Publications by authors named "David M Smith"

232 Publications

DNA Nanostructures in the Fight Against Infectious Diseases.

Adv Nanobiomed Res 2021 Jan 6:2000049. Epub 2021 Jan 6.

Technical and Macromolecular Chemistry Paderborn University Warburger Str. 100 33098 Paderborn Germany.

Throughout history, humanity has been threatened by countless epidemic and pandemic outbreaks of infectious diseases, from the Justinianic Plague to the Spanish flu to COVID-19. While numerous antimicrobial and antiviral drugs have been developed over the last 200 years to face these threats, the globalized and highly connected world of the 21st century demands for an ever-increasing efficiency in the detection and treatment of infectious diseases. Consequently, the rapidly evolving field of nanomedicine has taken up the challenge and developed a plethora of strategies to fight infectious diseases with the help of various nanomaterials such as noble metal nanoparticles, liposomes, nanogels, and virus capsids. DNA nanotechnology represents a comparatively recent addition to the nanomedicine arsenal, which, over the past decade, has made great progress in the area of cancer diagnostics and therapy. However, the past few years have seen also an increasing number of DNA nanotechnology-related studies that particularly focus on the detection and inhibition of microbial and viral pathogens. Herein, a brief overview of this rather young research field is provided, successful concepts as well as potential challenges are identified, and promising directions for future research are highlighted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/anbr.202000049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883073PMC
January 2021

Dual-Factor Representation of the Environmental Context in the Retrosplenial Cortex.

Cereb Cortex 2020 Dec 31. Epub 2020 Dec 31.

Department of Psychology, Cornell University, Ithaca, NY 14853, USA.

The retrosplenial cortex (RSC) is thought to be involved in a variety of spatial and contextual memory processes. However, we do not know how contextual information might be encoded in the RSC or whether the RSC representations may be distinct from context representations seen in other brain regions such as the hippocampus. We recorded RSC neuronal responses while rats explored different environments and discovered 2 kinds of context representations: one involving a novel rate code in which neurons reliably fire at a higher rate in the preferred context regardless of spatial location, and a second involving context-dependent spatial firing patterns similar to those seen in the hippocampus. This suggests that the RSC employs a unique dual-factor representational mechanism to support contextual memory.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cercor/bhaa386DOI Listing
December 2020

Pluripotent Stem Cell-Derived Hepatocytes Phenotypic Screening Reveals Small Molecules Targeting the CDK2/4-C/EBPα/DGAT2 Pathway Preventing ER-Stress Induced Lipid Accumulation.

Int J Mol Sci 2020 Dec 15;21(24). Epub 2020 Dec 15.

Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.

Non-alcoholic fatty liver disease (NAFLD) has a large impact on global health. At the onset of disease, NAFLD is characterized by hepatic steatosis defined by the accumulation of triglycerides stored as lipid droplets. Developing therapeutics against NAFLD and progression to non-alcoholic steatohepatitis (NASH) remains a high priority in the medical and scientific community. Drug discovery programs to identify potential therapeutic compounds have supported high throughput/high-content screening of in vitro human-relevant models of NAFLD to accelerate development of efficacious anti-steatotic medicines. Human induced pluripotent stem cell (hiPSC) technology is a powerful platform for disease modeling and therapeutic assessment for cell-based therapy and personalized medicine. In this study, we applied AstraZeneca's chemogenomic library, hiPSC technology and multiplexed high content screening to identify compounds that significantly reduced intracellular neutral lipid content. Among 13,000 compounds screened, we identified hits that protect against hiPSC-derived hepatic endoplasmic reticulum stress-induced steatosis by a mechanism of action including inhibition of the cyclin D3-cyclin-dependent kinase 2-4 (CDK2-4)/CCAAT-enhancer-binding proteins (C/EBPα)/diacylglycerol acyltransferase 2 (DGAT2) pathway, followed by alteration of the expression of downstream genes related to NAFLD. These findings demonstrate that our phenotypic platform provides a reliable approach in drug discovery, to identify novel drugs for treatment of fatty liver disease as well as to elucidate their underlying mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21249557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765409PMC
December 2020

AI-guided discovery of the invariant host response to viral pandemics.

bioRxiv 2020 Sep 22. Epub 2020 Sep 22.

We sought to define the host immune response, a.k.a, the "cytokine storm" that has been implicated in fatal COVID-19 using an AI-based approach. Over 45,000 transcriptomic datasets of viral pandemics were analyzed to extract a 166-gene signature using ACE2 as a 'seed' gene; ACE2 was rationalized because it encodes the receptor that facilitates the entry of SARS-CoV-2 (the virus that causes COVID-19) into host cells. Surprisingly, this 166-gene signature was conserved in all ral andemics, including COVID-19, and a subset of 20-genes classified disease severity, inspiring the nomenclatures and signatures, respectively. The signatures pinpointed a paradoxical phenomenon wherein lung epithelial and myeloid cells mount an IL15 cytokine storm, and epithelial and NK cell senescence and apoptosis determines severity/fatality. Precise therapeutic goals were formulated and subsequently validated in high-dose SARS-CoV-2-challenged hamsters using neutralizing antibodies that abrogate SARS-CoV-2•ACE2 engagement. IL15/IL15RA were elevated in the lungs of patients with fatal disease, and plasma levels of the cytokine tracked with disease severity. Thus, the signatures provide a quantitative and qualitative framework for titrating the immune response in viral pandemics and may serve as a powerful unbiased tool to rapidly assess disease severity and vet candidate drugs.

One Sentence Summary: The host immune response in COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2020.09.21.305698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523116PMC
September 2020

A small molecule inhibitor of HER3: a proof-of-concept study.

Biochem J 2020 09;477(17):3329-3347

Protein Phosphorylation Laboratory, The Francis Crick Institute, London, U.K.

