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District heating systems are considered a feasible heating alternative to replace natural gas to mitigate emissions in cities. However, urban transitions are very complex because energy systems often operate in densely populated areas, which gives rise to all kinds of interdependencies in cities. These interdependencies can result in unintended consequences which can indirectly help or hinder urban energy transitions. Understanding these influences the transition to climate neutrality. This research investigates the lessons learned from a project conducted in Rotterdam: a high-density city in the Netherlands which is expanding its district heating systems. We use qualitative system dynamics models to explore the underlying complexity and to recognize indirect consequences of policies. Our results cover both technologically oriented and policy-oriented insights, contributing to the literature on transition governance in cities. On the one hand, the national and urban strategies in the Netherlands activate mechanisms that support cities with district heating systems such as Rotterdam. On the other hand, the same strategies could also lead to a potential rivalry between energy efficiency and energy security, which are both crucial goals in urban transition governance. Participative modeling provides policy-makers with an analytical tool to detect systemic dependencies which can be used to identify synergies and barriers among different energy policy objectives. This helps avoiding potential unintended consequences including the use of carbon-heavy systems and displacing investments from energy efficiency and renewable heating systems., Organisation & Governance

Item does not contain fulltext, Although tuberculosis (TB) is preventable and curable, the lengthy treatment (generally 6 months), poor patient adherence, high inter-individual variability in pharmacokinetics (PK), emergence of drug resistance, presence of comorbidities, and adverse drug reactions complicate TB therapy and drive the need for new drugs and/or regimens. Hence, new compounds are being developed, available drugs are repurposed, and the dosing of existing drugs is optimized, resulting in the largest drug development portfolio in TB history. This review highlights a selection of clinically available drug candidates that could be part of future TB regimens, including bedaquiline, delamanid, pretomanid, linezolid, clofazimine, optimized (high dose) rifampicin, rifapentine, and para-aminosalicylic acid. The review covers drug development history, preclinical data, PK, and current clinical development.

Contains fulltext : 299995.pdf (Publisher’s version ) (Open Access), BACKGROUND: The glycopeptide teicoplanin is considered first-line treatment for severe infections caused by Gram-positive bacteria. Individualized treatment of teicoplanin is gaining interest. As only protein-unbound drug is pharmacologically active, a sensitive assay measuring unbound and total teicoplanin is indispensable for pharmacological research and dose optimization. OBJECTIVES: To develop and validate a UPLC-MS/MS method to quantify unbound and total teicoplanin in human serum. METHODS: The developed assay was validated according to the ICH guideline M10 on Bioanalytical Method Validation and study sample analysis. Unbound teicoplanin was obtained by ultrafiltration. The assay was cross-validated with a quantitative microsphere (QMS) immunoassay in a side-by-side comparison using 40 patient samples. RESULTS: With the developed and validated method, all main teicoplanin components (A2-1, A2-2/A2-3, A2-4/A2-5 and A3-1) can be quantified. Total run time was 5.5 min. Concentration range was 2.5-150 mg/L for total and 0.1-25 mg/L for unbound teicoplanin. Precision (coefficient of variation) and accuracy (bias) of total teicoplanin were 5.97% and 107%, respectively, and 7.17% and 108%, respectively, for unbound teicoplanin.Bland-Altman analysis showed total concentrations measured with the UPLC-MS/MS method were equivalent to the results of the QMS immunoassay. A total of 188 samples from 30 patients admitted to the ICU and haematology department were measured; total concentrations ranged between 2.92 and 98.5 mg/L, and unbound concentrations ranged between 0.37 and 30.7 mg/L. CONCLUSIONS: The developed method provided rapid, precise and accurate measurement of unbound and total teicoplanin. The developed method is now routinely applied in pharmacological research and clinical practice.

Contains fulltext : 298931.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 252053.pdf (Publisher’s version ) (Open Access), BACKGROUND AND OBJECTIVES: Although dose optimization studies have been performed for piperacillin and tazobactam separately, a combined integral analysis is not yet reported. As piperacillin and tazobactam pharmacokinetics are likely to show correlation, a combined pharmacokinetic model should be preferred to account for this correlation when predicting the exposure. Therefore, the aim of this study was to describe the pharmacokinetics and evaluate different dosing regimens of piperacillin and tazobactam in critically ill patients using an integral population pharmacokinetic model in plasma and urine. METHODS: In this observational study, a total of 39 adult intensive care unit patients receiving piperacillin-tazobactam as part of routine clinical care were included. Piperacillin and tazobactam concentrations in plasma and urine were measured and analyzed using non-linear mixed-effects modeling. Monte Carlo simulations were performed to predict the concentrations for different dosing strategies and different categories of renal function. RESULTS: A combined two-compartment linear pharmacokinetic model for both piperacillin and tazobactam was developed, with an output compartment for the renally excreted fraction. The addition of 24-h urine creatinine clearance significantly improved the model fit. A dose of 12/1.5 g/24 h as a continuous infusion is sufficient to reach a tazobactam concentration above the target (2.89 mg/L) and a piperacillin concentration above the target of 100% f T(>1×MIC) (minimum inhibitory concentration [MIC] ≤ 16 mg/L). To reach a target of 100% f T(>5×MIC) with an MIC of 16 mg/L, piperacillin doses of up to 20 g/24 h are inadequate. Potential toxic piperacillin levels were reached in 19.6% and 47.8% of the population with a dose of 12 g/24 h and 20 g/24 h, respectively. CONCLUSIONS: A regular dose of 12/1.5 g/24 h is sufficient in > 90% of the critically ill population to treat infections caused by Escherichia coli and Klebsiella pneumoniae

Contains fulltext : 238315.pdf (Publisher’s version ) (Open Access), Introduction: Guidelines recommend the use of amikacin in the treatment of nontuberculous mycobacterial (NTM) disease. The authors have evaluated the evidence for the position of amikacin in NTM disease treatment.Areas covered: The authors performed a literature search for original research on amikacin in NTM disease, including its mechanism of action, emergence of resistance, pre-clinical and clinical investigations.Expert opinion: Amikacin shows moderate in vitro activity against the clinically most relevant NTM species (M. avium complex and M. abscessus). It is synergistic with ethambutol, clofazimine, and macrolides and these combinations are effective in animal models. Liposomal encapsulation increases amikacin efficacy. Clinically, the recommended dose of 15 mg/kg intravenous amikacin does not lead to PK/PD target attainment in all patients and a positive impact on long-term treatment outcomes remains unproven in both M. avium complex and M. abscessus disease. Adding the amikacin liposome inhalation suspension did prove to be effective in short and long term in patients not responding to recommended treatment for M. avium complex pulmonary disease. Its optimal use in M. avium complex and M. abscessus pulmonary disease warrants further evaluation.

Contains fulltext : 195339.pdf (publisher's version ) (Open Access)