Publications by authors named "Kevin Stewart"

50 Publications

Mice with Brain-Specific Deletion of Hsd11b2 have an impaired renal vascular and tubular response to high salt intake.

FASEB J 2022 May;36 Suppl 1

Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh.

Loss-of-function mutations in Hsd11b2, the gene encoding the cortisol-metabolising enzyme 11βHSD2, causes the hypertensive syndrome of Apparent Mineralocorticoid Excess. In affected individuals, overactivation of the mineralocorticoid receptor by cortisol is causative. Hypertension is salt-sensitive, attributed to enhanced sodium reabsorption in the distal nephron and renal sodium retention. However, in the brain, 11βHSD2-expressing neurons regulate salt appetite. We previously generated mice with conditional knockout of Hsd11b2 in the brain (Hsd11b2.BKO), which displayed enhanced salt preference and salt-sensitive hypertension (DOI: 10.1161/CIRCULATIONAHA.115.019341). The mechanisms of salt-sensitivity are unknown. In the current study we examined renal artery vasoreactivity and the in vivo acute pressure natriuresis response in male Hsd11b2.BKO mice and control littermates. Mice (n=10 per genotype/diet) were fed either high salt (3% Na) or 0.3% Na diet for 7 days. Animals were humanely killed, the renal arteries were isolated and mounted on a wire-myograph to generate cumulative concentration-response curves to phenylephrine and the nitric oxide donor, sodium nitroprusside. High salt diet significantly increased the sensitivity of the renal artery to phenylephrine-induced vasoconstriction in Hsd11b2.BKO mice (LogEC50 0.3% diet -6.41±0.07 vs high salt -6.91±0.11; p=0.0013) but not in control mice. Sodium nitroprusside induced concentration-dependent relaxation of renal arteries: the maximum relaxation was significantly reduced from 88±3% to 65±4% in Hsd11b2.BKO after high salt feeding (p<0.01); this was not seen in control mice. In other experiments, mice (n=5-7 per genotype/diet) were anesthetised (thiobutabarbital sodium, 120mg/kg IP) and fractional renal sodium excretion was measured at baseline and following acutely increased blood pressure, achieved by sequential arterial ligation. In all mice, sodium excretion increased with blood pressure. In the high salt group, the pressure natriuresis response was significantly attenuated in Hsd11b2.BKO mice, compared to control animals. We find that genetic amplification of mineralocorticoid signalling in the brain attenuates the normal renal vascular and tubular adaptation to high salt intake. This regulation of renal salt excretion by the central nervous system may have implications for salt-sensitive hypertension in humans.
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http://dx.doi.org/10.1096/fasebj.2022.36.S1.R5176DOI Listing
May 2022

Systems-based investigation of patient safety incidents.

Future Healthc J 2021 Nov;8(3):e593-e597

Healthcare Safety Investigation Branch, Farnborough, UK.

Patient safety events are common in healthcare. We can learn from other safety-critical industries that further incidents are most likely to be prevented where lessons are learned at the system level rather than looking to attribute blame for errors to individuals. Progress has been made over the last 20 years and relies on a positive safety culture (or just culture) where staff trust organisations to investigate safety events for learning rather than blame. Systems-based investigation models, such as the Systems Engineering Initiative for Patient Safety (SEIPS), help investigators to consider the full range of contributory factors across a system and to identify important findings. Considering the hierarchy of controls, recommendations should be targeted at system changes which are more likely to produce sustained safety improvements, rather than at individual behaviours or training, which are less likely to influence future safety. Systems-based safety investigations can positively influence safety culture in organisations.
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http://dx.doi.org/10.7861/fhj.2021-0147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8651333PMC
November 2021

Plurality of governance - plurality of systems.

J R Coll Physicians Edinb 2021 Dec;51(4):424-3427

Healthcare Safety Investigation Branch, Farnborough, UK.

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http://dx.doi.org/10.4997/JRCPE.2021.431DOI Listing
December 2021

Single-cell RNA-seq profiling of mouse endothelial cells in response to pulmonary arterial hypertension.

Cardiovasc Res 2021 Sep 16. Epub 2021 Sep 16.

The Queen's Medical Research Institute, Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, EH16 4TJ, UK.

Aims: Endothelial cell dysfunction drives the initiation and pathogenesis of pulmonary arterial hypertension (PAH). We aimed to characterise endothelial cell (EC) dynamics in PAH at single-cell resolution.