Despite being catalytically defective, pseudokinases are typically essential players of cellular signalling, acting as allosteric regulators of their active counterparts. Deregulation of a growing number of pseudokinases has been linked to human diseases, making pseudokinases therapeutic targets of interest. Pseudokinases can be dynamic, adopting specific conformations critical for their allosteric function. Interfering with their allosteric role, with small molecules that would lock pseudokinases in a conformation preventing their productive partner interactions, is an attractive therapeutic strategy to explore. As a well-known allosteric activator of epidermal growth factor receptor family members, and playing a major part in cancer progression, the pseudokinase HER3 is a relevant context in which to address the potential of pseudokinases as drug targets for the development of allosteric inhibitors. In this proof-of-concept study, we developed a multiplex, medium-throughput thermal shift assay screening strategy to assess over 100 000 compounds and identify selective small molecule inhibitors that would trap HER3 in a conformation which is unfavourable for the formation of an active HER2-HER3 heterodimer. As a proof-of-concept compound, AC3573 bound with some specificity to HER3 and abrogated HER2-HER3 complex formation and downstream signalling in cells. Our study highlights the opportunity to identify new molecular mechanisms of action interfering with the biological function of pseudokinases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1042/BCJ20200496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489893PMC
September 2020

Preservation of microvascular barrier function requires CD31 receptor-induced metabolic reprogramming.

Nat Commun 2020 07 17;11(1):3595. Epub 2020 Jul 17.

William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.

Endothelial barrier (EB) breaching is a frequent event during inflammation, and it is followed by the rapid recovery of microvascular integrity. The molecular mechanisms of EB recovery are poorly understood. Triggering of MHC molecules by migrating T-cells is a minimal signal capable of inducing endothelial contraction and transient microvascular leakage. Using this model, we show that EB recovery requires a CD31 receptor-induced, robust glycolytic response sustaining junction re-annealing. Mechanistically, this response involves src-homology phosphatase activation leading to Akt-mediated nuclear exclusion of FoxO1 and concomitant β-catenin translocation to the nucleus, collectively leading to cMyc transcription. CD31 signals also sustain mitochondrial respiration, however this pathway does not contribute to junction remodeling. We further show that pathologic microvascular leakage in CD31-deficient mice can be corrected by enhancing the glycolytic flux via pharmacological Akt or AMPK activation, thus providing a molecular platform for the therapeutic control of EB response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-17329-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367815PMC
July 2020

Chronic glucokinase activator treatment activates liver Carbohydrate response element binding protein and improves hepatocyte ATP homeostasis during substrate challenge.

Diabetes Obes Metab 2020 11 7;22(11):1985-1994. Epub 2020 Jul 7.

Biosciences Institute, Newcastle University, Medical School, Newcastle upon Tyne, UK.

Aim: To test the hypothesis that glucokinase activators (GKAs) induce hepatic adaptations that alter intra-hepatocyte metabolite homeostasis.

Methods: C57BL/6 mice on a standard rodent diet were treated with a GKA (AZD1656) acutely or chronically. Hepatocytes were isolated from the mice after 4 or 8 weeks of treatment for analysis of cellular metabolites and gene expression in response to substrate challenge.

Results: Acute exposure of mice to AZD1656 or a liver-selective GKA (PF-04991532), before a glucose tolerance test, or challenge of mouse hepatocytes with GKAs ex vivo induced various Carbohydrate response element binding protein (ChREBP) target genes, including Carbohydrate response element binding protein beta isoform (ChREBP-β), Gckr and G6pc. Both glucokinase activation and ChREBP target gene induction by PF-04991532 were dependent on the chirality of the molecule, confirming a mechanism linked to glucokinase activation. Hepatocytes from mice treated with AZD1656 for 4 or 8 weeks had lower basal glucose 6-phosphate levels and improved ATP homeostasis during high substrate challenge. They also had raised basal ChREBP-β mRNA and AMPK-α mRNA (Prkaa1, Prkaa2) and progressively attenuated substrate induction of some ChREBP target genes and Prkaa1 and Prkaa2.

Conclusions: Chronic GKA treatment of C57BL/6 mice for 8 weeks activates liver ChREBP and improves the resilience of hepatocytes to compromised ATP homeostasis during high-substrate challenge. These changes are associated with raised mRNA levels of ChREBP-β and both catalytic subunits of AMP-activated protein kinase.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dom.14111DOI Listing
November 2020

Context-dependent odor learning requires the anterior olfactory nucleus.

Behav Neurosci 2020 Aug 7;134(4):332-343. Epub 2020 May 7.

Department of Neurobiology and Behavior.

Learning to associate the context in which a stimulus occurs is an important aspect of animal learning. We propose that the association of an olfactory stimulus with its multisensory context is mediated by projections from ventral hippocampus (vHC) networks to the anterior olfactory nucleus (AON). Using a contextually cued olfactory discrimination task, rats were trained to associate 2 olfactory stimuli with different responses depending on visuospatial context. Temporary lesions of the AON or vHC impaired performance on this task. In contrast, such lesions did not impair performance on a noncontextual olfactory discrimination task. Moreover, vHC lesions also impaired performance on an analogous contextually cued texture discrimination task, whereas AON lesions affected only olfactory contextual associations. We describe a distinct role for the AON in olfactory processing and conclude that early olfactory networks such as the olfactory bulb and AON function as multimodal integration networks rather than processing olfactory signals exclusively. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1037/bne0000371DOI Listing
August 2020

Charge-Shifting Polycations Based on ,-(dimethylamino)ethyl Acrylate for Improving Cytocompatibility During DNA Delivery.

ACS Omega 2020 Apr 16;5(16):9114-9122. Epub 2020 Apr 16.

Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario L8S 4L8, Canada.

