Population pharmacokinetics of tanezumab in phase 3 clinical trials for osteoarthritis pain

AimsThe aims were to 1) develop the pharmacokinetics model to describe and predict observed tanezumab concentrations over time, 2) test possible covariate parameter relationships that could influence clearance and distribution and 3) assess the impact of fixed dosing vs. a dosing regimen adjusted by body weight.MethodsIndividual concentration–time data were determined from 1608 patients in four phase 3 studies conducted to assess efficacy and safety of intravenous tanezumab. Patients received two or three intravenous doses (2.5, 5 or 10 mg) every 8 weeks. Blood samples for assessment of tanezumab PK were collected at baseline, 1 h post‐dose and at weeks 4, 8, 16 and 24 (or early termination) in all studies. Blood samples were collected at week 32 in two studies. Plasma samples were analyzed using a sensitive, specific, validated enzyme‐linked immunosorbent assay.ResultsA two compartment model with parallel linear and non‐linear elimination processes adequately described the data. Population estimates for clearance (CL), central volume (V ₁), peripheral volume (V ₂), inter‐compartmental clearance, maximum elimination capacity (VM) and concentration at half‐maximum elimination capacity were 0.135 l day^–1, 2.71 l, 1.98 l, 0.371 l day^–1, 8.03 μg day^–1 and 27.7 ng ml^–1, respectively. Inter‐individual variability (IIV) was included on CL, V ₁, V ₂ and VM. A mixture model accounted for the distribution of residual error. While gender, dose and creatinine clearance were significant covariates, only body weight as a covariate of CL, V ₁ and V ₂ significantly reduced IIV.ConclusionsThe small increase in variability associated with fixed dosing is consistent with other monoclonal antibodies and does not change risk : benefit.     

Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles

Background Immune checkpoint blockers (ICBs) activate CD8⁺ T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear.Methods Retrospective evaluation of irAEs on survival was performed across primary (N = 144) and secondary (N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab—sICB) or combination (nivolumab and ipilimumab—cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8⁺ T cells was sequenced and differential gene expression according to irAE development assessed.Results 58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS: P < 0.0001). Median survival for patients without irAEs was 16.6 months (95% CI: 10.9–33.4) versus not-reached (P = 2.8 × 10⁻⁶). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8⁺ T cells according to irAE development, and patients not developing irAEs demonstrating upregulated CXCR1 pre- and post-treatment.Conclusions Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.Subject terms: Immunotherapy, Melanoma     

Effect of obstructive sleep apnoea on retinal microvascular function: a randomised controlled trial

Graefe's Archive for Clinical and Experimental Ophthalmology - Retinal microvascular endothelial dysfunction is thought to be of importance in the development of ocular vascular diseases....     

Insights from examination of hearts from adults dying suddenly to the understanding of congenital cardiac malformations

Congenital heart disease is a rare but important finding in adults who experience sudden death. Examination of the congenitally malformed heart has historically been considered esoteric and best left to those with expertise. The Cardiac Risk in the Young cardiovascular pathology laboratory based at St George's University of London has now received over 6,000 cases. Of these, 21 congenitally malformed hearts were retained for research and educational purposes. Hearts were assessed using sequential segmental analysis, and causes of death were adjudicated based on thorough macroscopic examination and histology. Congenital malformations that were encountered included atrial septal defects, ventricular septal defects, tetralogy of Fallot, and transposition of the great arteries in both its regular and congenitally corrected variants. Findings also included hearts with mirror-imaged and isomeric atrial appendages. Direct causes of death included myocardial fibrosis, pulmonary hypertension, and hemorrhage. A small but notable proportion did not reveal a substrate for arrhythmia, raising the question of whether the terminal event was due to the congenital heart disease itself, or an underlying channelopathy. Here, we demonstrate the value of simple sequential segmental analysis in describing and categorizing the cases, with the concept of the “morphological method” serving to identify the distinguishing features of the cardiac components. Clin. Anat. 33:394–404, 2020. © 2019 Wiley Periodicals, Inc.     

Personal trauma among healthcare providers: implications for screening practices

ABSTRACT

Screening rates for trauma are low in health care settings. We examined the association between health care providers’ (HCPs) experience of physical or sexual trauma and their screening of female patients for trauma. HCPs at an urban academic medical institution were surveyed from September through November 2016. The Brief Trauma (BTQ) and Sexual and Physical Abuse History Questionnaires (SPAHQ) assessed their own experiences of trauma. The Screening Practices Questionnaire (SPQ) assessed HCPs trauma screening. Multiple regression analyses were performed. Among 212 respondents aged 22–67 years, most were female (78.3%) and white (76.1%). Nurses (41.0%) were the largest occupational group. Overall, 85.8% reported having experienced trauma. No significant difference was observed in median SPQ scores between HCPs who had experienced trauma (3.88 [Interquartile Range (IQR) 3.44–4.31]) and those who had not (4.00 [IQR 3.47–4.33], p = .645). In an adjusted model, screening policy awareness and having an obstetrics & gynecology or psychiatry specialty were associated with higher SPQ scores (p < .001). The prevalence of trauma experience in this sample was high, but not associated with screening. Screening policy awareness and practice specialty were associated with screening. HCP factors associated with greater trauma screening should be explored.     

