Loss of Function Filaggrin Mutations are Associated with Reduced History of Acne Vulgaris in a Cohort of Bangladeshi Atopic Eczema Patients in East London.

Acne vulgaris (AV) is the eighth most common non-fatal disease globally. Previous work identified an association between AV and increased Filaggrin (FLG) expression in the follicular epidermis, but further work did not find a clear link between loss of function (LoF) Filaggrin gene (FLG) mutations and protection from AV. In this work we aimed to explore any association between AV and FLG LoF mutations using a cohort of genotyped Bangladeshi patients with atopic eczema (AE) in East London. Retrospective notes review was performed on 245 patients who had been genotyped for FLG LoF mutations and undergone clinical assessment. The Chi squared or Fisher's exact test was used to determine differences between groups. We found a significant reduction in history of AV in AE patients with FLG LoF mutations relative to AE patients without FLG mutations (p = 0.02). We showed a non-significant reduction in AV diagnosis in patients with impaired barrier function (measured by trans epidermal water loss) and palmar hyperlinearity. We found that patients with severe AE were less likely to have a history of AV only if they had an existing FLG LoF mutation (p = 0.02). In the context of AE, our work suggests that FLG LoF mutations protect patients from developing AV.

Deep palmar phenotyping in atopic eczema: patterns associated with filaggrin variants, disease severity and barrier function in a South Asian population.

BACKGROUND: Hyperlinear palms are described as a feature of loss-of-function (LoF) variants in filaggrin (FLG). OBJECTIVES: To explore the phenotype of participants (age < 31 years) with atopic eczema of Bangladeshi ancestry from East London and investigate which factors best associate with LoF FLG variants. METHODS: A cross-sectional study with participants recruited between May 2018 and December 2020. Patterns of palmar linearity were categorized and modelled with the Eczema Area and Severity Index (EASI), transepidermal water loss (TEWL), skin hydration (SH) and LoF FLG variants. RESULTS: There were 506 complete cases available. Five palm patterns were noted. The 'prominent diamond' pattern associated best with EASI [marginal effects (ME) 2.53, 95% confidence interval (CI) 1.74-3.67], SH (ME 0.85, 95% CI 0.78-0.96) and TEWL (ME 1.32, 95% CI 1.11-1.62). Using five palm patterns had some ability to discriminate LoF FLG variants [area under the receiver operator characteristic (AUROC) 76.32%, 95% CI 71.91-80.73], improving to 77.99% (73.70-82.28) with the addition of SH. In subgroup analysis with only fine perpendicular/prominent diamond patterns the AUROC was 89.11% (95% CI 84.02-94.19). CONCLUSIONS: This was a single-centre study design with humans classifying clinical patterns. The stability of temperature and humidity was not guaranteed across TEWL and SH measurements despite using a climate-controlled room. Palm patterns associate with EASI and TEWL. The fine perpendicular/prominent diamond patterns are markers to detect the absence/presence of LoF FLG variants, respectively.

Vitamin D deficiency and atopic dermatitis severity in a Bangladeshi population living in East London: A cross-sectional study.

Background: Atopic eczema is a common, chronic, inflammatory skin condition with considerable heterogeneity. South Asian people living in the UK frequently have low serum vitamin D3 (25(OH)D3), and those with atopic disease can present with severe eczema. The association between vitamin D deficiency and eczema severity, and the role of vitamin D supplementation in atopic eczema is inconsistent, and under-researched in people with Asian ancestry. Objectives: This cross-sectional study investigates the association between serum 25(OH)D3 and eczema severity in a cohort of South Asian children and young adults living in London. Methods: Eligible participants were Bangladeshi children and young adults aged 0-30 years with eczema, living in London and participating in the Tower Hamlets Eczema Assessment study. Data was collected via parent/patient self-reporting, clinical history and examination, and hospital databases. 25(OH)D3 levels were documented retrospectively, if available, from hospital databases. Eczema severity was classified by Eczema Area and Severity Index (EASI) score less than or greater than 10 (clear-mild vs. moderate-severe). Multivariate logistic regression was used to adjust for confounding factors. Results: 681 participants were included in analyses. 25(OH)D3 results were available for 49.6% (338/681), 84.3% of which had deficient or insufficient lowest 25(OH)D3. Lowest 25(OH)D3 was inversely correlated with EASI score (Spearman's rank R 2 = -0.24, p < 0.001). 26.1% (178/681) had EASI >10 and a lower median lowest and nearest 25(OH)D3. After adjustment for confounding EASI > 10 was significantly associated with a lowest 25(OH)D3 < 25 (OR 3.21, 95%CI 1.35, 8.60), use of mild-moderate potency topical steroid on the face and neck (OR 3.11, 95%CI 1.86, 5.31), calcineurin inhibitor on the face and neck (OR 2.79, 95% CI 1.26, 6.10) and potent - very potent topical steroid on the face and neck (OR2.23, 95%CI 1.02, 4.77) and body (OR 2.11, 95%CI 1.18, 3.87). Discussion: Vitamin D plays a role in modulation of proteins required for skin barrier function and regulation of the innate immune system, suggesting 25(OH)D3 deficiency contributes to skin inflammation. This study demonstrates a relationship between 25(OH)D3 deficiency and worse eczema severity in a cohort of South Asian children and young adults.

Relationships between Intrascalar Tissue, Neuron Survival, and Cochlear Implant Function.