Methods And Results: We carried out single-cell RNA sequencing (scRNA-seq) of lung ECs isolated from an EC lineage-tracing mouse model in Control and SU5416/Hypoxia-induced PAH conditions. EC populations corresponding to distinct lung vessel types, including two discrete capillary populations, were identified in both Control and PAH mice. Differential gene expression analysis revealed global PAH-induced EC changes that were confirmed by bulk RNA-seq. This included upregulation of the major histocompatibility complex class II pathway, supporting a role for ECs in the inflammatory response in PAH. We also identified a PAH response specific to the second capillary EC population including upregulation of genes involved in cell death, cell motility and angiogenesis. Interestingly, four genes with genetic variants associated with PAH were dysregulated in mouse ECs in PAH. To compare relevance across PAH models and species, we performed a detailed analysis of EC heterogeneity and response to PAH in rats and humans through whole-lung PAH scRNA-seq datasets, revealing that 51% of up-regulated mouse genes were also up-regulated in rat or human PAH. We identified promising new candidates to target endothelial dysfunction including CD74, the knockdown of which regulates EC proliferation and barrier integrity in vitro. Finally, with an in silico cell ordering approach, we identified zonation-dependent changes across the arteriovenous axis in mouse PAH and showed upregulation of the Serine/threonine-protein kinase Sgk1 at the junction between the macro- and micro-vasculature.

Conclusions: This study uncovers PAH-induced EC transcriptomic changes at a high resolution, revealing novel targets for potential therapeutic candidate development.
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http://dx.doi.org/10.1093/cvr/cvab296DOI Listing
September 2021

Activation of the Sympathetic Nervous System Promotes Blood Pressure Salt-Sensitivity in C57BL6/J Mice.

Hypertension 2021 01 16;77(1):158-168. Epub 2020 Nov 16.

From the University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, The University of Edinburgh, United Kingdom.

Global salt intake averages >8 g/person per day, over twice the limit advocated by the American Heart Association. Dietary salt excess leads to hypertension, and this partly mediates its poor health outcomes. In ≈30% of people, the hypertensive response to salt is exaggerated. This salt-sensitivity increases cardiovascular risk. Mechanistic cardiovascular research relies heavily on rodent models and the C57BL6/J mouse is the most widely used reference strain. We examined the effects of high salt intake on blood pressure, renal, and vascular function in the most commonly used and commercially available C57BL6/J mouse strain. Changing from control (0.3% Na) to high salt (3% Na) diet increased systolic blood pressure in male mice by ≈10 mm Hg within 4 days of dietary switch. This hypertensive response was maintained over the 3-week study period. Returning to control diet gradually reduced blood pressure back to baseline. High-salt diet caused a rapid and sustained downregulation in mRNA encoding renal (sodium-hydrogen-exchanger 3) and (epithelial sodium channel), although we did not observe a suppression in aldosterone until ≈7 days. During the development of salt-sensitivity, the acute pressure natriuresis relationship was augmented and neutral sodium balance was maintained throughout. High-salt diet increased ex vivo sensitivity of the renal artery to phenylephrine and increased urinary excretion of adrenaline, but not noradrenaline. The acute blood pressure-depressor effect of hexamethonium, a ganglionic blocker, was enhanced by high salt. Salt-sensitivity in commercially sourced C57BL6/J mice is attributable to sympathetic overactivity, increased adrenaline, and enhanced vascular sensitivity to alpha-adrenoreceptor activation and not sodium retention or attenuation of the acute pressure natriuresis response.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720873PMC
January 2021

Kidney Single-Cell Atlas Reveals Myeloid Heterogeneity in Progression and Regression of Kidney Disease.

J Am Soc Nephrol 2020 12 25;31(12):2833-2854. Epub 2020 Sep 25.

Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

Background: Little is known about the roles of myeloid cell subsets in kidney injury and in the limited ability of the organ to repair itself. Characterizing these cells based only on surface markers using flow cytometry might not provide a full phenotypic picture. Defining these cells at the single-cell, transcriptomic level could reveal myeloid heterogeneity in the progression and regression of kidney disease.

Methods: Integrated droplet- and plate-based single-cell RNA sequencing were used in the murine, reversible, unilateral ureteric obstruction model to dissect the transcriptomic landscape at the single-cell level during renal injury and the resolution of fibrosis. Paired blood exchange tracked the fate of monocytes recruited to the injured kidney.

Results: A single-cell atlas of the kidney generated using transcriptomics revealed marked changes in the proportion and gene expression of renal cell types during injury and repair. Conventional flow cytometry markers would not have identified the 12 myeloid cell subsets. Monocytes recruited to the kidney early after injury rapidly adopt a proinflammatory, profibrotic phenotype that expresses , before transitioning to become macrophages that accumulate in late injury. Conversely, a novel macrophage subset acts during repair.

Conclusions: Complementary technologies identified novel myeloid subtypes, based on transcriptomics in single cells, that represent therapeutic targets to inhibit progression or promote regression of kidney disease.
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http://dx.doi.org/10.1681/ASN.2020060806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790206PMC
December 2020

Reducing transmission of SARS-CoV-2 in ophthalmology with nasal and oral decontamination.

Ther Adv Ophthalmol 2020 Jan-Dec;12:2515841420951392. Epub 2020 Aug 26.

ProHealth Ear Nose and Throat, Farmington, CT, USA.

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http://dx.doi.org/10.1177/2515841420951392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453452PMC
August 2020

Endothelin-1 Mediates the Systemic and Renal Hemodynamic Effects of GPR81 Activation.

