Mapping the Antimicrobial Supply Chain in Bangladesh: A Scoping-Review-Based Ecological Assessment Approach.

INTRODUCTION: Maintaining access to antimicrobials while preventing misuse is essential to combating the threat of antimicrobial resistance (AMR). The study objectives are to propose a framework of 16 indicators that can be used at the national level to assess the capacity to ensure access and curtail inappropriate use and to profile the antimicrobial supply chain for Bangladesh. METHODS: Using a framework based on a rational construct, we assessed the antimicrobial supply chain of Bangladesh, with a focus on key players and products using a scoping review to obtain and describe information on 16 indicators. With players, we mapped linkages, manufacturers' production capacity, and ownership, among others, and demand point characteristics-pharmacy and pharmacist density, pharmacy/medicine outlets dispersion, veterinary clinic/hospitals, veterinarians' density, product quality, and regulation. We assessed product characteristics including listing on the World Health Organization (WHO) Model Essential Medicines List (EML) and WHO Access, Watch, and Reserve (AWaRe) classification of the major (top 10) antibiotics for human use; the proportion of medically important antimicrobials (MIAs) in veterinary use; and pricing. Production capacity and price controls were used to assess access and listing on the WHO EML, AWaRe/MIA classification, and a calculated pharmacy-to-pharmacist ratio to assess use. RESULTS: Bangladesh has a high (98%) local antibiotic production capacity with pricing controls indicating the ability to ensure access. The presence of a high proportion of medicine outlets not under the control of pharmacists (4:1) and the high percentages of WHO Watch (54%) and MIAs (90%) of the major antibiotics are indicators of possible misuse. DISCUSSION: Most of the data used in the framework were publicly available. Bangladesh has the capacity to ensure access but needs to strengthen its ability to regulate the quality of antimicrobials and prevent their inappropriate use through antimicrobial stewardship at the community (medicine outlet) levels to check AMR. There may also be a need for more regulations on licensing of MIAs.

Impact of ciprofloxacin impurities on bacterial growth, antibiotic resistance development and content assays.

In addition to active pharmaceutical ingredient (API), antibiotics may contain small amounts of excipients and impurities and be prone to accumulation of degradation products. There has been limited work characterizing how these substances impact bacterial growth and antibiotic resistance development. We investigated how two ciprofloxacin (CIP) impurities, fluoroquinolonic acid (FQA) and ciprofloxacin ethylenediamine analogue (CEA), impact growth and antibiotic resistance in Escherichia coli. Additionally, we investigated how these impurities impact a frequently used API content assay. Both impurities displayed modest antimicrobial activity compared to the CIP API. The effective antimicrobial activity of a medicine containing increased impurity levels may permit bacterial growth and resistance development. Our results also suggest that increasing exposure concentration and duration to CEA and FQA, independent of CIP, can promote antibiotic resistance development. However, at concentrations of 100% and below the MIC of the API, impurities had limited contributions to resistance development compared to the CIP API. From a methodological standpoint, we found that UV spectrophotometry may be inadequate to account for antibiotic impurities or degradation products. This can lead to incorrect estimations of API content and we propose additional multi-wavelength measures when using UV spectrophotometry to help identify impurities or degradation.

Tackling the blind spot of poor-quality medicines in Universal Health Coverage.

BACKGROUND: Universal Health Coverage (UHC) is challenged by the prevalence of poor-quality medicines, those that either do not meet required specifications (substandard) or are outrightly fraudulent (falsified), especially in Low- and Middle-Income Countries, LMICs. Whereas poor-quality medicines are a significant burden in these countries, medicine quality still remains a neglected component of UHC programs. This article describes key barriers to quality medicines and presents five select approaches leveraging the scale-up of UHC for medicine quality assurance. MAIN BODY: Barriers to medicine quality assurance, while numerous, are described in five key inter-related domains as: low political priority, weak regulatory systems capacity, poor access to accredited facilities and licensed outlets, medicine manufacturing and other supply-chain challenges, and lack of public awareness. Five select approaches for leveraging the scale-up of UHC for medicine quality assurance in LMICs are (1): political commitment (2) strengthening the capacity of regulatory authorities and investment in detection technologies as part of national security (3); licensing of medicines outlets and expanding pharmacovigilance (4); strengthening the supply-chain; and (5) public awareness and participation. CONCLUSIONS: Unchecked, poor-quality medicines can jeopardize UHC. National governments in LMICs need to prioritize medicine quality assurance through enforcing policies, regulatory strengthening and investments in technologies. Healthcare facilities and insurance schemes under UHC also play critical roles through incorporating medicine quality assurance into procurement practices and by promoting awareness among beneficiaries. Tackling medicine quality with a committed systems approach will enhance progress towards UHC implementation.

Environmental reservoirs of Vibrio cholerae.