Synthetic polycations are studied extensively as DNA delivery agents because of their ease of production, good chemical stability, and low cost relative to viral vectors. This report describes the synthesis of charge-shifting polycations based on ,-(dimethylamino)ethyl acrylate (DMAEA) and 3-aminopropylmethacryamide (APM), called PAD copolymers, and their use for DNA delivery into HeLa cells. PAD copolymers of varying compositions were prepared by RAFT polymerization to yield polymers of controlled molecular weights with low dispersities. Model hydrolysis studies were carried out to assess the rate of charge-shifting of the polycations by loss of the cationic dimethylaminoethanol side chains. They showed reduction in the net cationic charge by about 10-50% depending on composition after 2 days at pH 7, forming polyampholytes comprising permanent cationic groups, residual DMAEA, as well as anionic acrylic acid groups. HeLa cells exposed for 4 h to PAD copolymers with the greatest charge-shifting ability showed comparable or higher viability at high concentrations, relative to the noncharge shifting polycations PAPM and polyethyleneimine (PEI) 2 days post-exposure. Cell uptake efficiency of PAD/60bp-Cy3 DNA polyplexes at 2.5:1 N/P ratio was very high (>95%) for all compositions, exceeding the uptake efficiency of PEI polyplexes of equivalent composition. These results suggest that these PAD copolymers, and in particular PAD containing 80 mol % DMAEA, have suitable rates of charge-shifting hydrolysis for DNA delivery, as PAD showed reduced cytotoxicity at high concentrations, while still retaining high uptake efficiencies. In addition, the polyampholytes formed during DMAEA hydrolysis in PAD copolymers can offer enhanced long-term cytocompatibility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsomega.9b03734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191589PMC
April 2020

Inhibition of the prostaglandin D-GPR44/DP2 axis improves human islet survival and function.

Diabetologia 2020 07 29;63(7):1355-1367. Epub 2020 Apr 29.

Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Peppredsleden 1, 431 83 Mölndal, Gothenburg, Sweden.

Aims/hypothesis: Inflammatory signals and increased prostaglandin synthesis play a role during the development of diabetes. The prostaglandin D (PGD) receptor, GPR44/DP2, is highly expressed in human islets and activation of the pathway results in impaired insulin secretion. The role of GPR44 activation on islet function and survival rate during chronic hyperglycaemic conditions is not known. In this study, we investigate GPR44 inhibition by using a selective GPR44 antagonist (AZ8154) in human islets both in vitro and in vivo in diabetic mice transplanted with human islets.

Methods: Human islets were exposed to PGD or proinflammatory cytokines in vitro to investigate the effect of GPR44 inhibition on islet survival rate. In addition, the molecular mechanisms of GPR44 inhibition were investigated in human islets exposed to high concentrations of glucose (HG) and to IL-1β. For the in vivo part of the study, human islets were transplanted under the kidney capsule of immunodeficient diabetic mice and treated with 6, 60 or 100 mg/kg per day of a GPR44 antagonist starting from the transplantation day until day 4 (short-term study) or day 17 (long-term study) post transplantation. IVGTT was performed on mice at day 10 and day 15 post transplantation. After termination of the study, metabolic variables, circulating human proinflammatory cytokines, and hepatocyte growth factor (HGF) were analysed in the grafted human islets.

Results: PGD or proinflammatory cytokines induced apoptosis in human islets whereas GPR44 inhibition reversed this effect. GPR44 inhibition antagonised the reduction in glucose-stimulated insulin secretion induced by HG and IL-1β in human islets. This was accompanied by activation of the Akt-glycogen synthase kinase 3β signalling pathway together with phosphorylation and inactivation of forkhead box O-1and upregulation of pancreatic and duodenal homeobox-1 and HGF. Administration of the GPR44 antagonist for up to 17 days to diabetic mice transplanted with a marginal number of human islets resulted in reduced fasting blood glucose and lower glucose excursions during IVGTT. Improved glucose regulation was supported by increased human C-peptide levels compared with the vehicle group at day 4 and throughout the treatment period. GPR44 inhibition reduced plasma levels of TNF-α and growth-regulated oncogene-α/chemokine (C-X-C motif) ligand 1 and increased the levels of HGF in human islets.

Conclusions/interpretation: Inhibition of GPR44 in human islets has the potential to improve islet function and survival rate under inflammatory and hyperglycaemic stress. This may have implications for better survival rate of islets following transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00125-020-05138-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286861PMC
July 2020

Identification of Small-Molecule Positive Modulators of Calcitonin-like Receptor-Based Receptors.

ACS Pharmacol Transl Sci 2020 Apr 12;3(2):305-320. Epub 2020 Mar 12.

School of Biological Sciences, University of Auckland, Auckland 1010, New Zealand.

Class B G protein-coupled receptors are highly therapeutically relevant but challenges remain in identifying suitable small-molecule drugs. The calcitonin-like receptor (CLR) in particular is linked to conditions such as migraine, cardiovascular disease, and inflammatory bowel disease. The CLR cannot act as a cell-surface receptor alone but rather must couple to one of three receptor activity-modifying proteins (RAMPs), forming heterodimeric receptors for the peptides adrenomedullin and calcitonin gene-related peptide. These peptides have extended binding sites across their receptors. This is one reason why there are few small-molecule ligands that can modulate these receptors. Here we describe small molecules that are able to positively modulate the signaling of the CLR with all three RAMPs but are not active at the related calcitonin receptor. These compounds were selected from a β-arrestin recruitment screen, coupled with rounds of medicinal chemistry to improve their activity. Translational potential is shown as the compounds can positively modulate cAMP signaling in a vascular cell line model. Binding experiments do not support an extracellular domain binding site; however, molecular modeling reveals potential allosteric binding sites in multiple receptor regions. These are the first small-molecule positive modulators described for the CLR:RAMP complexes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsptsci.9b00108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155196PMC
April 2020

Cryopreservation of DNA Origami Nanostructures.

Small 2020 04 4;16(13):e1905959. Epub 2020 Mar 4.