Hypertension 2020 05 23;75(5):1213-1222. Epub 2020 Mar 23.

From the University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Scotland, United Kingdom (N.K.J., K.S., A.C., R.I.M., A.T., C.M.M., C.C., B.R.C., L.D., D.E.W.L., P.W.H., D.J.W., N.D., J.W.D., J.J.M., M.A.B.).

GPR81 (G-protein-coupled receptor 81) is highly expressed in adipocytes, and activation by the endogenous ligand lactate inhibits lipolysis. GPR81 is also expressed in the heart, liver, and kidney, but roles in nonadipose tissues are poorly defined. GPR81 agonists, developed to improve blood lipid profile, might also provide insights into GPR81 physiology. Here, we assessed the blood pressure and renal hemodynamic responses to the GPR81 agonist, AZ'5538. In male wild-type mice, intravenous AZ'5538 infusion caused a rapid and sustained increase in systolic and diastolic blood pressure. Renal artery blood flow, intrarenal tissue perfusion, and glomerular filtration rate were all significantly reduced. AZ'5538 had no effect on blood pressure or renal hemodynamics in mice. mRNA was expressed in renal artery vascular smooth muscle, in the afferent arteriole, in glomerular and medullary perivascular cells, and in pericyte-like cells isolated from kidney. Intravenous AZ'5538 increased plasma ET-1 (endothelin 1), and pretreatment with BQ123 (endothelin-A receptor antagonist) prevented the pressor effects of GPR81 activation, whereas BQ788 (endothelin-B receptor antagonist) did not. Renal ischemia-reperfusion injury, which increases renal extracellular lactate, increased the renal expression of genes encoding ET-1, KIM-1 (Kidney Injury Molecule 1), collagen type 1-α1, TNF-α (tumor necrosis factor-α), and F4/80 in wild-type mice but not in mice. In summary, activation of GPR81 in vascular smooth muscle and perivascular cells regulates renal hemodynamics, mediated by release of the potent vasoconstrictor ET-1. This suggests that lactate may be a paracrine regulator of renal blood flow, particularly relevant when extracellular lactate is high as occurs during ischemic renal disease.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.14308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176350PMC
May 2020

Camk2n1 Is a Negative Regulator of Blood Pressure, Left Ventricular Mass, Insulin Sensitivity, and Promotes Adiposity.

Hypertension 2019 09 22;74(3):687-696. Epub 2019 Jul 22.

From the MRC Institute of Genetics and Molecular Medicine, Edinburgh, United Kingdom (N.A., M.B., S.M.d.P., T.J.A., P.M.C.).

Metabolic syndrome is a cause of coronary artery disease and type 2 diabetes mellitus. Camk2n1 resides in genomic loci for blood pressure, left ventricle mass, and type 2 diabetes mellitus, and in the spontaneously hypertensive rat model of metabolic syndrome, Camk2n1 expression is cis-regulated in left ventricle and fat and positively correlates with adiposity. Therefore, we knocked out Camk2n1 in spontaneously hypertensive rat to investigate its role in metabolic syndrome. Compared with spontaneously hypertensive rat, Camk2n1 rats had reduced cardiorenal CaMKII (Ca/calmodulin-dependent kinase II) activity, lower blood pressure, enhanced nitric oxide bioavailability, and reduced left ventricle mass associated with altered hypertrophic networks. Camk2n1 deficiency reduced insulin resistance, visceral fat, and adipogenic capacity through the altered cell cycle and complement pathways, independent of CaMKII. In human visceral fat, CAMK2N1 expression correlated with adiposity and genomic variants that increase CAMK2N1 expression associated with increased risk of coronary artery disease and type 2 diabetes mellitus. Camk2n1 regulates multiple networks that control metabolic syndrome traits and merits further investigation as a therapeutic target in humans.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.12409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686962PMC
September 2019

Comprehensive transcriptome analysis and functional characterization of PR-5 for its involvement in tomato Sw-7 resistance to tomato spotted wilt tospovirus.

Sci Rep 2019 05 21;9(1):7673. Epub 2019 May 21.

USDA-Agricultural Research Service, U.S. Vegetable Laboratory, Charleston, South Carolina, USA.

Tomato spotted wilt tospovirus (TSWV), one of the most important plant viruses, causes yield losses to many crops including tomato. The current disease management for TSWV is based mainly on breeding tomato cultivars containing the Sw-5 locus. Unfortunately, several Sw-5 resistance-breaking strains of TSWV have been identified. Sw-7 is an alternative locus conferring resistance to a broad range of TSWV strains. In an effort to uncover gene networks that are associated with the Sw-7 resistance, we performed a comparative transcriptome profiling and gene expression analysis between a nearly-isogenic Sw-7 line and its susceptible recurrent parent (Fla. 8059) upon infection by TSWV. A total of 1,244 differentially expressed genes were identified throughout a disease progression process involving networks of host resistance genes, RNA silencing/antiviral defense genes, and crucial transcriptional and translational regulators. Notable induced genes in Sw-7 include those involved in callose accumulation, lignin deposition, proteolysis process, transcriptional activation/repression, and phosphorylation. Finally, we investigated potential involvement of PR-5 in the Sw-7 resistance. Interestingly, PR-5 overexpressed plants conferred enhanced resistance, resulting in delay in virus accumulation and symptom expression. These findings will facilitate breeding and genetic engineering efforts to incorporate this new source of resistance in tomato for protection against TSWV.
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http://dx.doi.org/10.1038/s41598-019-44100-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529424PMC
May 2019

Can we import improvements from industry to healthcare?

