Human plasma phospholipid transfer protein increases the antiatherogenic potential of high density lipoproteins in transgenic mice

Plasma phospholipid transfer protein (PLTP) transfers phospholipids between lipoprotein particles and alters high density lipoprotein (HDL) subfraction patterns in vitro, but its physiological function is poorly understood. Transgenic mice that overexpress human PLTP were generated. Compared with wild-type mice, these mice show a 2.5- to 4.5-fold increase in PLTP activity in plasma. This results in a 30% to 40% decrease of plasma levels of HDL cholesterol. Incubation of plasma from transgenic animals at 37 degrees C reveals a 2- to 3-fold increase in the formation of pre-beta-HDL compared with plasma from wild-type mice. Although pre-beta-HDL is normally a minor subfraction of HDL, it is known to be a very efficient acceptor of peripheral cell cholesterol and a key mediator in reverse cholesterol transport. Further experiments show that plasma from transgenic animals is much more efficient in preventing the accumulation of intracellular cholesterol in macrophages than plasma from wild-type mice, despite lower total HDL concentrations. It is concluded that PLTP can act as an antiatherogenic factor preventing cellular cholesterol overload by generation of pre-beta-HDL

Assessing quality of life in psychosocial and mental health disorders in children:a comprehensive overview and appraisal of generic health related quality of life measures

Background: Mental health problems often arise in childhood and adolescence and can have detrimental effects on people's quality of life (QoL). Therefore, it is of great importance for clinicians, policymakers and researchers to adequately measure QoL in children. With this review, we aim to provide an overview of existing generic measures of QoL suitable for economic evaluations in children with mental health problems. Methods: First, we undertook a meta-review of QoL instruments in which we identified all relevant instruments. Next, we performed a systematic review of the psychometric properties of the identified instruments. Lastly, the results were summarized in a decision tree. Results: This review provides an overview of these 22 generic instruments available to measure QoL in children with psychosocial and or mental health problems and their psychometric properties. A systematic search into the psychometric quality of these instruments found 195 suitable papers, of which 30 assessed psychometric quality in child and adolescent mental health. Conclusions: We found that none of the instruments was perfect for use in economic evaluation of child and adolescent mental health care as all instruments had disadvantages, ranging from lack of psychometric research, no proxy version, not being suitable for young children, no age-specific value set for children under 18, to insufficient focus on relevant domains (e.g. social and emotional domains)

Lipophilic nalmefene prodrugs to achieve a one-month sustained release

Nalmefene is an opioid antagonist which as a once-a-day tablet formulation has recently been approved for reducing ethanol intake in alcoholic subjects. In order to address the compliance issue in this patient population, a number of potential nalmefene prodrugs were synthesized with the aim of providing a formulation that could provide plasma drug concentrations in the region of 0.5–1.0 ng/mL for a one-month period when dosed intramuscular to dogs or minipigs. In an initial series of studies, three different lipophilic nalmefene derivatives were evaluated: the palmitate (C16), the octadecyl glutarate diester (C18-C5) and the decyl carbamate (CB10). They were administered intramuscularly to dogs in a sesame oil solution at a dose of 1 mg-eq. nalmefene/kg. The decyl carbamate was released relatively quickly from the oil depot and its carbamate bond was too stable to be used as a prodrug. The other two derivatives delivered a fairly constant level of 0.2–0.3 ng nalmefene/mL plasma for one month and since there was no significant difference between these two, the less complex palmitate monoester was chosen to demonstrate that dog plasma nalmefene concentrations were dose-dependent at 1, 5 and 20 mg-eq. nalmefene/kg. In a second set of experiments, the effect of the chain length of the fatty acid monoester promoieties was examined. The increasingly lipophilic octanoate (C8), decanoate (C10) and dodecanoate (C12) derivatives were evaluated in dogs and in minipigs, at a dose of 5 mg-eq. nalmefene/kg and plasma nalmefene concentrations were measured over a four-week period. The pharmacokinetic profiles were very similar in both species with Cmax decreasing and Tmax increasing with increasing fatty acid chain length and the target plasma concentrations (0.5–1.0 ng/mL over a month-long period) were achieved with the dodecanoate (C12) prodrug. These data therefore demonstrate that sustained plasma nalmefene concentrations can be achieved in both dog and minipig using nalmefene prodrugs and that the pharmacokinetic profile of nalmefene can be tuned by varying the length of the alkyl group

Radiographic rib fracture nonunion and association with fracture classification in adults with multiple rib fractures without flail segment:A multicenter prospective cohort study

Background: Rib fracture nonunion is a probable cause of chronic pain following chest trauma, although its prevalence remains unknown. The aims of this study were to determine rib fracture nonunion prevalence following nonoperative management and to determine if presence of nonunion was associated with the number of rib fractures, or the rib fracture classification of anatomical location, type, and displacement. Methods: This multicenter prospective cohort study included trauma patients with three or more fractured ribs but without a flail segment, who participated in the nonoperative management group of the FixCon trial between January 2019 and June 2022. The number and classification of rib fractures were assessed on trauma chest CT. Chest CTs conducted six months post-trauma were evaluated for the presence of nonunion. Radiological characteristics of nonunions were compared with normally healed rib fractures using the Mann-Whitney U, χ2 test, and Fisher's exact test as appropriate. A generalized linear model adjusted for multiple observations per patient when assessing the associations between nonunion and fracture characteristics. Results: A total of 68 patients were included with 561 post-traumatic fractures in 429 ribs. Chest CT after six months revealed nonunions in 67 (12 %) rib fractures in 29 (43 %) patients with a median of 2 (P25-P75 1–3) nonunions per patient. Nonunion was most commonly observed in ribs seven to 10 (20–23 %, p &lt; 0.001, adjusted p = 0.006). Nonunion occurred in 14 (5 %) undisplaced, 22 (19 %) offset, and 20 (23 %) displaced rib fractures (p &lt; 0.001). No statistically significant association between rib fracture type and nonunion was found. Conclusions: Forty-three percent of patients with multiple rib fractures had radiographic nonunion six months after trauma. Fractures in ribs seven to 10 and dislocated fractures had an increased risk of rib fracture nonunion.</p

