Publications by authors named "Jonathan M Crowther"

11 Publications

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Topical emollient therapy with sunflower seed oil alters the skin microbiota of young children with severe acute malnutrition in Bangladesh: A randomised, controlled study.

J Glob Health 2021 17;11:04047. Epub 2021 Jul 17.

Division of Infectious Diseases & Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.

Background: Topical emollient therapy with sunflower seed oil (SSO) reduces risk of sepsis and mortality in very preterm infants in low- or middle-income countries (LMICs). Proposed mechanisms include modulation of skin and possibly gut barrier function. The skin and gut microbiota play important roles in regulating barrier function, but the effects of emollient therapy on these microbiotas are poorly understood.

Methods: We characterised microbiota structure and diversity with 16S rRNA gene amplicon sequence data and ecological statistics in 20 children with severe acute malnutrition (SAM) aged 2-24 months, at four skin sites and in stool, during a randomised, controlled trial of emollient therapy with SSO in Bangladesh. Microbes associated with therapy were identified with tree-based sparse discriminant analysis.

Results: The skin microbiota of Bangladeshi children with SAM was highly diverse and displayed significant variation in structure as a function of physical distance between sites. Microbiota structure differed between the study groups ( = 0.005), was more diverse in emollient-treated subjects-including on the forehead which did not receive direct treatment-and changed with each day ( = 0.005) at all skin sites. Overall, were the most differentially affected by emollient treatment; several genera within this family became more abundant in the emollient group than in the controls across several skin sites. Gut microbiota structure was associated with sample day ( = 0.045) and subject age ( = 0.045), but was not significantly affected by emollient treatment ( = 0.060).

Conclusions: Emollient therapy altered the skin microbiota in a consistent and temporally coherent manner. We speculate that therapy with SSO enhances skin barrier function in part through alterations in the microbiota, and through systemic mechanisms. Strategies to strengthen skin and gut barrier function in populations at risk, such as children in LMICs like Bangladesh, might include deliberate manipulation of their skin microbiota.

Trial Registration: ClinicalTrials.gov: NCT02616289.
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http://dx.doi.org/10.7189/jogh.11.04047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325932PMC
August 2021

Understanding humectant behaviour through their water-holding properties.

Int J Cosmet Sci 2021 Jul 6. Epub 2021 Jul 6.

JMC Scientific Consulting Ltd, Egham, UK.

Objective: Humectants perform essential roles in the formulation of topical moisturizing products in terms of delivery of active ingredients, consumer experience and biophysical behaviour. How they retain and release water is key to understanding their behaviour.

Methods: Dynamic vapour sorption (DVS) was used to monitor the dehydration kinetics of three humectants widely used in topical formulations-glycerine, dexpanthenol and urea. Model aqueous solutions with concentrations of 20% w/w were tested and compared against pure deionized water.

Results: The three humectants varied in their ability to retain water during the dehydration process. Dexpanthenol was able to retain water most efficiently during the latter stages of dehydration. Urea demonstrated evidence of crystallization during the final stage of water loss, which was not shown by glycerine or dexpanthenol.

Conclusions: Humectants perform vital roles in the formulation of consumer acceptable topical products including the delivery of actives to the skin. Their ability to influence water movement in the skin is also essential for the maintenance of stratum corneum flexibility. DVS assessment of aqueous solutions has demonstrated how the behaviour of three commonly used humectants differs. Knowledge of the mechanisms by which these humectants operate enables the formulator to develop topical products optimized for the roles for which they are intended.
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http://dx.doi.org/10.1111/ics.12723DOI Listing
July 2021

Effect of topical applications of sunflower seed oil on systemic fatty acid levels in under-two children under rehabilitation for severe acute malnutrition in Bangladesh: a randomized controlled trial.

Nutr J 2021 06 6;20(1):51. Epub 2021 Jun 6.

Department of Pediatrics, Stanford University School of Medicine, 1701 Page Mill Road, Room 121, Palo Alto, Stanford, CA, 94304, USA.

Background: Children with severe acute malnutrition (SAM) have inadequate levels of fatty acids (FAs) and limited capacity for enteral nutritional rehabilitation. We hypothesized that topical high-linoleate sunflower seed oil (SSO) would be effective adjunctive treatment for children with SAM.

Methods: This study tested a prespecified secondary endpoint of a randomized, controlled, unblinded clinical trial with 212 children with SAM aged 2 to 24 months in two strata (2 to < 6 months, 6 to 24 months in a 1:2 ratio) at Dhaka Hospital of icddr,b, Bangladesh between January 2016 and December 2017. All children received standard-of-care management of SAM. Children randomized to the emollient group also received whole-body applications of 3 g/kg SSO three times daily for 10 days. We applied difference-in-difference analysis and unsupervised clustering analysis using t-distributed stochastic neighbor embedding (t-SNE) to visualize changes in FA levels in blood from day 0 to day 10 of children with SAM treated with emollient compared to no-emollient.