BMJ 2019 Mar 21;364:l1039. Epub 2019 Mar 21.

Healthcare Safety Investigation Branch, Farnborough, UK.

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http://dx.doi.org/10.1136/bmj.l1039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6427425PMC
March 2019

Is Physician Mentorship Associated With the Occurrence of Adverse Patient Safety Events?

J Patient Saf 2021 Dec;17(8):e1633-e1637

Healthcare Safety Investigation Branch, Farnborough, United Kingdom.

Background: Mentorship has been identified as a beneficial practice for doctors and key aspect of continuing professional development, associated with a number of potential clinical and nonclinical gains. The likely contribution of mentorship to enhancing patient safety is acknowledged, but there is a dearth of empirical studies that attempt to make associations between the impact of mentorship for physicians on patient safety outcomes. This article begins to fill this gap by exploring whether a physician with a mentor reports having fewer near-misses or adverse events, compared with a physician with no mentor.

Methods: An online survey was administered to fellows and members of the Royal College of Physicians London using their membership database in April 2013. Adverse events and near misses are modeled as two separate binary variables using a logit regression framework with "having a mentor" being the main covariate. The marginal effect of this covariate captures the effect of mentorship on adverse events.

Results: A total of 1755 doctors (37% female) responded who represented all internal medical specialties. Our results show that compared with physicians with no mentor, the probability of getting involved in an adverse event or near miss is reduced by 12.69% (95% confidence interval = -17.41 to -7.98) and 11.12% (95% confidence interval = -15.84 to -6.41) for physicians with a mentor.

Conclusions: Having a mentor may contribute toward minimizing preventable harm to patients, which is a priority for health systems internationally, but longer-term studies of mentorship are necessary to determine the aspects of mentorship that are particularly important for enhancing patient safety outcomes.
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http://dx.doi.org/10.1097/PTS.0000000000000592DOI Listing
December 2021

Green Methodologies for Copper(I)-Catalyzed Azide-Alkyne Cycloadditions: A Comparative Study.

Molecules 2019 Mar 10;24(5). Epub 2019 Mar 10.

Department of Chemistry and Biochemistry, University of Colorado Colorado Springs, Colorado Springs, CO 80918, USA.

Successful copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions may be achieved by several methods. In this paper, four synthetic protocols were performed for direct comparison of time required for the synthesis, yield, and purity of the 1-1,2,3-triazole products. The methods with Cu(I) catalysts were conventional, microwave heating, solvent-free, and a method using glycerol solvent. The compounds synthesized in this paper were known non-fluorinated triazoles and new fluorinated triazoles. The results lead to the conclusion that the microwave method should be strongly considered for CuAAC syntheses.
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http://dx.doi.org/10.3390/molecules24050973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429464PMC
March 2019

Impaired pressure natriuresis and non-dipping blood pressure in rats with early type 1 diabetes mellitus.

J Physiol 2019 02 23;597(3):767-780. Epub 2018 Dec 23.

The British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, The University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.

Key Points: Type 1 diabetes mellitus increases cardiovascular risk; hypertension amplifies this risk, while pressure natriuresis regulates long-term blood pressure. We induced type 1 diabetes in rats by streptozotocin injection and demonstrated a substantial impairment of pressure natriuresis: acute increases in blood pressure did not increase renal medullary blood flow, tubular sodium reabsorption was not downregulated, and proximal tubule sodium reabsorption, measured by lithium clearance, was unaffected. Insulin reduced blood glucose in diabetic rats, and rescued the pressure natriuresis response without influencing lithium clearance, but did not restore medullary blood flow. Radiotelemetry showed that diastolic blood pressure was increased in diabetic rats, and its diurnal variation was reduced. Increases in medullary blood flow and decreases in distal tubule sodium reabsorption that offset acute rises in BP are impaired in early type 1 diabetes, and this impairment could be a target for preventing hypertension in type 1 diabetes.

