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Background: Lipedema is a chronic disorder of the adipose tissue that affects mainly women, characterised by symmetrical, excessive fatty tissue on the legs and pain. Standard conservative treatment is long-term comprehensive decongestive therapy (CDT) to alleviate lipedema-related pain and to improve psychosocial well-being, mobility and physical activity. Patients may benefit from surgical removal of abnormally propagated adipose tissue by liposuction. The LIPLEG trial evaluates the efficacy and safety of liposuction compared to standard CDT.
Methods/design: LIPLEG is a randomised controlled multicentre investigator-blinded trial. Women with lipedema (n=405) without previous liposuction will be allocated 2:1 to liposuction or CDT. The primary outcome of the trial is leg pain reduction by ≥2 points on a visual analogue scale ranging 0–10 at 12 months on CDT or post-completion of liposuction. Secondary outcomes include changes in leg pain severity, health-related quality of life, depression tendency, haematoma tendency, prevalence of oedema, modification physical therapy scope, body fat percentage, leg circumference and movement restriction.
The primary analysis bases on intention-to-treat. Success proportions are compared using the Mantel-Haenszel test stratified by lipedema stage at a 5% two-sided significance level. If this test is statistically significant, the equality of the response proportions in the separate strata is evaluated by Fisher’s exact test in a hierarchical test strategy.
Discussion: LIPLEG assesses whether surgical treatment of lipedema is safe and effective to reduce pain and other lipedema-related health issues. The findings of this trial have the potential to change the standard of care in lipedema.
Trial registration: ClinicalTrials.gov NCT04272827. Registered on February 14, 2020.
Trial status: Protocol version is 02_0, December 17, 2019
The two main phytocannabinoids—delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD)—have been extensively studied, and it has been shown that THC can induce transient psychosis. At the same time, CBD appears to have no psychotomimetic potential. On the contrary, emerging evidence for CBD's antipsychotic properties suggests that it may attenuate effects induced by THC. Thus, we investigated and compared the effects of THC and CBD administration on emotion, cognition, and attention as well as the impact of CBD pre-treatment on THC effects in healthy volunteers. We performed a placebo-controlled, double-blind, experimental trial (GEI-TCP II; ClinicalTrials.gov identifier: NCT02487381) with 60 healthy volunteers randomly allocated to four parallel intervention groups, receiving either placebo, 800 mg CBD, 20 mg THC, or both cannabinoids. Subjects underwent neuropsychological tests assessing working memory (Letter Number Sequencing test), cognitive processing speed (Digit Symbol Coding task), attention (d2 Test of Attention), and emotional state (adjective mood rating scale [EWL]). Administration of CBD alone did not influence the emotional state, cognitive performance, and attention. At the same time, THC affected two of six emotional categories—more precisely, the performance-related activity and extraversion—, reduced the cognitive processing speed and impaired the performance on the d2 Test of Attention. Interestingly, pre-treatment with CBD did not attenuate the effects induced by THC. These findings show that the acute intake of CBD itself has no effect per se in healthy volunteers and that a single dose of CBD prior to THC administration was insufficient to mitigate the detrimental impact of THC in the given setting. This is in support of a complex interaction between CBD and THC whose effects are not counterbalanced by CBD under all circumstances.