Results: Emollient therapy led to systematically higher increases in 26 of 29 FAs over time compared to the control. These effects were driven primarily by changes in younger subjects (27 of 29 FAs). Several FAs, especially those most abundant in SSO showed high-magnitude but non-significant incremental increases from day 0 to day 10 in the emollient group vs. the no-emollient group; for linoleic acid, a 237 μg/mL increase was attributable to enteral feeding and an incremental 98 μg/mL increase (41%) was due to emollient therapy. Behenic acid (22:0), gamma-linolenic acid (18:3n6), and eicosapentaenoic acid (20:5n3) were significantly increased in the younger age stratum; minimal changes were seen in the older children.

Conclusions: SSO therapy for SAM augmented the impact of enteral feeding in increasing levels of several FAs in young children. Further research is warranted into optimizing this novel approach for nutritional rehabilitation of children with SAM, especially those < 6 months.

Trial Registration: ClinicalTrials.gov : NCT02616289 .
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http://dx.doi.org/10.1186/s12937-021-00707-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183055PMC
June 2021

Targeted dry skin treatment using a multifunctional topical moisturizer.

Int J Cosmet Sci 2021 Apr 3;43(2):191-200. Epub 2021 Jan 3.

Bayer Healthcare SAS, Gaillard, France.

Objective: The development of dry skin is a complex process, with a wide variety of factors each playing different roles in its evolution. Given this, it is important when designing a formulation to tackle dry skin that these varied aspects of skin behaviour are addressed. Presented here are the results of a 3-week moisturization study carried out on dry legs. A wide range of traditional and more recently developed biophysical measurement methods have been combined with visual assessment of skin condition to enable multiple aspects of skin function to be determined. The observed changes in the skin are discussed in terms of the ingredients used in the moisturizing formulation.

Methods: A range of novel and traditional skin assessment methods and techniques were used to assess the effects of an oil in water-based moisturizing product compared to an untreated site during a 3-week in vivo study on dry lower leg skin.

Results: Statistically significant improvements were observed in a range of skin parameters as a result of product usage. Skin hydration assessed using Corneometer®, Epsilon® and visual dry skin grading all increased after 3 weeks of use. Skin barrier function measured using transepidermal water loss also improved. Levels of cholesterol, free fatty acids and Ceramide NH increased, as well as the average length of the stratum corneum (SC) lipid lamella bilayers, and the ratio of lipid to protein increased (measured using Lipbarvis® and in vivo Confocal Raman Spectroscopy). Increases in the levels of Ceramide EOS and NP were also observed, along with an improvement in corneocyte maturity, although these were not statistically significant.

Conclusions: Using a variety of traditional and novel skin assessment techniques, a wide range of factors associated with the evolution of dry skin have been assessed upon treatment with a new topical moisturizer. Product usage resulted in significant improvements to skin hydration and barrier function, the levels and morphology of SC barrier lipids, and overall epidermal differentiation. As a result there was a significant reduction in the characteristics associated with the development of dry skin after use of the test product.
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http://dx.doi.org/10.1111/ics.12680DOI Listing
April 2021

Topical emollient therapy in the management of severe acute malnutrition in children under two: A randomized controlled clinical trial in Bangladesh.

J Glob Health 2020 Jun;10(1):010414

Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.

Background: Topical emollient therapy can improve neonatal health and growth and potentially provides an additional avenue for augmenting the provision of nutrition to children with severe acute malnutrition (SAM). We hypothesised that topical treatment of hospitalised children with SAM using sunflower seed oil (SSO), in addition to standard-of-care for SAM, would improve skin barrier function and weight gain, reduce risk of infection, and accelerate clinical recovery.

Methods: We conducted a randomised, two-arm, controlled, unblinded clinical trial in 212 subjects aged 2 to 24 months who were admitted for care of SAM at the 'Dhaka Hospital' of icddr,b during January 2016 to November 2017. Enrollment was age-stratified into 2 to <6 months and 6 to 24 months age groups in a 1:2 ratio. All children received SAM standard-of-care, and the SSO group was also treated with 3 g of SSO per kg body weight three times daily for 10 days. Primary outcome was rate of weight gain over the 10-day study period. Secondary endpoints included rate of nosocomial infection, time to recovery from acute illness, skin condition score, rate of transepidermal water loss (TEWL) and C-reactive protein (CRP) level.

