision for infection among antibiotic prophylaxis regimens was found when adjusting for confounders. Interpretation - In a large observational cohort we found no apparent association between the type or duration of antibiotic prophylaxis and the risk of complete revision for infection. This does question whether there is any advantage to the use of prolonged antibiotic prophylaxis beyond a single dose.Orthopaedics, Trauma Surgery and Rehabilitatio

Target achievement and cardiovascular event rates with Lomitapide in homozygous Familial Hypercholesterolaemia

Background Homozygous familial hypercholesterolaemia (HoFH) is characterized by a markedly increased risk of premature cardiovascular (CV) events and cardiac death. Lomitapide reduces low-density lipoprotein cholesterol (LDL-C) levels; however, the probable impact on LDL-C goals and CV events is unknown. Methods We used data collected in the first 26 weeks of the lomitapide pivotal phase 3 study (NCT00730236) to evaluate achievement of European Atherosclerosis Society (EAS) LDL-C targets. We used publicly available data reporting major adverse CV events (MACE) rates from other cohorts of HoFH patients to compare event rates for an equivalent number of patient years of exposure (98) in the lomitapide extension trial (NCT00943306). Results Twenty-nine patients were included in the phase 3 study. During the first 26 weeks, 15 (51%) and eight (28%) reached LDL-C targets of 100 mg/dL and 70 mg/dL, respectively, at least once. Fourteen (74%) and 11 (58%) of the 19 patients who remained in the extension study after week 126 reached LDL-C targets of 100 mg/dL and 70 mg/dL at least once during the entire study period. Only two MACE were reported in the lomitapide trials (one cardiac death and one coronary artery bypass graft (CABG)) – equivalent to 1.7 events per 1000 patient months of treatment. MACE rates were 21.7, 9.5 and 1.8 per 1000 patient-months respectively in cohorts of HoFH patients pre- and post-mipomersen, and receiving evolocumab. On treatment LDL-C levels were 166, 331 and 286 mg/dL for lomitapide, mipomersen and evolocumab, respectively. Conclusions Approximately three quarters and half of patients who took lomitapide for at least 2 years reached LDL-C goals of 100 mg/dL and 70 mg/dL, respectively. There were fewer major CV events per 1000 patient months of treatment in patients taking lomitapide, mipomersen or evolocumab than reported in the mipomersen cohort prior to starting mipomersen. These results support the hypothesis that novel lipid-lowering therapies may reduce CV events in HoFH patients by lowering LDL-C further. Trial registration NCT00730236 (registered 8 Aug 2008) and NCT00943306 (registered 22 July 2009)