Middle Meningeal Artery Embolization Using Combined Particle Embolization and n-BCA with the Dextrose 5% in Water Push Technique for Chronic Subdural Hematomas: A Prospective Safety and Feasibility Study

BACKGROUND AND PURPOSE:Embolization of the middle meningeal artery for treatment of refractory or recurrent chronic subdural hematomas has gained momentum during the past few years. Little has been reported on the use of the n-BCA liquid embolic system for middle meningeal artery embolization. We present the technical feasibility of using diluted n-BCA for middle meningeal artery embolization.MATERIALS AND METHODS:We sought to examine the safety and technical feasibility of the diluted n-BCA liquid embolic system for middle meningeal artery embolization. Patients with chronic refractory or recurrent subdural hematomas were prospectively enrolled from September 2019 to June 2020. The primary outcome was the safety and technical feasibility of the use of diluted n-BCA for embolization of the middle meningeal artery. The secondary end point was the efficacy in reducing hematoma volume.RESULTS:A total of 16 patients were prospectively enrolled. Concomitant burr-hole craniotomies were performed in 12 of the 16 patients. Two patients required an operation following middle meningeal artery embolization for persistent symptoms. The primary end point was met in 100% of cases in which there were no intra- or postprocedural complications. Distal penetration of the middle meningeal artery branches was achieved in all the enrolled cases. A 7-day post–middle meningeal artery embolization follow-up head CT demonstrated improvement (>50% reduction in subdural hematoma volume) in 9/15 (60%) patients, with 6/15 (40%) showing an unchanged or stable subdural hematoma. At day 21, available CT scans demonstrated substantial further improvement (>75% reduction in subdural hematoma volume).CONCLUSIONS:Embolization of the middle meningeal artery using diluted n-BCA and ethiodized oil (1:6) is safe and feasible from a technical standpoint. The use of a dextrose 5% bolus improves distal penetration of the glue.

Despite traditional treatment with surgical evacuation, chronic subdural hematomas (cSDHs) tend to have an indolent course with frequent recurrences.¹ In recent years, embolization of the middle meningeal artery (MMA) for treatment of refractory or recurrent cSDH has gained momentum, with recent literature showing a significant reduction in the size of the cSDH as well as lower rates of recurrence.² The primary endovascular techniques used to date have involved the use of polyvinyl alcohol particles (PVA) and Onyx liquid embolic (ethylene-vinyl alcohol dissolved in dimethyl-sulfoxide; Medtronic). Another commonly used liquid embolic agent in the neurointerventional area is n-BCA, which is a liquid adhesive that polymerizes rapidly on contact with ionic substances and can be injected to achieve permanent vessel occlusion. The rates of polymerization and flow and the penetration depth can be modified using varying amounts of ethiodized oil as well as concurrent infusion of dextrose 5% in water (D5W) during n-BCA (Trufill, Cordis Neurovascular) injection (D5W-push technique).³ Data on the use of n-BCA as an embolic agent in cases of cSDH are extremely limited. Herein, we sought to study the safety and technical feasibility of using diluted n-BCA for embolization of the MMA for cSDHs.     

A Preliminary Study of Negative Self-Beliefs in Anorexia Nervosa: A Detailed Exploration of Their Content, Origins and Functional Links to “Not Eating Enough” and Other Characteristic Behaviors

Objective: The study explored the semantic content and origins of negative self-beliefs, and their functional links to “not eating enough” and other behaviors, in participants with anorexia nervosa (AN). Method: Fifteen women meeting DSM-IV criteria for AN were compared with 17 dieting and 18 non-dieting women matched on age and number of years of education. The main outcome measure was a semi-structured interview. Results: Six themes were identified in the beliefs of participants with AN. These were, in order of decreasing frequency, powerlessness (present in all but three AN participants), failure, defectiveness, unattractiveness, worthlessness and emptiness. Importantly, powerlessness and failure beliefs were consistently present independent of Beck Depression Inventory-II scores. The negative early life experiences associated with these beliefs had high distress and responsibility ratings. Participants with AN reported that they employed specific behaviors, particularly ‘not eating enough,’ and ‘placating others,’ to try to reduce the cognitive and emotional impact of their negative self-beliefs. Discussion: The findings are discussed in relation to the role of powerlessness and the function of “not eating enough” in cognitive theory and therapy for AN.

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