Abstract: Type 1 diabetes mellitus (T1DM) substantially increases cardiovascular risk, and hypertension amplifies this risk. Blood pressure (BP) and body sodium homeostasis are linked. T1DM patients have increased total exchangeable sodium, correlating directly with BP. Pressure natriuresis is an important physiological regulator of BP. We hypothesised that pressure natriuresis would be impaired, and BP increased, in the early phase of T1DM. Male Sprague-Dawley rats were injected with streptozotocin (30-45 mg/kg) or citrate vehicle. After 3 weeks, pressure natriuresis was induced by serial arterial ligation. In non-diabetic controls, this increased fractional excretion of sodium from ∼1% to ∼25% of the filtered load (P < 0.01); in T1DM rats, the response was significantly blunted, peaking at only ∼3% (P < 0.01). Mechanistically, normal lithium clearance suggested that distal tubule sodium reabsorption was not downregulated with increased BP in T1DM rats. The pressure dependence of renal medullary perfusion, considered a key factor in the integrated response, was abolished. Insulin therapy rescued the natriuretic response in diabetic rats, restoring normal downregulation of tubular sodium reabsorption when BP was increased. However, the pressure dependence of medullary perfusion was not restored, suggesting persistent vascular dysfunction despite glycaemic control. Radiotelemetry showed that T1DM did not affect systolic BP, but mean diastolic BP was ∼5 mmHg higher than in non-diabetic controls (P < 0.01), and normal diurnal variation was reduced. In conclusion, functional impairment of renal sodium and BP homeostasis is an early manifestation of T1DM, preceding hypertension and nephropathy. Early intervention to restore pressure natriuresis in T1DM may complement reductions in cardiovascular risk achieved with glycaemic control.
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http://dx.doi.org/10.1113/JP277332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355628PMC
February 2019

Safety investigation practices can be adapted from aviation for use in healthcare.

BMJ 2018 06 29;361:k2822. Epub 2018 Jun 29.

Healthcare Safety Investigation Branch, Farnborough GU14 0LE, UK.

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http://dx.doi.org/10.1136/bmj.k2822DOI Listing
June 2018

Chemotherapy-associated paronychia treated with 2% povidone-iodine: a series of cases.

Cancer Manag Res 2017 26;9:225-228. Epub 2017 Jun 26.

Veloce BioPharma LLC, Fort Lauderdale, FL.

Background: Nail changes are known to occur during the use of chemotherapy for a variety of malignancies, particularly those treated with taxanes and EGFR inhibitors. There are currently no actively recruiting prospective clinical trials investigating potential treatments. There are also no US Food and Drug Administration-approved medical treatments for chemotherapy-associated paronychia and no consensus on the best way to treat these common chemotherapy-induced events.

Methods: A retrospective review of all cases presenting to a single dermatology private practice from June 2016 to January 2017 identified nine patients with chemotherapy-associated paronychia seeking treatment. Each patient was prescribed a topical solution comprised of 2% povidone-iodine in a dimethylsulfoxide vehicle that was prepared by a licensed compounding pharmacy. Patients were seen at 3 week and 6 week follow-up visits.

Results: All 9/9 patients demonstrated complete or partial resolution. The number of nails involved for each patient ranged from 4-12. There were a total of 58 nails affected in the case series, and 44/58 (76%) resolved overall. The treatment was well tolerated.

Conclusion: The topical povidone-iodine/dimethylsufoxide solution described is very effective in alleviating the signs and symptoms of paronychia associated with chemotherapy. This novel combination warrants further investigation in randomized, controlled trials to further elucidate its clinical utility.
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http://dx.doi.org/10.2147/CMAR.S139301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500570PMC
June 2017

Demodex Blepharitis Treated with a Novel Dilute Povidone-Iodine and DMSO System: A Case Report.

Ophthalmol Ther 2017 Dec 22;6(2):361-366. Epub 2017 Jun 22.

Plessen Ophthalmology Consultants, PO Box 910, Christiansted, USVI, USA.

Introduction: Povidone-iodine aqueous solution is an antiseptic commonly used in ophthalmology for treatment of the ocular surface. Dimethylsulfoxide (DMSO) is a well-known skin penetration enhancer that is scarcely utilized in ophthalmic drug formulations. We describe here a low-dose formulation of 0.25% PVP-I in a gel containing DMSO for the treatment of Demodex blepharitis.

Case Report: A 95-year-old female presented with chronic blepharitis involving both the anterior and posterior eyelid margins. The anterior eyelid margins demonstrated pathognomonic features consistent with Demodex infection, and this diagnosis was confirmed with microscopy. Previous traditional therapies had been ineffective at controlling her signs and symptoms.

Conclusion: The topical PVP-I/DMSO system was effective at treating the signs and symptoms of Demodex blepharitis. Further investigation of the novel agent is warranted.
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http://dx.doi.org/10.1007/s40123-017-0097-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5693835PMC
December 2017

Optimization of a micro-scale, high throughput process development tool and the demonstration of comparable process performance and product quality with biopharmaceutical manufacturing processes.

J Chromatogr A 2017 Jul 18;1506:73-81. Epub 2017 May 18.