Technical and Macromolecular Chemistry, Paderborn University, Warburger Str. 100, 33098, Paderborn, Germany.

Although DNA origami nanostructures have found their way into numerous fields of fundamental and applied research, they often suffer from rather limited stability when subjected to environments that differ from the employed assembly conditions, that is, suspended in Mg -containing buffer at moderate temperatures. Here, means for efficient cryopreservation of 2D and 3D DNA origami nanostructures and, in particular, the effect of repeated freezing and thawing cycles are investigated. It is found that, while the 2D DNA origami nanostructures maintain their structural integrity over at least 32 freeze-thaw cycles, ice crystal formation makes the DNA origami gradually more sensitive toward harsh sample treatment conditions. Whereas no freeze damage could be detected in 3D DNA origami nanostructures subjected to 32 freeze-thaw cycles, 1000 freeze-thaw cycles result in significant fragmentation. The cryoprotectants glycerol and trehalose are found to efficiently protect the DNA origami nanostructures against freeze damage at concentrations between 0.2 × 10 and 200 × 10 m and without any negative effects on DNA origami shape. This work thus provides a basis for the long-term storage of DNA origami nanostructures, which is an important prerequisite for various technological and medical applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/smll.201905959DOI Listing
April 2020

Phenotypic high-throughput screening platform identifies novel chemotypes for necroptosis inhibition.

Cell Death Discov 2020 11;6. Epub 2020 Feb 11.

1Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal.

Regulated necrosis or necroptosis, mediated by receptor-interacting kinase 1 (RIPK1), RIPK3 and pseudokinase mixed lineage kinase domain-like protein (MLKL), contributes to the pathogenesis of inflammatory, infectious and degenerative diseases. Recently identified necroptosis inhibitors display moderate specificity, suboptimal pharmacokinetics, off-target effects and toxicity, preventing these molecules from reaching the clinic. Here, we developed a cell-based high-throughput screening (HTS) cascade for the identification of small-molecule inhibitors of necroptosis. From the initial library of over 250,000 compounds, the primary screening phase identified 356 compounds that strongly inhibited TNF-α-induced necroptosis, but not apoptosis, in human and murine cell systems, with EC < 6.7 μM. From these, 251 compounds were tested for RIPK1 and/or RIPK3 kinase inhibitory activity; some were active and several have novel mechanisms of action. Based on specific chemical descriptors, 110 compounds proceeded into the secondary screening cascade, which then identified seven compounds with maximum ability to reduce MLKL activation, IC >100 μM, EC 2.5-11.5 μM under long-term necroptosis execution in murine fibroblast L929 cells, and full protection from ATP depletion and membrane leakage in human and murine cells. As a proof of concept, compound SN-6109, with binding mode to RIPK1 similar to that of necrostatin-1, confirmed RIPK1 inhibitory activity and appropriate pharmacokinetic properties. SN-6109 was further tested in mice, showing efficacy against TNF-α-induced systemic inflammatory response syndrome. In conclusion, a phenotypic-driven HTS cascade promptly identified robust necroptosis inhibitors with in vivo activity, currently undergoing further medicinal chemistry optimization. Notably, the novel hits highlight the opportunity to identify new molecular mechanisms of action in necroptosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41420-020-0240-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026080PMC
February 2020

Incidental giant cystic pheochromocytoma: a case report and review of the literature.

Scott Med J 2020 May 13;65(2):64-70. Epub 2020 Jan 13.

Consultant Surgeon, Department of General Surgery, Ninewells Hospital, UK.

Introduction: Pheochromocytoma is a tumour arising from the adrenal medulla, which secretes catecholamines. Approximately 20% of pheochromocytomas are cystic and more likely to be asymptomatic. They should be surgically resected as all have a malignant potential and pose cardiovascular risk. We report the case of a 61-year-old female patient admitted electively for laparoscopic adrenalectomy for a large cystic pheochromocytoma detected incidentally. Diagnosis was confirmed preoperatively by elevated 24-h urinary metanephrines. The patient was treated preoperatively with alpha and beta blockade. Surgery was without complication; she had an uneventful postoperative recovery and no evidence of recurrence at one-year follow-up.

Conclusion: This case highlights the necessity of investigating for biochemical function in all adrenal lesions by measuring metanephrines, even when entirely cystic on imaging. Given the surgical and anaesthetic risk in resection of pheochromocytoma, attaining a preoperative diagnosis allows for careful preoperative planning and safe surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0036933019900339DOI Listing
May 2020

Healthcare Costs of Potential Glucocorticoid-Associated Adverse Events in Patients with Giant Cell Arteritis.

Clinicoecon Outcomes Res 2019 23;11:799-807. Epub 2019 Dec 23.

Genentech, Inc., South San Francisco, CA, USA.

Objective: To quantify the healthcare expenditures associated with potential oral glucocorticoid (OGC)-related adverse events (AEs) in patients with giant cell arteritis (GCA).

Methods: Patients with GCA and ≥ 1 OGC prescription fill between 2009 and 2014 were identified from the MarketScan Commercial and Medicare Supplemental claims databases. Patients were stratified into four groups based on cumulative OGC dose (> 0 to ≤ 2607 mg, > 2607 to ≤ 4800 mg, > 4800 to ≤ 7200 mg, and > 7200 mg) during the 1-year follow-up period; incidence of potential AEs and AE-related direct healthcare costs in USD were assessed. Association between the log of cumulative OGC dose and AE-related direct healthcare costs was evaluated, adjusting for baseline characteristics.