Fibrous tissue and/or new bone are often found surrounding a cochlear implant in the cochlear scalae. This new intrascalar tissue could potentially limit cochlear implant function by increasing impedance and altering signaling pathways between the implant and the auditory nerve. In this study, we investigated the relationship between intrascalar tissue and 5 measures of implant function in guinea pigs. Variation in both spiral ganglion neuron (SGN) survival and intrascalar tissue was produced by implanting hearing ears, ears deafened with neomycin, and neomycin-deafened ears treated with a neurotrophin. We found significant effects of SGN density on 4 functional measures but adding intrascalar tissue level to the analysis did not explain more variation in any measure than was explained by SGN density alone. These results suggest that effects of intrascalar tissue on electrical hearing are relatively unimportant in comparison to degeneration of the auditory nerve, although additional studies in human implant recipients are still needed to assess the effects of this tissue on complex hearing tasks like speech perception. The results also suggest that efforts to minimize the trauma that aggravates both tissue development and SGN loss could be beneficial.

Neurotrophin Gene Therapy in Deafened Ears with Cochlear Implants: Long-term Effects on Nerve Survival and Functional Measures.

Because cochlear implants function by stimulating the auditory nerve, it is assumed that the condition of the nerve plays an important role in the efficacy of the prosthesis. Thus, considerable research has been devoted to methods of preserving the nerve following deafness. Neurotrophins have been identified as a potential contributor to neural health, but most of the research to date has been done in young animals and for short periods (less than 3 to 6 months) after the onset of treatment. The first objective of the current experiment was to examine the effects of a neurotrophin gene therapy delivery method on spiral ganglion neuron (SGN) preservation and function in the long term (5 to 14 months) in mature guinea pigs with cochlear implants. The second objective was to examine several potential non-invasive monitors of auditory nerve health following the neurotrophin gene therapy procedure. Eighteen mature adult male guinea pigs were deafened by cochlear perfusion of neomycin and then one ear was inoculated with an adeno-associated viral vector with an Nft3-gene insert (AAV.Ntf3) and implanted with a cochlear implant electrode array. Five control animals were deafened and inoculated with an empty AAV and implanted. Data from 43 other guinea pig ears from this and previous experiments were used for comparison: 24 animals implanted in a hearing ear, nine animals deafened and implanted with no inoculation, and ten normal-hearing non-implanted ears. After 4 to 21 months of psychophysical and electrophysiological testing, the animals were prepared for histological examination of SGN densities and inner hair cell (IHC) survival. Seventy-eight percent of the ears deafened and inoculated with AAV.Ntf3 showed better SGN survival than the 14 deafened-control ears. The degree of SGN preservation following the gene therapy procedure was variable across animals and across cochlear turns. Slopes of psychophysical multipulse integration (MPI) functions were predictive of SGN density, but only in animals with preserved IHCs. MPI was not affected by the AAV.Ntf3 treatment, but there was a minor improvement in temporal integration (TI). AAV.Ntf3 treatment had significant effects on ECAP and EABR amplitude growth func-tion (AGF) slopes; the reduction in slope in deafened ears was ameliorated by the AAV.Ntf3 treatment. Slopes of the ECAP and EABR AGFs were predictive of SGN density in a broad area near and just apical to the implant. The highest ensemble spontaneous activity (ESA) values were seen in animals with surviving IHCs, but AAV.Ntf3 treatment in deafened ears resulted in slightly higher ESA values compared to deafened untreated ears. Overall, a combination of the psychophysical and electrophysiological measures can be useful for monitoring the health of the implanted cochlea in guinea pigs. These measures should be applicable for assessing cochlear health in human subjects.

Insertion trauma and recovery of function after cochlear implantation: Evidence from objective functional measures.

Partial loss and subsequent recovery of cochlear implant function in the first few weeks following cochlear implant surgery has been observed in previous studies using psychophysical detection thresholds. In the current study, we explored this putative manifestation of insertion trauma using objective functional measures: electrically-evoked compound action potential (ECAP) amplitude-growth functions (ECAP amplitude as a function of stimulus level). In guinea pigs implanted in a hearing ear with good post-implant hearing and good spiral ganglion neuron (SGN) survival, consistent patterns of ECAP functions were observed. The slopes of ECAP growth functions were moderately steep on the day of implant insertion, decreased to low levels over the first few days after implantation and then increased slowly over several weeks to reach a relatively stable level. In parallel, ECAP thresholds increased over time after implantation and then recovered, although more quickly, to a relatively stable low level as did thresholds for eliciting a facial twitch. Similar results were obtained in animals deafened but treated with an adenovirus with a neurotrophin gene insert that resulted in good SGN preservation. In contrast, in animals implanted in deaf ears that had relatively poor SGN survival, ECAP slopes reached low levels within a few days after implantation and remained low. These results are consistent with the idea that steep ECAP growth functions require a healthy population of auditory nerve fibers and that cochlear implant insertion trauma can temporarily impair the function of a healthy SGN population.

Interleaved multichannel epimysial stimulation for eliciting smooth contraction of muscle with reduced fatigue.

Functional electrical stimulation (FES) refers to the method by which sensory or motor functionality is restored through the use of coordinated stimulation of tissue. Our group has developed a mechanically conformable multielectrode array (cMEA) that can stimulate and record from the surface of muscles with high fidelity and low invasiveness, making the device well suited for various FES applications. The research presented here investigates the feasibility of using a cMEA to deliver asynchronous spatiotemporal stimulation patterns epimysially (on the surface of muscles). Specifically, we employ an interleaved stimulation protocol to achieve force responses with less fatigue and less ripple than those produced by standard simultaneous stimulation protocols delivered at high and low frequencies, respectively. This experimentation demonstrates that asynchronous spatiotemporal stimulation protocols delivered epimysially via a cMEA can improve the characteristics of the resulting force profiles.