Purification Process Sciences, MedImmune, One MedImmune Way, Gaithersburg, MD 20878, USA. Electronic address:

In this paper, we discuss the optimization and implementation of a high throughput process development (HTPD) tool that utilizes commercially available micro-liter sized column technology for the purification of multiple clinically significant monoclonal antibodies. Chromatographic profiles generated using this optimized tool are shown to overlay with comparable profiles from the conventional bench-scale and clinical manufacturing scale. Further, all product quality attributes measured are comparable across scales for the mAb purifications. In addition to supporting chromatography process development efforts (e.g., optimization screening), comparable product quality results at all scales makes this tool is an appropriate scale model to enable purification and product quality comparisons of HTPD bioreactors conditions. The ability to perform up to 8 chromatography purifications in parallel with reduced material requirements per run creates opportunities for gathering more process knowledge in less time.
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http://dx.doi.org/10.1016/j.chroma.2017.05.041DOI Listing
July 2017

Molluscum Contagiosum Treated with Dilute Povidone-Iodine: A Series of Cases.

J Clin Aesthet Dermatol 2017 Mar 1;10(3):41-45. Epub 2017 Mar 1.

Veloce BioPharma LLC;; Plessen Ophthalmology Consultants.

To report our experience using a broad spectrum antimicrobial, povidone-iodine, as a novel at-home prescription treatment for molluscum contagiosum. A systematic review of cases presenting to one of the author's private dermatology clinics from January to July of 2015 identified 12 patients with molluscum contagiosum seeking treatment. The population was pediatric, with six males and six female patients included (age range 2-17 years, mean age 6 years). Patients were evaluated at baseline and returned to the office for evaluation at four-week intervals until resolution or failure to show for appointments, with number and location of lesions being recorded at each visit. Adverse effects were evaluated at each visit. All 12/12 (100%) patients demonstrated complete or partial resolution. There were a total of 115 lesions treated in the case series, and 103/115 (90%) resolved. Complete resolution occurred in 8/12 (67%) patients. Of the 8/12 with complete resolution, 4/8 (50%) patients showed complete resolution at the four-week follow-up visit and 4/8 (50%) showed complete resolution at the eight-week follow-up. Of the 4/12 (33%) patients who failed to demonstrate complete resolution, 4/4 (100%) showed partial resolution. This case series demonstrates considerable success for treatment of molluscum contagiosum with a dilute povidone-iodine preparation. The treatment was well-tolerated, with minimal side effects.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5367881PMC
March 2017

How well do we currently care for our dying patients in acute hospitals: the views of the bereaved relatives?

BMJ Support Palliat Care 2017 Sep 17;7(3):316-325. Epub 2017 Jan 17.

Clinical Effectiveness and Evaluation Unit, Royal College of Physicians, London, UK.

Background: The National Care of the Dying Audit-Hospitals (NCDAH) is used as a method to evaluate care for dying patients in England. An additional component to the 2013/2014 audit was the Local Survey of Bereaved Relatives Views using the 'Care Of the Dying Evaluation' (CODE) questionnaire.

Aim: Within the context of the NCDAH audit, to evaluate quality of care provided to dying patients and their families in acute hospitals from the perspective of bereaved relatives.

Design: Postbereavement survey to bereaved relatives.

Setting/participants: For acute hospitals wishing to participate, consecutive 'expected' adult deaths occurring between 1 May and 30 June 2013 were identified and the CODE questionnaire was sent to the next-of-kin.

Results: From 3414 eligible next-of-kin, 95 (2.8%) were excluded due to being involved in a complaint procedure and 1006 (29.5%) due to insufficient next-of-kin details. From the remaining 2313 potential participants, 858 returned a completed CODE questionnaire (37.1% response rate). Generally, symptoms were perceived to be well controlled with 769 (91%) participants reporting that either no pain was present or only there 'some of the time'. Unmet information needs, however, was a recognised area for improvement, for example, 230 (29%) reporting having a discussion about hydration would have been beneficial.

Conclusions: Adopting a postbereavement survey to NCDAH appears to be feasible, acceptable and a valuable addition. On the whole, the majority of participants reported good or excellent care. A small but significant minority, however, perceived poor quality of patient care with clear and timely communication urgently needed.
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http://dx.doi.org/10.1136/bmjspcare-2014-000810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5574388PMC
September 2017

Learning from hospital mortality.

Clin Med (Lond) 2016 Dec;16(6):530-534

Care Quality Improvement Department, Royal College of Physicians, London, UK.

Understanding and learning from hospital deaths is an important component of good clinical practice but current approaches and measures are complex, controversial and difficult to understand. Patients who die are not a homogeneous group but fall into three distinct categories; most learning will be achieved by recognising this and investigating categories of deaths in different ways, relying heavily on qualitative approaches. Numerical measures of overall hospital mortality, such as hospital standardised mortality ratio (HSMR) or measures of 'preventable' deaths, are most unlikely to be helpful at a hospital level and may even give false reassurance, as accuracy of measurement is strongly influenced by factors apart from quality of care.
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http://dx.doi.org/10.7861/clinmedicine.16-6-530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297330PMC
December 2016

The Royal College of Physician's Quality Improvement Hub - how can it help physicians to improve patient care?