Radiographic rib fracture nonunion and association with fracture classification in adults with multiple rib fractures without flail segment:A multicenter prospective cohort study

Background: Rib fracture nonunion is a probable cause of chronic pain following chest trauma, although its prevalence remains unknown. The aims of this study were to determine rib fracture nonunion prevalence following nonoperative management and to determine if presence of nonunion was associated with the number of rib fractures, or the rib fracture classification of anatomical location, type, and displacement. Methods: This multicenter prospective cohort study included trauma patients with three or more fractured ribs but without a flail segment, who participated in the nonoperative management group of the FixCon trial between January 2019 and June 2022. The number and classification of rib fractures were assessed on trauma chest CT. Chest CTs conducted six months post-trauma were evaluated for the presence of nonunion. Radiological characteristics of nonunions were compared with normally healed rib fractures using the Mann-Whitney U, χ2 test, and Fisher's exact test as appropriate. A generalized linear model adjusted for multiple observations per patient when assessing the associations between nonunion and fracture characteristics. Results: A total of 68 patients were included with 561 post-traumatic fractures in 429 ribs. Chest CT after six months revealed nonunions in 67 (12 %) rib fractures in 29 (43 %) patients with a median of 2 (P25-P75 1–3) nonunions per patient. Nonunion was most commonly observed in ribs seven to 10 (20–23 %, p &lt; 0.001, adjusted p = 0.006). Nonunion occurred in 14 (5 %) undisplaced, 22 (19 %) offset, and 20 (23 %) displaced rib fractures (p &lt; 0.001). No statistically significant association between rib fracture type and nonunion was found. Conclusions: Forty-three percent of patients with multiple rib fractures had radiographic nonunion six months after trauma. Fractures in ribs seven to 10 and dislocated fractures had an increased risk of rib fracture nonunion.</p

Routine versus on demand removal of the syndesmotic screw; A protocol for an international randomised controlled trial (RODEO-trial)

Background: Syndesmotic injuries are common and their incidence is rising. In case of surgical fixation of the syndesmosis a metal syndesmotic screw is used most often. It is however unclear whether this screw needs to be removed routinely after the syndesmosis has healed. Traditionally the screw is removed after six to 12 weeks as it is thought to hamper ankle functional and to be a source of pain. Some studies however suggest this is only the case in a minority of patients. We therefore aim to investigate the effect of retaining the syndesmotic screw on functional outcome. Design: This is a pragmatic international multicentre randomised controlled trial in patients with an acute syndesmotic injury for which a metallic syndesmotic screw was placed. Patients will be randomised to either routine removal of the syndesmotic screw or removal on demand. Primary outcome is functional recovery at 12 months measured with the Olerud-Molander Score. Secondary outcomes are quality of life, pain and costs. In total 194 patients will be needed to demonstrate non-inferiority between the two interventions at 80% power and a significance level of 0.025 including 15% loss to follow-up. Discussion: If removal on demand of the syndesmotic screw is non-inferior to routine removal in terms of functional outcome, this will offer a strong argument to adopt this as standard practice of care. This means that patients will not have to undergo a secondary procedure, leading to less complications and subsequent lower costs. Trial registration: This study was registered at the Netherlands Trial Register (NTR5965), Clinicaltrials.gov (NCT02896998) on July 15th 2016

International consensus guidelines for scoring the histopathological growth patterns of liver metastasis

BACKGROUND: Liver metastases present with distinct histopathological growth patterns (HGPs), including the desmoplastic, pushing and replacement HGPs and two rarer HGPs. The HGPs are defined owing to the distinct interface between the cancer cells and the adjacent normal liver parenchyma that is present in each pattern and can be scored from standard haematoxylin-and-eosin-stained (H&E) tissue sections. The current study provides consensus guidelines for scoring these HGPs. METHODS: Guidelines for defining the HGPs were established by a large international team. To assess the validity of these guidelines, 12 independent observers scored a set of 159 liver metastases and interobserver variability was measured. In an independent cohort of 374 patients with colorectal liver metastases (CRCLM), the impact of HGPs on overall survival after hepatectomy was determined. RESULTS: Good-to-excellent correlations (intraclass correlation coefficient >0.5) with the gold standard were obtained for the assessment of the replacement HGP and desmoplastic HGP. Overall survival was significantly superior in the desmoplastic HGP subgroup compared with the replacement or pushing HGP subgroup (P=0.006). CONCLUSIONS: The current guidelines allow for reproducible determination of liver metastasis HGPs. As HGPs impact overall survival after surgery for CRCLM, they may serve as a novel biomarker for individualised therapies

Consensus guidelines for the use and interpretation of angiogenesis assays

The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference