Cost-effectiveness and budget impact of the microprocessor-controlled knee C-Leg in transfemoral amputees with and without diabetes mellitus

Background: The safe use of a prosthesis in activities of daily living is key for transfemoral amputees. However, the number of falls varies significantly between different prosthetic device types. This study aims to compare medical and economic consequences of falls in transfemoral amputees who use the microprocessor-controlled knee joint C-Leg with patients who use non-microprocessor-controlled (mechanical) knee joints (NMPK). The main objectives of the analysis are to investigate the cost-effectiveness and budget impact of C-Legs in transfemoral amputees with diabetes mellitus (DM) and without DM in Germany. Methods: A decision-analytic model was developed that took into account the effects of prosthesis type on the risk of falling and fall-related medical events. Cost-effectiveness and budget impact analyses were performed separately for transfemoral amputees with and without DM. The study took the perspective of the statutory health insurance (SHI). Input parameters were derived from the published literature. Univariate and probabilistic sensitivity analyses (PSA) were performed to investigate the impact of changes in individual input parameter values on model outcomes and to explore parameter uncertainty. Results: C-Legs reduced the rate of fall-related hospitalizations from 134 to 20 per 1000 person years (PY) in amputees without DM and from 146 to 23 per 1000 PY in amputees with DM. In addition, the C-Leg prevented 15 or 14 fall-related death per 1000 PY. Over a time horizon of 25 years, the incremental cost-effectiveness ratio (ICER) was 16,123 Euro per quality-adjusted life years gained (QALY) for amputees without DM and 20,332 Euro per QALY gained for amputees with DM. For the period of 2020–2024, the model predicted an increase in SHI expenditures of 98 Mio Euro (53 Mio Euro in prosthesis users without DM and 45 Mio Euro in prosthesis users with DM) when all new prosthesis users received C-Legs instead of NMPKs and 50% of NMPK user whose prosthesis wore out switched to C-Legs. Results of the PSA showed moderate uncertainty and a probability of 97–99% that C-Legs are cost-effective at an ICER threshold of 40,000 Euro (˜ German GDP per capita in 2018) per QALY gained. Conclusion: Results of the study suggest that the C-Leg provides substantial additional health benefits compared with NMPKs and is likely to be cost-effective in transfemoral amputees with DM as well as in amputees without DM at an ICER threshold of 40,000 Euro per QALY gained. © 2020, The Author(s)

Targeted inhibition of Gq signaling induces airway relaxation in mouse models of asthma

Obstructive lung diseases are common causes of disability and death worldwide. A hallmark feature is aberrant activation of Gq protein–dependent signaling cascades. Currently, drugs targeting single G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptors (GPCRs) are used to reduce airway tone. However, therapeutic efficacy is often limited, because various GPCRs contribute to bronchoconstriction, and chronic exposure to receptor-activating medications results in desensitization. We therefore hypothesized that pharmacological Gq inhibition could serve as a central mechanism to achieve efficient therapeutic bronchorelaxation. We found that the compound FR900359 (FR), a membrane-permeable inhibitor of Gq, was effective in silencing Gq signaling in murine and human airway smooth muscle cells. Moreover, FR both prevented bronchoconstrictor responses and triggered sustained airway relaxation in mouse, pig, and human airway tissue ex vivo. Inhalation of FR in healthy wild-type mice resulted in high local concentrations of the compound in the lungs and prevented airway constriction without acute effects on blood pressure and heart rate. FR administration also protected against airway hyperreactivity in murine models of allergen sensitization using ovalbumin and house dust mite as allergens. Our findings establish FR as a selective Gq inhibitor when applied locally to the airways of mice in vivo and suggest that pharmacological blockade of Gq proteins may be a useful therapeutic strategy to achieve bronchorelaxation in asthmatic lung disease

The Kenevo microprocessor-controlled prosthetic knee compared with non-microprocessor-controlled knees in individuals older than 65 years in Sweden : A cost-effectiveness and budget-impact analysis