Background: Transfusion of red blood cell concentrate can be life-saving, but requires accurate dose calculations in children. Aims: We tested the hypothesis that cognitive aids would improve identification of the correct recommended volumes and products, according to the German National Transfusion guidelines, in pediatric transfusion scenarios. Methods: Four online questionnaire-based scenarios, two with hemodynamically stable and two with hemodynamically unstable children, were sent to German and international pediatric anesthetists for completion. In the two stable scenarios, participants were given pre-filled tables that contained all required information. For the two emergency scenarios, existing algorithms were used and required calculation by the user. The results were classified into three categories of deviations from the recommended values (DRV): DRV120 (<80% or >120%), as the acceptable variation; DRV 300 (<33% or >300%), the deviation of concern for potential harm; and DRV 1000 (<10% or >1000%), the excessive deviation with a high probability of harm. Results: A total of 1.458 pediatric anesthetists accessed this simulation questionnaire, and 402 completed questionnaires were available for analysis. A pre-filled tabular aid, avoiding calculations, led to a reduction in deviation rates in the category of DRV120 by 60% for each and of DRV300 by 17% and 20%, respectively. The use of algorithms as aids for unstable emergencies led to a reduction in the deviation rate only for DRV120 (20% and 15% respectively). In contrast, the deviation rates for DRV300 and DRV1000 rose by 37% and 16%, respectively. Participants used higher transfusion thresholds for the emergency case of a 2-year-old compromised child than for the stable case with a patient of the same age (on average, 8.6 g/dL, 95% CI 8.5–8.8 versus 7.1 g/dL, 95% CI 7.0–7.2, p < 0.001) if not supported by our aids. Participants also used a higher transfusion threshold for unstable children aged 3 months than for stable children of the same age (on average, 8.9 g/dL, 95% CI 8.7–9.0 versus 7.9 g/dL, 95% CI 7.7–8.0, p < 0.001). Conclusions: The use of cognitive aids with precalculated transfusion volumes for determining transfusion doses in children may lead to improved adherence to published recommendations, and could potentially reduce dosing deviations outside those recommended by the German national transfusion guidelines.
Macrophage infectivity potentiator (MIP) proteins are widespread in human pathogens including Legionella pneumophila, the causative agent of Legionnaires’ disease and protozoans such as Trypanosoma cruzi. All MIP proteins contain a FKBP (FK506 binding protein)-like prolyl-cis/trans- isomerase domain that hence presents an attractive drug target. Some MIPs such as the Legionella pneumophila protein (LpMIP) have additional appendage domains of mostly unknown function. In full- length, homodimeric LpMIP, the N-terminal dimerization domain is linked to the FKBP-like domain via a long, free-standing stalk helix. Combining X-ray crystallography, NMR and EPR spectroscopy and SAXS, we elucidated the importance of the stalk helix for protein dynamics and inhibitor binding to the FKBP-like domain and bidirectional crosstalk between the different protein regions. The first comparison of a microbial MIP and a human FKBP in complex with the same synthetic inhibitor was made possible by high-resolution structures of LpMIP with a [4.3.1]-aza-bicyclic sulfonamide and provides a basis for designing pathogen-selective inhibitors. Through stereospecific methylation, the affinity of inhibitors to L. pneumophila and T. cruzi MIP was greatly improved. The resulting X-ray inhibitor-complex structures of LpMIP and TcMIP at 1.49 and 1.34 Å, respectively, provide a starting point for developing potent inhibitors against MIPs from multiple pathogenic microorganisms.
Macrophage infectivity potentiator (MIP) proteins are widespread in human pathogens including Legionella pneumophila, the causative agent of Legionnaires’ disease and protozoans such as Trypanosoma cruzi. All MIP proteins contain a FKBP (FK506 binding protein)-like prolyl-cis/trans-isomerase domain that hence presents an attractive drug target. Some MIPs such as the Legionella protein (LpMIP) have additional appendage domains of mostly unknown function. In full-length, homodimeric LpMIP, the N-terminal dimerization domain is linked to the FKBP-like domain via a long, free-standing stalk helix. Combining X-ray crystallography, NMR and EPR spectroscopy and SAXS, we elucidated the importance of the stalk helix for protein dynamics and inhibitor binding to the FKBP-like domain and bidirectional crosstalk between the different protein regions. The first comparison of a microbial MIP and a human FKBP in complex with the same synthetic inhibitor was made possible by high-resolution structures of LpMIP with a [4.3.1]-aza-bicyclic sulfonamide and provides a basis for designing pathogen-selective inhibitors. Through stereospecific methylation, the affinity of inhibitors to to L. pneumophila and T. cruzi MIP was greatly improved. The resulting X-ray inhibitor-complex structures of LpMIP and TcMIP at 1.49 and 1.34 Å, respectively, provide a starting point for developing potent inhibitors against MIPs from multiple pathogenic microorganisms.