Future Hosp J 2016 Oct;3(3):211-216

West of England Academic Health Science Network, Bristol, UK.

Doctors have a central role in managing patients across a multitude of clinical environments, which places them in the ideal position to identify systemic issues. Traditional medical training focuses on the knowledge and technical skills required; rarely are doctors trained in leadership, management or how to analyse and understand systems so as to design safer, better care. Quality improvement methodology is an approach that is known to enable improvement of the systems in which healthcare professionals work in order to provide safe, timely, evidence-based, equitable, efficient and patient-centred care. To address the current disparity, the Royal College of Physicians (RCP) has launched a Quality Improvement Hub, which will aim to support physicians to face the challenges of improving medical care, enabling them to navigate the tools with more confidence and share and implement the learning more swiftly.
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http://dx.doi.org/10.7861/futurehosp.3-3-211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465801PMC
October 2016

Improving quality of care through national clinical audit.

Future Hosp J 2016 Oct;3(3):203-206

Care Quality Improvement Department, Royal College of Physicians, London, UK.

The UK's national health services are unique in having a well established programme of national clinical audits and databases across medical, surgical and mental health conditions. The Royal College of Physicians' (RCP) Clinical Effectivess and Evaluation Unit leads many of the largest and most mature audits in partnership with specialist societies, other colleges, patient groups and academic institutions. In this paper, we shall trace the development of national audit over the last 2 decades, explore the mechanisms by which this has helped improve care and discuss how national clinical audits and databases can best support quality improvement in the NHS of the future.
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http://dx.doi.org/10.7861/futurehosp.3-3-203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465800PMC
October 2016

Variations in care quality occur across the whole week, not just at weekends.

BMJ 2016 Jun 7;353:i3151. Epub 2016 Jun 7.

Royal College of Physicians, London NW1 4LE, UK.

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http://dx.doi.org/10.1136/bmj.i3151DOI Listing
June 2016

Weekly variation in health-care quality by day and time of admission: a nationwide, registry-based, prospective cohort study of acute stroke care.

Lancet 2016 07 10;388(10040):170-7. Epub 2016 May 10.

Division of Health and Social Care Research, King's College London, London, UK.

Background: Studies in many health systems have shown evidence of poorer quality health care for patients admitted on weekends or overnight than for those admitted during the week (the so-called weekend effect). We postulated that variation in quality was dependent on not only day, but also time, of admission, and aimed to describe the pattern and magnitude of variation in the quality of acute stroke care across the entire week.

Methods: We did this nationwide, registry-based, prospective cohort study using data from the Sentinel Stroke National Audit Programme. We included all adult patients (aged >16 years) admitted to hospital with acute stroke (ischaemic or primary intracerebral haemorrhage) in England and Wales between April 1, 2013, and March 31, 2014. Our outcome measure was 30 day post-admission survival. We estimated adjusted odds ratios for 13 indicators of acute stroke-care quality by fitting multilevel multivariable regression models across 42 4-h time periods per week.

Findings: The study cohort comprised 74,307 patients with acute stroke admitted to 199 hospitals. Care quality varied across the entire week, not only between weekends and weekdays, with different quality measures showing different patterns and magnitudes of temporal variation. We identified four patterns of variation: a diurnal pattern (thrombolysis, brain scan within 12 h, brain scan within 1 h, dysphagia screening), a day of the week pattern (stroke physician assessment, nurse assessment, physiotherapy, occupational therapy, and assessment of communication and swallowing by a speech and language therapist), an off-hours pattern (door-to-needle time for thrombolysis), and a flow pattern whereby quality changed sequentially across days (stroke-unit admission within 4 h). The largest magnitude of variation was for door-to-needle time within 60 min (range in quality 35-66% [16/46-232/350]; coefficient of variation 18·2). There was no difference in 30 day survival between weekends and weekdays (adjusted odds ratio 1·03, 95% CI 0·95-1·13), but patients admitted overnight on weekdays had lower odds of survival (0·90, 0·82-0·99).

Interpretation: The weekend effect is a simplification, and just one of several patterns of weekly variation occurring in the quality of stroke care. Weekly variation should be further investigated in other health-care settings, and quality improvement should focus on reducing temporal variation in quality and not only the weekend effect.

Funding: None.
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http://dx.doi.org/10.1016/S0140-6736(16)30443-3DOI Listing
July 2016

Optomechanical Quantum Control of a Nitrogen-Vacancy Center in Diamond.

Phys Rev Lett 2016 04 7;116(14):143602. Epub 2016 Apr 7.

Department of Physics, University of Oregon, Eugene, Oregon 97403, USA.