Results: Rate of weight gain was higher in the SSO than the control group (adjusted mean difference, AMD = 0.90 g/kg/d, 95% confidence interval (CI) = -1.22 to 3.03 in the younger age stratum), but did not reach statistical significance. Nosocomial infection rate was significantly lower in the SSO group in the older age stratum (adjusted odds ratio (OR) = 0.41, 95% CI = 0.19 to 0.85;  = 0.017), but was comparable in the younger age stratum and overall. Skin condition score improved (AMD = -14.88, 95% CI = -24.12 to -5.65,  = 0.002) and TEWL was reduced overall (AMD = -2.59, 95% CI = -3.86 to -1.31,  < 0.001) in the SSO group. Reduction in CRP level was significantly greater in the SSO group (median: -0.28) than the control group (median 0.00) ( = 0.019) in the younger age stratum.

Conclusions: Topical therapy with SSO was beneficial for children with SAM when applied as adjunctive therapy. A community-based trial with a longer intervention period is recommended to validate these results.

Trial Registration: ClinicalTrials.gov: NCT02616289.
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http://dx.doi.org/10.7189/jogh.10.010414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243074PMC
June 2020

A Preliminary Investigation of Additive Manufacture to Fabricate Human Nail Plate Surrogates for Pharmaceutical Testing.

Pharmaceutics 2019 May 28;11(6). Epub 2019 May 28.

Department of Pharmaceutics, UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK.

In vitro permeation studies using nail clippings or nail plates are commonly used in the development of transungual formulations. However, there are ethical, safety and cost issues associated with sourcing such tissues. Herein, we describe a preliminary approach is described for the design and manufacture of a human nail model surrogate based on 3D printing. To evaluate these 3D printed constructs, nails were mounted in conventional glass Franz cells and a commercial antifungal lacquer formulation containing ciclopirox olamine was applied daily to the surrogate printed surfaces for a period of 14 days. On days 8 and 14, the surfaces of the 3D printed nails were washed with ethanol to remove excess formulation. Confocal Raman spectroscopy (CRS) was used to profile the drug in the 3D printed nail. At the end of the Franz cell studies, no drug was observed in the receptor phase. CRS studies confirmed penetration of the active into the model nails with reproducible depth profiles. Our ongoing work is focused on synthesising commercial and non-commercial printable resins that can replicate the physical and chemical characteristics of the human nail. This will allow further evaluation of actives for ungual therapy and advance the development of the surrogate nail tissue model.
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http://dx.doi.org/10.3390/pharmaceutics11060250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6630397PMC
May 2019

Optimised detection of mitochondrial DNA strand breaks.

Mitochondrion 2019 05 4;46:172-178. Epub 2018 May 4.

Dermatological Sciences, Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle NE24HH, UK. Electronic address:

Intrinsic and extrinsic factors that induce cellular oxidative stress damage tissue integrity and promote ageing, resulting in accumulative strand breaks to the mitochondrial DNA (mtDNA) genome. Limited repair mechanisms and close proximity to superoxide generation make mtDNA a prominent biomarker of oxidative damage. Using human DNA we describe an optimised long-range qPCR methodology that sensitively detects mtDNA strand breaks relative to a suite of short mitochondrial and nuclear DNA housekeeping amplicons, which control for any variation in mtDNA copy number. An application is demonstrated by detecting 16-36-fold mtDNA damage in human skin cells induced by hydrogen peroxide and solar simulated radiation.
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http://dx.doi.org/10.1016/j.mito.2018.04.009DOI Listing
May 2019

Spectrophotometry of Thin Films of Light-Absorbing Particles.

Langmuir 2017 04 6;33(15):3720-3730. Epub 2017 Apr 6.

GSK Consumer Healthcare, 184 Liberty Corner Road, Warren, New Jersey 07059, United States.

Thin films of dispersions of light-absorbing solid particles or emulsions containing a light-absorbing solute all have a nonuniform distribution of light-absorbing species throughout the sample volume. This results in nonuniform light absorption over the illuminated area, which causes the optical absorbance, as measured using a conventional specular UV-vis spectrophotometer, to deviate from the Beer-Lambert relationship. We have developed a theoretical model to account for the absorbance properties of such films, which are shown to depend on the size and volume fraction of the light-absorbing particles plus other sample variables. We have compared model predictions with measured spectra for samples consisting of emulsions containing a dissolved light-absorbing solute. Using no adjustable parameters, the model successfully predicts the behavior of nonuniform, light-absorbing emulsion films with varying values of droplet size, volume fraction, and other parameters.
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http://dx.doi.org/10.1021/acs.langmuir.6b04443DOI Listing
April 2017

In vitro permeation and disposition of niacinamide in silicone and porcine skin of skin barrier-mimetic formulations.

Int J Pharm 2017 Mar 31;520(1-2):158-162. Epub 2017 Jan 31.

GSK Consumer Healthcare, 184 Liberty Corner Road, Suite 200, Warren, NJ, 07059, United States.

