Delay in desmopressin therapy: Disaster in waiting.

WHAT IS KNOWN AND OBJECTIVE: Central diabetes insipidus (DI) is a complex disease that requires firm adherence to desmopressin therapy. There is little information on the onset of hypernatremia after withdrawal of desmopressin. CASE SUMMARY: We present a case of an elderly woman with central DI whose serum sodium jumped from 141 to 171 mEq/L after 48-72 h of holding oral desmopressin. Her DI crisis resolved with intravenous desmopressin and free water administration. WHAT IS NEW AND CONCLUSION: Based on this precipitous onset of DI crisis, we recommend not withholding desmopressin for more than 24 h.

International spillover effects in the EU's textile supply chains: A global SDG assessment.

Successful implementation of the Sustainable Development Goals (SDGs) requires world countries to account for actions that inadvertently generate negative impacts on other countries. These actions/effects are called 'spillovers', and can hinder a country's SDG progress. In this work, we analyse negative social spillover effects, focussing specifically on the occupational health and safety aspects of workers in textile supply chains. We select two indicators: fatal accidents and non-fatal accidents that take place in global supply chains for satisfying consumption of textile products (such as clothing, leather products) by European Union (EU) countries. Specifically, we scan global supply chains originating in countries outside of EU for meeting the demands of its citizens. To this end, we employ a well-established technique of multi-regional input-output analysis, featuring information on 15,000 sectors for 189 countries, to scan international supply chain routes that are linked to consumption of textile products by EU countries. Our findings suggest that Italy, Germany, France, Spain, Poland, Belgium and Portugal are collectively responsible for about 80% of both fatal- and non-fatal accidents that are attributed to the EU's consumption-based footprint. These findings not only call for a need for coherent SDG policies that consider spillover effects, but also the need for these effects to be included in EU's strategic instruments and policy-related tools.

Role of Endocytosis in Nanoparticle Penetration of 3D Pancreatic Cancer Spheroids.

Robust deposition of extracellular matrix is a significant barrier for delivery of nanotherapeutics and small-molecule anticancer drugs to different tumors including pancreatic ductal adenocarcinoma. Here, we investigated permeation and total uptake of polystyrene nanoparticles of different diameters in 3D multicellular spheroid models of pancreatic tumors. Special attention was given to analysis of the impact of endocytic processes on nanoparticle accumulation and distribution in spheroids. We generated spheroids of BxPC3 or PANC-1 cells that were able to internalize 20, 100, and 500 nm fluorescent polystyrene beads with different efficacies, resulting in 20 ≫100 > 500 nm and 100 > 500 > 20 nm trends, respectively. It was found that endocytosis and transcytosis increased overall nanoparticle uptake and facilitated permeation of 20 nm beads in BxPC3 spheroids, whereas 100 and 500 nm particles did not penetrate. In PANC-1 spheroids, penetration of nanoparticles also decreased with the increase of size but was not significantly affected by endocytic processes. Thus, our study showed that passive diffusion and endocytic processes may have a different contribution to nanoparticle accumulation and distribution in spheroid models of pancreatic cancer.

Cellular Uptake, Intracellular Trafficking, and Stability of Biocompatible Metal-Organic Framework (MOF) Particles in Kupffer Cells.

Rapid intracellular degradation of current drug-delivery nanocarriers presents a challenge for achieving ideal controlled drug-release kinetics. Recent in vivo studies have shown that porous hybrid metal-organic frameworks (MOFs), belonging to the Materials of Institute Lavoisier (MIL) family, display prolonged biodegradation behavior. In this study, we investigated stability of these materials in Kupffer cells, a relevant target for the treatment of several life-threatening immune-mediated liver diseases. For this aim, we selected fluorescently labeled microporous MOF particles of MIL88A and MIL88B-NH2, built from trimers of Fe(III) octahedra, as an inorganic component, and fumarate (MIL88A) or 2-amino terephthalate (MIL88B-NH2), as an organic linker. Cell uptake inhibition analysis of MOF particles by a Kupffer cell line (KUP5) has shown that phagocytosis is the major endocytic pathway involved in MIL88B-NH2 internalization. Investigation of MOF interaction with KUP5 cells by real-time microscopy indicated that the structure of MIL88B-NH2 MOFs stays intact up to 15 min after uptake, followed by MOF accumulation in acidic cell compartments and slow degradation, reaching a minimum of 10-15% decomposition over 24 h. MIL88A particles demonstrated similar degradation kinetics. Analysis of the mechanisms of MOF degradation has shown that inhibition of phagosome acidification as well as protease activity does not prevent decomposition of MIL88B-NH2 particles. Thus, our study demonstrates the relative stability of the MOF structure in the phagolysosomal environment of Kupffer cells, revealing potential use of these materials for controlled drug delivery in a case of immune-mediated liver diseases.