The environmental reservoir of Vibrio cholerae, the causative agent of cholera, has been a topic of scientific investigation ever since the discovery of the bacterium itself. While the bacteria can be isolated from both clinical and environmental sources during epidemics, it evades isolation by conventional culture techniques during the period between successive epidemics. The problem is identifying the location and mode of survival and multiplication of V. cholerae during this inter-epidemic period. This information is crucial not only for epidemiological reasons, but also because the seasonality of cholera epidemics is plausibly mediated by the climate-regulated activity of the reservoir. This article focuses on the epidemiological importance of the environmental reservoir of V. cholerae, considering several investigations made on different types of aquatic fauna (zooplanktons, crustaceans, etc.) and flora (macrophytes and microphytes). After evaluating different lines of evidence, we make the case that certain species of cyanobacteria (Anabaena variabilis, Microcystis aeruginosa) can act as inter-epidemic reservoirs of V. cholerae. Physiological and functional aspects of this association are also discussed. We then present a hypothesis, expanding upon a previously published conceptual model, of how the climate-regulated seasonality of cholera epidemics is mediated by the effect of climatic factors on algal bloom and other local abiotic variables in the water, using Bangladesh as a model. Finally, another aspect of the climate-dependence of disease patterns is briefly explored: large-scale environmental signatures associated with cholera, and recent modelling efforts to predict cholera outbreaks based on coastal phytoplankton. The review, therefore, serves not only as a study of the identity of the inter-epidemic reservoir of V. cholerae, but also explores different ways in which the reservoir and the pathogen behaviour is affected by the climate, and the possible consequences it may have on disease pattern.

Compressive Remodeling Alters Fluid Transport Properties of Collagen Networks - Implications for Tumor Growth.

Biomechanical alterations to the tumor microenvironment include accumulation of solid stresses, extracellular matrix (ECM) stiffening and increased fluid pressure in both interstitial and peri-tumoral spaces. The relationship between interstitial fluid pressurization and ECM remodeling in vascularized tumors is well characterized, while earlier biomechanical changes occurring during avascular tumor growth within the peri-tumoral ECM remain poorly understood. Type I collagen, the primary fibrous ECM constituent, bears load in tension while it buckles under compression. We hypothesized that tumor-generated compressive forces cause collagen remodeling via densification which in turn creates a barrier to convective fluid transport and may play a role in tumor progression and malignancy. To better understand this process, we characterized the structure-function relationship of collagen networks under compression both experimentally and computationally. Here we show that growth of epithelial cancers induces compressive remodeling of the ECM, documented in the literature as a TACS-2 phenotype, which represents a localized densification and tangential alignment of peri-tumoral collagen. Such compressive remodeling is caused by the unique features of collagen network mechanics, such as fiber buckling and cross-link rupture, and reduces the overall hydraulic permeability of the matrix.

Modeling of adhesion, protrusion, and contraction coordination for cell migration simulations.

Cell migration is a highly complex, dynamical biological phenomenon that involves precise spatio-temporal coordination of distinctive sub-processes including adhesion, protrusion, and contraction of the cell. Observations of individual tumor cell migration reveal that cells generally exhibit either mesenchymal-type or amoeboid-type migration modes in native like environments. However, it has also been observed that some migrating cells are capable of morphologically adapting to their environment by modifying their type of migration. Recent studies suggest in fact that changes in biophysical and biomechanical properties of tumor cells can reversibly control their transition from one type of migration to the other. These changes may be caused by internal cell biomechanical mechanisms as well as mechanical and topological properties of the extracellular matrix. In order to understand the complex transition between the two modes and the role played by internal cellular mechanics during migration, we have developed a novel axisymmetric hyperviscoelastic cell model to simulate the dynamical behavior of a migrating cell. Numerical results from our study quantitatively demonstrate that the biomechanical properties of the cell may play an important role in the amoeboid-mesenchymal transition during migration. Our study will therefore not only help in creating a new platform for simulating cellular processes but will also provide insights into the role of sub-cellular mechanics in regulating various modes of migration during tumor invasion and metastasis.

Viscoelastic gel-strip model for the simulation of migrating cells.

Migrating tumor cells can exhibit both mesenchymal- and amoeboid-type behaviors. Recent studies have shown that both cellular and extracellular structural and mechanical variables control the transition of tumor cells from one mode to the other and provide them with morphological plasticity. The mesenchymal-mode migration is characterized by strong adhesion and proteolytic machinery to navigate through complex extracellular matrices. The amoeboid-mode migration is characterized by little or no adhesion and strong actomyosin contraction to squeeze through the matrices. While adhesion dependent migration has been computationally and experimentally studied in both 2D and 3D environments, quantitative models of amoeboid motion in native environments are lacking. In order to address this major gap in our understanding and to probe the mesenchymal to amoeboid transitions quantitatively and comprehensively, we have developed an axisymmetric viscoelastic gel-strip model of a single cell to investigate a cell migrating in native-like environments. In this model, cell migration and morphology are governed by internal stresses as well as external forces. The internal stresses are controlled by F-actin density distribution, protrusion strength, and contraction strength. The external forces are controlled by adhesion strength and steric resistance from the extracellular matrix. Our model predicts that the transition of the cell migration mode from mesenchymal- to amoeboid-type, and vice versa, is closely related to the loss of adhesion as well as increased contraction strength of the cells. Our results indicate that amoeboid migration is more suited for low-resistance environment while mesenchymal migration is preferred in high-resistance environment, which would explain the versatile behaviors of tumor cells in complex environments.

A rare malposition of the central venous catheter.

The left pericardiacophrenic vein was accidentally cannulated during an attempt to establish central venous catheterization through the left internal jugular vein. Chest roentgenograms and intravenous contrast material confirmed the position of the catheter. Although our patient developed no problems during a five-day cannulation, based on published information, it is advisable to reposition the catheter to avoid perforation of the pericardiacophrenic vein and possible cardiac tamponade.