Results: Of 1602 patients with GCA included, 69% were women; the mean age was 73 years. The mean cumulative OGC dose was 5806 mg during the 1-year follow-up; most exposure occurred in the first 6 months. The proportion of patients with potential OGC-related AEs was 36.5% overall and increased as cumulative dose increased (30.7%-45.3% across dose groups). Unadjusted mean AE-related costs for patients with an AE was USD $12,818. In the multivariable model including all patients, increasing OGC dose was associated with increasing AE-related healthcare costs (cost ratio, 1.38 [95% CI, 1.16-1.64] per 1-unit increase in log of cumulative OGC dose [ < 0.001]). Mean (median)-predicted AE costs for the dose groups were USD $4389 ($2749) for > 0 to ≤ 2607 mg, USD $5176 ($3009) for > 2607 to ≤ 4800 mg, USD $5576 ($3633) for > 4800 to ≤ 7200 mg, and USD $6609 ($4447) for > 7200 mg.

Conclusion: In patients with GCA, OGC-related AEs increased with increasing cumulative OGC dose, resulting in increased healthcare costs. These results highlight the need for efficacious therapies that reduce the exposure to and potential risks associated with OGCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/CEOR.S228400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934125PMC
December 2019

Structural characterization of an ionic liquid in bulk and in nano-confined environment using data from MD simulations.

Data Brief 2020 Feb 23;28:104794. Epub 2019 Nov 23.

Group for Computational Life Sciences, Department of Physical Chemistry, Ruđer Bošković Institute, Bijenička 54, 10000, Zagreb, Croatia.

This article contains data on structural characterization of the [C2Mim][NTf2] in bulk and in nano-confined environment obtained using MD simulations. These data supplement those presented in the paper "Insights from Molecular Dynamics Simulations on Structural Organization and Diffusive Dynamics of an Ionic Liquid at Solid and Vacuum Interfaces" [1], where force fields with three different charge methods and three charge scaling factors were used for the analysis of the IL in the bulk, at the interface with the vacuum and the IL film in the contact with a hydroxylated alumina surface. Here, we present details on the construction of the model systems in an extended detailed methods section. Furthermore, for best parametrization, structural and dynamic properties of IL in different environment are studied with certain features presented herein.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dib.2019.104794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909096PMC
February 2020

Acetylation of Aβ Alters Aggregation in the Presence and Absence of Lipid Membranes.

ACS Chem Neurosci 2020 01 27;11(2):146-161. Epub 2019 Dec 27.

The C. Eugene Bennett Department of Chemistry , West Virginia University , 217 Clark Hall , Morgantown , West Virginia 26506 , United States.

A hallmark of Alzheimer's disease (AD) is the formation of senile plaques comprised of the β-amyloid (Aβ) peptide. Aβ fibrillization is a complex nucleation-dependent process involving a variety of metastable intermediate aggregates and features the formation of inter- and intramolecular salt bridges involving lysine residues, K16 and K28. Cationic lysine residues also mediate protein-lipid interactions via association with anionic lipid headgroups. As several toxic mechanisms attributed to Aβ involve membrane interactions, the impact of acetylation on Aβ aggregation in the presence and absence of membranes was determined. Using chemical acetylation, varying mixtures of acetylated and nonacetylated Aβ were produced. With increasing acetylation, fibril and oligomer formation decreased, eventually completely arresting fibrillization. In the presence of total brain lipid extract (TBLE) vesicles, acetylation reduced the interaction of Aβ with membranes; however, fibrils still formed at near complete levels of acetylation. Additionally, the combination of TBLE and acetylated Aβ promoted annular aggregates. Finally, toxicity associated with Aβ was reduced with increasing acetylation in a cell culture assay. These results suggest that in the absence of membranes that the cationic character of lysine plays a major role in fibril formation. However, acetylation promotes unique aggregation pathways in the presence of lipid membranes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acschemneuro.9b00483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477891PMC
January 2020

Hippocampal state transitions at the boundaries between trial epochs.

Hippocampus 2020 06 3;30(6):582-595. Epub 2019 Dec 3.

Department of Psychology, Cornell University, Ithaca, New York.

The hippocampus encodes distinct contexts with unique patterns of activity. Representational shifts with changes in context, referred to as remapping, have been extensively studied. However, less is known about transitions between representations. In this study, we leverage a large dataset of neuronal recordings taken while rats performed an olfactory memory task with a predictable temporal structure involving trials and intertrial intervals (ITIs), separated by salient boundaries at the trial start and trial end. We found that trial epochs were associated with stable hippocampal representations despite moment-to-moment variability in stimuli and behavior. Representations of trial and ITI epochs were far more distinct than spatial factors would predict and the transitions between the two were abrupt. The boundary was associated with a large spike in multiunit activity, with many individual cells specifically active at the start or end of each trial. Both epochs and boundaries were encoded by hippocampal populations, and these representations carried information on orthogonal axes readily identified using principal component analysis. We suggest that the hippocampus orthogonalizes representations of the trial and ITI epochs and the activity spike at trial boundaries might serve to drive hippocampal activity from one stable state to the other.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hipo.23180DOI Listing
June 2020

The medial prefrontal cortex is needed for resolving interference even when there are no changes in task rules and strategies.

Behav Neurosci 2020 Feb 2;134(1):15-20. Epub 2019 Dec 2.

Department of Psychology.

The prefrontal cortex (PFC) plays a key role in behavioral flexibility, and the ability to resolve conflict from shifting strategies, task rules or attentional demands seems to be a hallmark of PFC function. Conflict also occurs in the domain of memory and the PFC plays an important role in the ability to cope with interference between competing retrieval targets. Previous studies often involved both interference and changes in task demands, which makes it difficult to determine the degree to which mnemonic interference per se engages PFC processing. We trained rats on a continuous matching to sample task in two conditions that varied in terms of the amount of interference present but not the task demands and found that temporary inactivation of the medial PFC caused a greater impairment in the high-interference condition. This result suggests that the PFC plays an important role in resolving interference which can be distinguished from its role in shifting task demands. (PsycINFO Database Record (c) 2020 APA, all rights reserved).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1037/bne0000347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944745PMC
February 2020

Exploring Reactive Conformations of Coenzyme A during Binding and Unbinding to Pyruvate Formate-Lyase.