Implementation and safety evaluation of autoverification for select low-risk, high-volume medications in the emergency department.

PURPOSE: Use of autoverification has decreased in many emergency departments (EDs) with the expansion of emergency medicine (EM) pharmacists. Few studies have evaluated ways to prioritize verification of medications. Here we describe a process to design, implement, and measure the safety of autoverification of low-risk, high-volume medications. SUMMARY: A 3-month retrospective review of medications ordered and administered in the ED generated a list of medications to be considered for autoverification. Concurrently, a novel risk stratification tool was created to identify low-risk medications. Taking these together, medications that were high volume and low risk were considered potentially autoverified medications (PAMs). To evaluate the safety of PAMs, a retrospective review of the ED medication orders placed before implementation of autoverification was performed. A total of 7,433 medication orders were reviewed. Of these, 3,057 orders (41%) were identified as PAMs. EM pharmacists verified 2,982 (97.5%) of the orders without changes. Of the remaining 93 orders that were modified or discontinued and met autoverification criteria, only 2 (0.07%) were identified as potentially inappropriate for autoverification. CONCLUSION: Low-risk, high-volume medications can be safely autoverified in the ED by using a systematic approach to order selection. Using these methods can provide large decreases in verification volume, close to 41%, without compromising patient safety.

Application of X-ray fluorescence spectrometry for screening pharmaceutical products for Elemental Impurities according to ICH guideline Q3D.

Energy-dispersive X-ray fluorescence spectrometry (EDXRF) is a suitable analytical procedure for screening drug products for Elemental Impurities (EI) according to ICH guideline Q3D. EDXRF represents a cost-efficient, robust and standard-free alternative compared to other methodologies for trace analysis, and therefore utilization of this application should be encouraged. This study demonstrates the capability of EDXRF for EI screening of oral solid dosage drug products (OSD products) within a defined matrix range. Method development and validation focused on class 1 (Cd, Pb, As, Hg) and class 2A (Co, V, Ni) elements, as defined by ICH guideline Q3D. In order to limit validation activities, a novel cluster approach was applied, based on matrix properties. This included comprehensive characterization of method performance parameters for exemplary pharmaceutical matrices and demonstration of LOQ independence from matrix effects by using a set of limit samples representing typical matrix variations of OSD products. The methodology can be used as a limit test for class 1 and class 2A elements and is fully compliant with method validation requirements according to the European Pharmacopeia. The novelty of the present work is the application of EDXRF for a routine screening of OSD products for Elemental Impurities within the pharmaceutical industry beyond previously published feasibility studies for a limited number of pharmaceutical raw materials or products.

Subcutaneous Inoculation of 3D Pancreatic Cancer Spheroids Results in Development of Reproducible Stroma-Rich Tumors.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease characterized by high expression of extracellular matrix in tumor tissue, which contributes to chemoresistance and poor prognosis. Here, we developed 3D pancreatic cancer spheroids, based on pancreatic cancer cells and fibroblast co-culture, which demonstrate innate desmoplastic properties and stay poorly permeable for model nanoparticles. Our study revealed that establishment of tumors by transplantation of spheroids significantly improved subcutaneous xenograft model of PDAC, which stays the most widely used animal model for testing of new drugs and drug delivery approaches. Spheroid based tumors abundantly produced different extracellular matrix (ECM) components including collagen I, fibronectin, laminin and hyaluronic acid. These tumors were highly reproducible with excellent uniformity in terms of ECM architecture recapitulating clinical PDAC tumors, whereas in more common cell based xenografts a significant intertumor heterogeneity in extracellular matrix production was found. Moreover, spheroid based xenografts demonstrated higher expression of pro-fibrotic and pro-survival PDAC hallmarks in opposite to cell based counterparts. We believe that future development of this model will provide an effective instrument for testing of anti-cancer drugs with improved predictive value.