Background:Growing evidence suggests that individuals with transfemoral amputation or knee disarticulation using a prosthesis equipped with a microprocessor-controlled knee (MPK) benefit from enhanced mobility and safety, including less falls. In elderly individuals, high mortality rates are assumed to reduce the expected useful life of MPKs, and this raises concerns regarding their economic effectiveness.Objective:To investigate the cost-effectiveness and budget impact of the Kenevo/MPK (Ottobock, Germany) compared with non-microprocessor-controlled knees (NMPKs) in people older than 65 years at the time of transfemoral amputation/knee disarticulation, from a Swedish payer's perspective.Methods:A decision-analytic model was developed to conduct the economic analysis of the Kenevo/MPK. Model parameters were derived from Swedish databases and published literature. Univariate and probabilistic sensitivity analyses were performed to explore parameter uncertainty.Results:Compared with NMPKs, the Kenevo/MPK reduced the frequency of hospitalizations by 137 per 1,000 person years while the frequency of fatal falls was reduced by 19 per 1,000 person-years in the simulation. Over a 25-year time horizon, the incremental cost-effectiveness ratio was EUR11,369 per quality-adjusted life year. The probability of the MPK being cost-effective at a threshold of EUR40,000 per quality-adjusted life year was 99%. The 5-year budget impact model predicted an increase in payer expenditure of EUR1.76 million if all new patients received a Kenevo/MPK, and 50% of current NMPK users switched to the MPK.Conclusions:Results of the modeling suggest that the Kenevo/MPK is likely to be cost-effective for elderly individuals, primarily because of a reduction in falls

The endocannabinoid anandamide is an airway relaxant in health and disease

Chronic obstructive airway diseases are a global medical burden that is expected to increase in the near future. However, the underlying mechanistic processes are poorly understood so far. Herein, we show that the endocannabinoid anandamide (AEA) induces prominent airway relaxation in vitro and in vivo. In contrast to 2-arachidonlyglycerol-induced airway relaxation, this is mediated by fatty acid amide hydrolase (FAAH)-dependent metabolites. In particular, we identify mouse and also human epithelial and airway smooth muscle cells as source of AEA-induced prostaglandin E2 production and cAMP as direct mediator of AEA-dependent airway relaxation. Mass spectrometry experiments demonstrate reduced levels of endocannabinoid-like compounds in lungs of ovalbumin-sensitized mice indicating a pathophysiological relevance of endocannabinoid signalling in obstructive airway disease. Importantly, AEA inhalation protects against airway hyper-reactivity after ovalbumin sensitization. Thus, this work highlights the AEA/FAAH axis as a critical regulator of airway tone that could provide therapeutic targets for airway relaxation

Heterologe Expression, Biosynthese und ökologische Funktion des selektiven Gq‐Signaltransduktionsinhibitors FR900359

Das cyclische Depsipeptid FR900359 (FR), isoliert aus der tropischen Pflanze Ardisia crenata, zeigt starke und selektive Inhibierung von Gq‐Proteinen. Dadurch ist es sowohl für die Erforschung Gq‐abhängiger Prozesse interessant als auch ein vielversprechender Arzneimittelkandidat. Gq‐Inhibierung ist ein neuer Wirkmechanismus für Abwehrstoffe und entscheidend für die ökologische Funktion von FR, wie durch In‐vivo‐Experimente an Mäusen, Affinität zu Gq‐Proteinen von Insekten und Toxizitätsstudien an Insekten gezeigt wurde. Die Sequenzierung des unkultivierten Endosymbionten von A. crenata führte zur Entdeckung des nichtribosomalen Peptidsynthetasegenclusters von FR (frs). Wir präsentieren hier ein Modell der Biosynthese von FR, unterstützt durch bioinformatische und In‐vitro‐Enzymstudien und das neue Derivat AC‐1, welches Flexibilität der Starter‐Kondensierungsdomänen von FR beweist. Expression der frs‐Gene in E. coli führte erstmals zu heterologen Produktion von FR in einem kultivierbaren bakteriellen Wirt

Heterologous Expression, Biosynthetic Studies, and Ecological Function of the Selective Gq-Signaling Inhibitor FR900359

The cyclic depsipeptide FR900359 (FR), isolated from the tropical plant Ardisia crenata, is a strong and selective inhibitor of Gq proteins, making it an indispensable pharmacological tool to study Gq-related processes, as well as a promising drug candidate. Gq inhibition is a novel mode of action for defense chemicals and crucial for the ecological function of FR, as shown by in vivo experiments in mice, its affinity to insect Gq proteins, and insect toxicity studies. The uncultured endosymbiont of A. crenata was sequenced, revealing the FR nonribosomal peptide synthetase (frs) gene cluster. We here provide a detailed model of FR biosynthesis, supported by in vitro enzymatic and bioinformatic studies, and the novel analogue AC-1, which demonstrates the flexibility of the FR starter condensation domains. Finally, expression of the frs genes in E. coli led to heterologous FR production in a cultivable, bacterial host for the first time