J Phys Chem A 2019 Oct 17;123(43):9345-9356. Epub 2019 Oct 17.

Group for Computational Life Sciences, Division for Physical Chemistry , Ruđer Bošković Institute , Bijenička cesta 54 , 10000 Zagreb , Croatia.

Pyruvate formate-lyase (PFL) is a glycyl radical enzyme that converts pyruvate and coenzyme A (CoA) into formate and acetyl-CoA in two half-reactions. Recently, we showed that the acetylation of the PFL active site in the first half-reaction induces subtle conformational changes, leading to the opening of a potential channel for CoA entry. Entry of CoA into the active site is crucial for the second half-reaction, involving the acetyl transfer to CoA, and the completion of the catalytic cycle. Using steered molecular dynamics (SMD) simulations, performed on acetylated and nonacetylated monomeric PFL model systems, we first of all investigate the possible entry/exit pathways of CoA with respect to the active site through the previously identified channel. We then perform umbrella sampling simulations on multiple snapshots from SMD trajectories as well as unrestrained molecular dynamics simulations starting from the final structures obtained from entry SMD, with a view to identifying possible bound states of CoA in the near vicinity of the active site. Detailed study of the unrestrained dissociation processes reveals the presence of stable and reactive bound states of CoA close to the active site, one of which is in an ideal position for triggering the second half-reaction. Examination of the spatial distributions associated with the reactive bound states allows us to discuss the free energy barriers. Umbrella sampling, performed on snapshots from unrestrained dynamics confirms the above findings. The significance of the results for the catalysis are discussed for both acetylated and nonacetylated systems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jpca.9b06913DOI Listing
October 2019

Correction: The role of stickiness in the rheology of semiflexible polymers.

Soft Matter 2019 Oct 2;15(40):8184. Epub 2019 Oct 2.

Peter Debye Institute for Soft Matter Physics, University of Leipzig, 04103 Leipzig, Germany. and Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany.

Correction for 'The role of stickiness in the rheology of semiflexible polymers' by Tom Golde et al., Soft Matter, 2019, 15, 4865-4872.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c9sm90200gDOI Listing
October 2019

Exercise training prevents the perivascular adipose tissue-induced aortic dysfunction with metabolic syndrome.

Redox Biol 2019 09 26;26:101285. Epub 2019 Jul 26.

Division of Exercise Physiology, WVU School of Medicine, Morgantown, WV, USA; Department of Neuroscience, WVU School of Medicine, Morgantown, WV, USA. Electronic address:

The aim of the study was to determine the effects of exercise training on improving the thoracic perivascular adipose tissue (tPVAT) phenotype (inflammation, oxidative stress, and proteasome function) in metabolic syndrome and its subsequent actions on aortic function.

Methods: Lean and obese (model of metabolic syndrome) Zucker rats (n=8/group) underwent 8-weeks of control conditions or treadmill exercise (70% of max speed, 1 h/day, 5 days/week). At the end of the intervention, the tPVAT was removed and conditioned media was made. The cleaned aorta was attached to a force transducer to assess endothelium-dependent and independent dilation in the presence or absence of tPVAT-conditioned media. tPVAT gene expression, inflammatory /oxidative phenotype, and proteasome function were assessed.

Results: The main findings were that Ex induced: (1) a beige-like, anti-inflammatory tPVAT phenotype; (2) a greater abundance of NO in tPVAT; (3) a reduction in tPVAT oxidant production; and (4) an improved tPVAT proteasome function. Regarding aortic function, endothelium-dependent dilation was greater in exercised lean and obese groups vs. controls (p < 0.05). Lean control tPVAT improved aortic relaxation, whereas obese control tPVAT decreased aortic relaxation. In contrast, the obese Ex-tPVAT increased aortic dilation, whereas the lean Ex-tPVAT did not affect aortic dilation.

Conclusion: Overall, exercise had the most dramatic impact on the obese tPVAT reflecting a change towards an environment with less oxidant load, less inflammation and improved proteasome function. Such beneficial changes to the tPVAT micro-environment with exercise likely played a significant role in mediating the improvement in aortic function in metabolic syndrome following 8 weeks of exercise.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.redox.2019.101285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669320PMC
September 2019

Effect of Staple Age on DNA Origami Nanostructure Assembly and Stability.

Molecules 2019 Jul 16;24(14). Epub 2019 Jul 16.

Technical and Macromolecular Chemistry, Paderborn University, Warburger Str. 100, 33098 Paderborn, Germany.

DNA origami nanostructures are widely employed in various areas of fundamental and applied research. Due to the tremendous success of the DNA origami technique in the academic field, considerable efforts currently aim at the translation of this technology from a laboratory setting to real-world applications, such as nanoelectronics, drug delivery, and biosensing. While many of these real-world applications rely on an intact DNA origami shape, they often also subject the DNA origami nanostructures to rather harsh and potentially damaging environmental and processing conditions. Furthermore, in the context of DNA origami mass production, the long-term storage of DNA origami nanostructures or their pre-assembled components also becomes an issue of high relevance, especially regarding the possible negative effects on DNA origami structural integrity. Thus, we investigated the effect of staple age on the self-assembly and stability of DNA origami nanostructures using atomic force microscopy. Different harsh processing conditions were simulated by applying different sample preparation protocols. Our results show that staple solutions may be stored at -20 °C for several years without impeding DNA origami self-assembly. Depending on DNA origami shape and superstructure, however, staple age may have negative effects on DNA origami stability under harsh treatment conditions. Mass spectrometry analysis of the aged staple mixtures revealed no signs of staple fragmentation. We, therefore, attribute the increased DNA origami sensitivity toward environmental conditions to an accumulation of damaged nucleobases, which undergo weaker base-pairing interactions and thus lead to reduced duplex stability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules24142577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6680526PMC
July 2019

Effect of Staple Age on DNA Origami Nanostructure Assembly and Stability.