We demonstrate optomechanical quantum control of the internal electronic states of a diamond nitrogen-vacancy (NV) center in the resolved-sideband regime by coupling the NV to both optical fields and surface acoustic waves via a phonon-assisted optical transition and by taking advantage of the strong excited-state electron-phonon coupling of a NV center. Optomechanically driven Rabi oscillations as well as quantum interferences between the optomechanical sideband and the direct dipole-optical transitions are realized. These studies open the door to using resolved-sideband optomechanical coupling for quantum control of both the atomlike internal states and the motional states of a coupled NV-nanomechanical system, leading to the development of a solid-state analog of trapped ions.
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http://dx.doi.org/10.1103/PhysRevLett.116.143602DOI Listing
April 2016

Molluscum Contagiosum Viral Infection Treated With a Dilute Povidone-Iodine/Dimethylsulfoxide Preparation.

Dermatol Ther (Heidelb) 2016 Mar 21;6(1):101-3. Epub 2015 Dec 21.

Veloce BioPharma LLC, Fort Lauderdale, FL, USA.

Introduction: Molluscum contagiosum is a viral infection of the skin that is spread from direct contact, either via person to person by touching affected lesions or innocuously via fomites. The condition is often socially stigmatizing, motivating patients to seek treatment. There are many anecdotal remedies, but none have been overwhelmingly effective in controlled clinical trials.

Case Report: A 16-year-old girl presented with approximately 75 lesions on her inner thighs as a result of friction from an athletic uniform. She tried over-the-counter antibiotic ointment and topical steroids for several weeks without improvement, and was concerned at the rate of spread of the lesions, along with the social implications.

Conclusion: The topical povidone-iodine/dimethylsulfoxide system is very effective in eradicating molluscum contagiosum. This novel combination warrants further investigation in randomized, controlled trials to further elucidate its clinical utility.
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http://dx.doi.org/10.1007/s13555-015-0091-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4799036PMC
March 2016

Glicentin-related pancreatic polypeptide inhibits glucose-stimulated insulin secretion from the isolated pancreas of adult male rats.

Physiol Rep 2015 Dec;3(12)

School of Biological Sciences, University of Auckland, Auckland, New Zealand The Maurice Wilkins Centre for Molecular BioDiscovery, New Zealand Centre for Advanced Discovery and Experimental Therapeutics, NIHR Manchester Biomedical Research Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK The Institute of Human Development, University of Manchester, Manchester, UK Department of Pharmacology, Medical Sciences Division, University of Oxford, Oxford, UK

Peptides derived from the glucagon gene Gcg, for example, glucagon and glucagon-like peptide 1 (GLP-1), act as physiological regulators of fuel metabolism and are thus of major interest in the pathogenesis of diseases, such as type-2 diabetes and obesity, and their therapeutic management. Glicentin-related pancreatic polypeptide (GRPP) is a further, 30 amino acid Gcg-derived peptide identified in human, mouse, rat, and pig. However, the potential glucoregulatory function of this peptide is largely unknown. Here, we synthesized rat GRPP (rGRPP) and a closely related peptide, rat GRPP-like peptide (rGRPP-LP), and investigated their actions in the liver and pancreas of adult male rats by employing isolated-perfused organ preparations. Rat GRPP and rGRPP-LP did not affect glucose output from the liver, but both elicited potent inhibition of glucose-stimulated insulin secretion (GSIS) from the rat pancreas. This action is unlikely to be mediated by glucagon or GLP-1 receptors, as rGRPP and rGRPP-LP did not stimulate cyclic adenosine monophosphate (cAMP) production from the glucagon or GLP-1 receptors, nor did they antagonize glucagon- or GLP-1-stimulated cAMP-production at either receptor. GRPP and GRPP-LP may be novel regulators of insulin secretion, acting through an as-yet undefined receptor.
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http://dx.doi.org/10.14814/phy2.12638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760439PMC
December 2015

The Stories Clinicians Tell: Achieving High Reliability and Improving Patient Safety.

Perm J 2016 9;20(1):85-90. Epub 2015 Nov 9.

Clinical Director of the Clinical Effectiveness and Evaluation Unit for the Royal College of Physicians and an Internal Medicine Consultant Physician for the English National Health Service in London, United Kingdom.

The patient safety movement has been deeply affected by the stories patients have shared that have identified numerous opportunities for improvements in safety. These stories have identified system and/or human inefficiencies or dysfunctions, possibly even failures, often resulting in patient harm. Although patients' stories tell us much, less commonly heard are the stories of clinicians and how their personal observations regarding the environments they work in and the circumstances and pressures under which they work may degrade patient safety and lead to harm.If the health care industry is to function like a high-reliability industry, to improve its processes and achieve the outcomes that patients rightly deserve, then leaders and managers must seek and value input from those on the front lines-both clinicians and patients. Stories from clinicians provided in this article address themes that include incident identification, disclosure and transparency, just culture, the impact of clinical workload pressures, human factors liabilities, clinicians as secondary victims, the impact of disruptive and punitive behaviors, factors affecting professional morale, and personal failings.
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http://dx.doi.org/10.7812/TPP/15-039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4732801PMC
December 2016
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