Niacinamide (NIA) is an amide form of vitamin B3 which is used in cosmetic formulations to improve various skin conditions and it has also been shown to increase stratum corneum thickness following repeated application. In this study, three doses (5, 20 and 50μL per cm) of two NIA containing oil-in-water skin barrier-mimetic formulations were evaluated in silicone membrane and porcine ear skin and compared with a commercial control formulation. Permeation studies were conducted over 24h in Franz cells and at the end of the experiment membranes were washed and niacinamide was extracted. For the three doses, retention or deposition of NIA was generally higher in porcine skin compared with silicone membrane, consistent with the hydrophilic nature of the active. Despite the control containing a higher amount of active, comparable amounts of NIA were deposited in skin for all formulations for all doses; total skin absorption values (permeation and retention) of NIA were also comparable across all formulations. For infinite (50μL) and finite (5μL) doses the absolute permeation of NIA from the control formulation was significantly higher in porcine skin compared with both test formulations. This likely reflects differences in formulation components and/or presence of skin penetration enhancers in the formulations. Higher permeation for the 50 and 20μL dose was also evident in porcine skin compared with silicone membrane but the opposite is the case for the finite dose. The findings point to the critical importance of dose and occlusion when evaluating topical formulations in vitro and also the likelihood of exaggerated effects of excipients on permeation at infinite and pseudo-finite dose applications.
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http://dx.doi.org/10.1016/j.ijpharm.2017.01.054DOI Listing
March 2017

Evaporation of Particle-Stabilized Emulsion Sunscreen Films.

ACS Appl Mater Interfaces 2016 Aug 12;8(33):21201-13. Epub 2016 Aug 12.

GSK Consumer Healthcare , 184 Liberty Corner Road, Warren, New Jersey 07059, United States.

We recently showed (Binks et al., ACS Appl. Mater. Interfaces, 2016, DOI: 10.1021/acsami.6b02696) how evaporation of sunscreen films consisting of solutions of molecular UV filters leads to loss of UV light absorption and derived sun protection factor (SPF). In the present work, we investigate evaporation-induced effects for sunscreen films consisting of particle-stabilized emulsions containing a dissolved UV filter. The emulsions contained either droplets of propylene glycol (PG) in squalane (SQ), droplets of SQ in PG or droplets of decane in PG. In these different emulsion types, the SQ is involatile and shows no evaporation, the PG is volatile and evaporates relatively slowly, whereas the decane is relatively very volatile and evaporates quickly. We have measured the film mass and area, optical micrographs of the film structure, and the UV absorbance spectra during evaporation. For emulsion films containing the involatile SQ, evaporation of the PG causes collapse of the emulsion structure with some loss of specular UV absorbance due to light scattering. However, for these emulsions with droplets much larger than the wavelength of light, the light is scattered only at small forward angles so does not contribute to the diffuse absorbance and the film SPF. The UV filter remains soluble throughout the evaporation and thus the UV absorption by the filter and the SPF remain approximately constant. Both PG-in-SQ and SQ-in-PG films behave similarly and do not show area shrinkage by dewetting. In contrast, the decane-in-PG film shows rapid evaporative loss of the decane, followed by slower loss of the PG resulting in precipitation of the UV filter and film area shrinkage by dewetting which cause the UV absorbance and derived SPF to decrease. Measured UV spectra during evaporation are in reasonable agreement with spectra calculated using models discussed here.
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http://dx.doi.org/10.1021/acsami.6b06310DOI Listing
August 2016

Evaporation of Sunscreen Films: How the UV Protection Properties Change.

ACS Appl Mater Interfaces 2016 Jun 18;8(21):13270-81. Epub 2016 May 18.

GSK Consumer Healthcare , STF 1N-45, 20 TW Alexander Drive, Research Triangle Park, North Carolina 27709-3398, United States.

We have investigated the evaporation of thin sunscreen films and how the light absorption and the derived sun protection factor (SPF) change. For films consisting of solutions of common UV filters in propylene glycol (PG) as solvent, we show how evaporation generally causes three effects. First, the film area can decrease by dewetting leading to a transient increase in the average film thickness. Second, the film thins by evaporative loss of the solvent. Third, precipitation of the UV filter occurs when solvent loss causes the solubility limit to be reached. These evaporation-induced changes cause the UV absorbance of the film to decrease with resultant loss of SPF over the time scale of the evaporation. We derive an approximate model which accounts semiquantitatively for the variation of SPF with evaporation. Experimental results for solutions of different UV filters on quartz, different skin mimicking substrates, films with added nanoparticles, films with an added polymer and films with fast-evaporating decane as solvent (instead of slow evaporating PG) are discussed and compared with model calculations. Addition of either nanoparticles or polymer suppress film dewetting. Overall, it is hoped that the understanding gained about the mechanisms whereby film evaporation affects the SPF will provide useful guidance for the formulation of more effective sunscreens.
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http://dx.doi.org/10.1021/acsami.6b02696DOI Listing
June 2016
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