Molecules 2019 Jul 16;24(14). Epub 2019 Jul 16.

Technical and Macromolecular Chemistry, Paderborn University, Warburger Str. 100, 33098 Paderborn, Germany.

DNA origami nanostructures are widely employed in various areas of fundamental and applied research. Due to the tremendous success of the DNA origami technique in the academic field, considerable efforts currently aim at the translation of this technology from a laboratory setting to real-world applications, such as nanoelectronics, drug delivery, and biosensing. While many of these real-world applications rely on an intact DNA origami shape, they often also subject the DNA origami nanostructures to rather harsh and potentially damaging environmental and processing conditions. Furthermore, in the context of DNA origami mass production, the long-term storage of DNA origami nanostructures or their pre-assembled components also becomes an issue of high relevance, especially regarding the possible negative effects on DNA origami structural integrity. Thus, we investigated the effect of staple age on the self-assembly and stability of DNA origami nanostructures using atomic force microscopy. Different harsh processing conditions were simulated by applying different sample preparation protocols. Our results show that staple solutions may be stored at -20 °C for several years without impeding DNA origami self-assembly. Depending on DNA origami shape and superstructure, however, staple age may have negative effects on DNA origami stability under harsh treatment conditions. Mass spectrometry analysis of the aged staple mixtures revealed no signs of staple fragmentation. We, therefore, attribute the increased DNA origami sensitivity toward environmental conditions to an accumulation of damaged nucleobases, which undergo weaker base-pairing interactions and thus lead to reduced duplex stability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules24142577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6680526PMC
July 2019

Insights from molecular dynamics simulations on structural organization and diffusive dynamics of an ionic liquid at solid and vacuum interfaces.

J Colloid Interface Sci 2019 Oct 6;553:350-363. Epub 2019 Jun 6.

Group of Computational Life Sciences, Department of Physical Chemistry, Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia; PULS Group, Center for Nanostructured Films, Department of Physics, FAU Erlangen-Nürnberg, Cauerstraße 3, 91058, Erlangen, Germany. Electronic address:

Hypothesis: A reliable modelling approach is required for simultaneous characterisation of static and dynamic properties of bulk and interfacial ionic liquids (ILs). This is a prerequisite for a successful investigation of experimentally inaccessible, yet important properties, including those that change significantly with the distance from both vacuum and solid interfaces.

Simulations: We perform molecular dynamics simulations of bulk [CMim][NTf], and thick IL films in contact with vacuum and hydroxylated sapphire surface, using the charge methods CHelpG, RESP-HF and RESP-B3LYP with charge scaling factors 1.0, 0.9 and 0.85.

Findings: By determining and employing appropriate system sizes and simulations lengths, and by benchmarking against self-diffusion coefficients, surface tension, X-ray reflectivity, and structural data, we identify RESP-HF/0.9 as the best non-polarizable force field for this IL. We use this optimal parametrisation to predict novel physical properties of confined IL films. First we fully characterise the internal configurations and orientations of IL molecules relative to, and as a function of the distance from the solid and vacuum interfaces. Second, we evaluate densities together with mobilities in-plane and normal to the interfaces and find that strong correlations between the IL's stratification and diffusive transport in the interfacial layers persist for several nanometres deep into IL films.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcis.2019.06.017DOI Listing
October 2019

Water balloon-induced orbital fracture in an aviator.

Mil Med Res 2019 06 11;6(1):17. Epub 2019 Jun 11.

Flight and Operational Medical Clinic, 5th Medical Group, 194 Missilie Ave, Minot AFB, ND, Minot, 58705, USA.

Background: Orbital fractures are common injuries found in facial trauma. Typical etiologies of orbital fractures include motor vehicle collisions and assault. We report the case of a 32-year-old male who suffered an orbital fracture from a water balloon. Additionally, we describe the aeromedical complications that may result from this injury. Finally, we attempt to answer the question of when a patient may return to flying after sustaining such an injury through review of the literature.

Case Presentation: A 32-year-old male pilot with the United States Air Force was at an outdoor event with his unit when he was struck with a water balloon launched from a sling shot into his left orbit. Shortly afterwards, he had an onset of subcutaneous emphysema and was escorted to a nearby Emergency Department. Computed tomography identified an orbital fracture with associated orbital and subcutaneous emphysema. The patient was evaluated by a plastic surgeon and was determined not to be a surgical candidate. Four weeks later, he returned to flying status.

Conclusions: Water balloons are thought to be safe and harmless toys. However, when coupled with slingshots, water balloons can become formidable projectiles capable of significant orbital injury including orbital fractures. These injuries are concerning to aviators, as the most common sites for fractures of the orbit are the thin ethmoid and maxillary bones adjacent to the sinuses. At altitude, gases in the sinuses may expand and enter the orbit through these fractures, which may suddenly incapacitate the flyer. It is important for flight surgeons to identify and assess these individuals to determine suitability for flying.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40779-019-0210-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558684PMC
June 2019

Retrosplenial Cortical Representations of Space and Future Goal Locations Develop with Learning.

Curr Biol 2019 06 6;29(12):2083-2090.e4. Epub 2019 Jun 6.

Department of Psychology, Cornell University, Ithaca, NY 14853, USA.

Recent findings suggest that long-term spatial and contextual memories depend on the retrosplenial cortex (RSC) [1-5]. RSC damage impairs navigation in humans and rodents [6-8], and the RSC is closely interconnected with brain regions known to play a role in navigation, including the hippocampus and anterior thalamus [9, 10]. Navigation-related neural activity is seen in humans [11] and rodents, including spatially localized firing [12, 13], directional firing [12, 14, 15], and responses to navigational cues [16]. RSC neuronal activity is modulated by allocentric, egocentric, and route-centered spatial reference frames [17, 18], consistent with an RSC role in integrating different kinds of navigational information [19]. However, the relationship between RSC firing patterns and spatial memory remains largely unexplored, as previous physiology studies have not employed behavioral tasks with a clear memory demand. To address this, we trained rats on a continuous T-maze alternation task and examined RSC firing patterns throughout learning. We found that the RSC developed a distributed population-level representation of the rat's spatial location and current trajectory to the goal as the rats learned. After the rats reached peak performance, RSC firing patterns began to represent the upcoming goal location as the rats approached the choice point. These neural simulations of the goal emerged at the same time that lesions impaired alternation performance, suggesting that the RSC gradually acquired task representations that contribute to navigational decision-making.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cub.2019.05.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637961PMC
June 2019

The role of stickiness in the rheology of semiflexible polymers.

Soft Matter 2019 Jun;15(24):4865-4872

Peter Debye Institute for Soft Matter Physics, University of Leipzig, 04103 Leipzig, Germany.

Semiflexible polymers form central structures in biological material. Modelling approaches usually neglect influences of polymer-specific molecular features aiming to describe semiflexible polymers universally. Here, we investigate the influence of molecular details on networks assembled from filamentous actin, intermediate filaments, and synthetic DNA nanotubes. In contrast to prevalent theoretical assumptions, we find that bulk properties are affected by various inter-filament interactions. We present evidence that these interactions can be merged into a single parameter in the frame of the glassy wormlike chain model. The interpretation of this parameter as a polymer specific stickiness is consistent with observations from macro-rheological measurements and reptation behaviour. Our findings demonstrate that stickiness should generally not be ignored in semiflexible polymer models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c9sm00433eDOI Listing
June 2019

Resolution of protein hydrogen/deuterium exchange by fitting amide exchange probabilities to the peptide isotopic envelopes.

Rapid Commun Mass Spectrom 2019 Aug;33(15):1248-1257

Department of Physical Chemistry, Institute "Ruđer Bošković", HR-10002, Zagreb, Croatia.

Rationale: Mass spectra processing in protein hydrogen/deuterium (H/D) exchange has been remarkably improved by the introduction of fitting of the amide exchange probabilities to peptide isotopic envelope intensities (Kan et al., 2013), in contrast to methods in which only the peptide deuterium uptakes (centroid shifts of isotopic envelopes) are used. However, the known implementations are based on the general fitting routines that use only the objective function values. Besides, applicability of more than one fitting method makes necessary their comparative evaluation.

Methods: Two fitting methods were considered: the common least squares and the fitting of the multinomial distribution representing the number of deuterium atoms exchanged in the individual peptides. Both methods were applied either directly to the isotopic envelope data or to the deuterium distributions obtained by envelope deconvolution (i.e. de-isotoping).

Results: An autonomous Matlab script was prepared, based on the exact expressions for the gradient and Hessian of the objective function, with the trust-region algorithm implemented in the compact analytical form recently made available. The least-squares fitting to the envelope data produced the best results, with the greatest precision and good coverage of exact values by the confidence intervals. The deuterium distributions were sensitive to the (simulated) experimental error whose progression by envelope deconvolution caused degradation in accuracy. The multinomial distribution fitting exhibited poor performance due to inadequate representation of the experimental error and missing of the appropriate weight parameters. Some specific peptide arrangement details were discussed as potential sources of ambiguity in the fitting results.

Conclusions: The method of fitting to peptide isotopic envelopes has been improved by using the exact gradient and Hessian of the objective function. The fitting should be repeated with different initial guesses in order to find not only the global minimum, but also the local minima with similar depths which may exist due to eventual ambiguity of the fitting results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/rcm.8460DOI Listing
August 2019

Economic Impact of Adherence to Pain Treatment Guidelines in Chronic Pain Patients.

Pain Med 2019 10;20(10):1907-1918

Pfizer Inc, New York, New York, USA.

Objectives: This research compared health care resource use (HCRU) and costs for pharmacotherapy prescribing that was adherent vs nonadherent to published pain management guidelines. Conditions included osteoarthritis (OA) and gout (GT) for nociceptive/inflammatory pain, painful diabetic peripheral neuropathy (pDPN) and post-herpetic neuralgia (PHN) for neuropathic pain, and fibromyalgia (FM) for sensory hypersensitivity pain.

Methods: This retrospective cohort study used claims from MarketScan Commercial and Medicare Databases identifying adults newly diagnosed with OA, GT, pDPN, PHN, or FM during July 1, 2006, to June 30, 2013, with 12-month continuous coverage before and after initial (index) diagnosis. Patients were grouped according to their pharmacotherapy pattern as adherent, nonadherent, or "unsure" according to published pain management guidelines using a claims-based algorithm. Adherent and nonadherent populations were compared descriptively and using multivariate statistical analyses for controlling bias.

Results: Final cohort sizes were 441,465 OA, 76,361 GT, 10,645 pDPN, 4,010 PHN, and 150,321 FM, with adherence to guidelines found in 51.1% of OA, 25% of GT, 59.5% of pDPN, 54.9% of PHN, and 33.5% of FM. Adherent cohorts had significantly (P < 0.05) fewer emergency department (ED) visits and lower proportions with hospitalizations or ED visits. Mean health care costs increased following diagnosis across all conditions; however, adherent cohorts had significantly lower increases in adjusted costs pre-index to postindex (OA $5,286 vs $9,532; GT $3,631 vs $7,873; pDPN $9,578 vs $16,337; PHN $2,975 vs $5,146; FM $2,911 vs $3,708; all P < 0.001; adherent vs nonadherent, respectively).

Conclusions: Adherence to pain management guidelines was associated with significantly lower HCRU and costs compared with nonadherence to guidelines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/pm/pnz085DOI Listing
October 2019