Treatment response to isotretinoin correlates with specific shifts in Cutibacterium acnes strain composition within the follicular microbiome.

There are no drugs as effective as isotretinoin for acne. Deciphering the changes in the microbiome induced by isotretinoin in the pilosebaceous follicle of successfully treated patients can pave the way to identify novel therapeutic alternatives. We determined how the follicular microbiome changes with isotretinoin and identified which alterations correlate with a successful treatment response. Whole genome sequencing was done on casts from facial follicles of acne patients sampled before, during and after isotretinoin treatment. Alterations in the microbiome were assessed and correlated with treatment response at 20 weeks as defined as a 2-grade improvement in global assessment score. We investigated the α-diversity, ß-diversity, relative abundance of individual taxa, Cutibacterium acnes strain composition and bacterial metabolic profiles with a computational approach. We found that increased ß-diversity of the microbiome coincides with a successful treatment response to isotretinoin at 20 weeks. Isotretinoin selectively altered C. acnes strain diversity in SLST A and D clusters, with increased diversity in D1 strains correlating with a successful clinical response. Isotretinoin significantly decreased the prevalence of KEGG Ontology (KO) terms associated with four distinct metabolic pathways inferring that follicular microbes may have limited capacity for growth or survival following treatment. Importantly, these alterations in microbial composition or metabolic profiles were not observed in patients that failed to achieve a successful response at 20 weeks. Alternative approaches to recapitulate this shift in the balance of C. acnes strains and microbiome metabolic function within the follicle may be beneficial in the future treatment of acne.

Vision and patient-reported outcomes with nondiffractive EDOF or neutral aspheric monofocal intraocular lenses.

PURPOSE: To compare outcomes in patients who underwent cataract extraction with implantation of nondiffractive extended depth-of-focus (ND-EDOF; Alcon AcrySof Vivity) or neutral aspheric monofocal (Bausch & Lomb enVista) intraocular lenses (IOLs). SETTING: Academic medical center. DESIGN: Prospective single-center double-arm patient- and assessor-masked randomized controlled trial. METHODS: Patients were randomized to receive either a ND-EDOF or monofocal IOL in both eyes, targeted for emmetropia. Uncorrected and corrected (CDVA) distance visual acuities, distance-corrected intermediate visual acuity (DCIVA), distance-corrected near visual acuity (DCNVA), level of spectacle independence, and severity of photic phenomena were assessed at 3 months postoperatively. RESULTS: 56 patients were enrolled, of which 24 in the ND-EDOF group and 27 in the monofocal group completed follow-up. The binocular mean CDVA, DCIVA, and DCNVA were 20/20, 20/19, and 20/21 for the ND-EDOF IOL and 20/18 ( P = .188), 20/31 ( P < .001), and 20/30 ( P = .004) for the monofocal IOL, respectively. At intermediate, 88% of the ND-EDOF vs 30% of the monofocal patients had a binocular DCIVA of 20/25 or better ( P < .001). Moderate or severe glare occurred in 20.8% of ND-EDOF vs 7.4% of monofocal patients ( P = .228), whereas moderate or severe halos occurred in 16.7% of ND-EDOF vs 11.1% of monofocal patients ( P = .697). CONCLUSIONS: The ND-EDOF and monofocal IOLs provided similarly excellent distance vision. Patients implanted with the ND-EDOF IOL had 2 more lines of vision at both intermediate and near, and a greater proportion reported spectacle independence. Most patients in both groups reported low severity of photic phenomena.

Keratinocytes and immune cells in the epidermis are key drivers of inflammation in hidradenitis suppurativa providing a rationale for novel topical therapies.

BACKGROUND: Hidradenitis suppurativa (HS) is a debilitating inflammatory skin disease characterized by painful nodules, drainage and scarring in skin folds. Injectable adalimumab is the only drug approved by the US Food and Drug Administration for the treatment of HS. Although systemic Janus kinase (JAK) inhibitors show promise, serious side-effects have been reported. There are no highly effective topical treatments for HS; furthermore, the contribution of epidermal keratinocytes to the intense inflammation has largely been unexplored. OBJECTIVES: We investigated the role of keratinocytes and epidermal immune cells in HS inflammation at all Hurley stages of disease severity. We aimed to determine whether ruxolitinib can mitigate inflammation from keratinocytes and to develop a better understanding of how topical therapeutics might benefit patients with HS. METHODS: We used skin samples from 87 patients with HS (Hurley stages I-III) and 39 healthy controls to compare keratinocyte- and immune cell-driven epidermal inflammation, in addition to the response of lesional HS keratinocytes to treatment with interferon (IFN)-γ and ruxolitinib. We used haematoxylin and eosin staining, immunohistochemistry, immunoblotting and quantitative reverse-transcription polymerase chain reaction assessments in whole skin, isolated epidermis, and cultured keratinocytes from healthy controls and both nonlesional and lesional HS skin to identify and define epidermal and keratinocyte-mediated inflammation in HS and how this may be targeted by therapeutics. RESULTS: HS lesional keratinocytes autonomously secreted high levels of chemokines, such as CCL2, CCL3 and CXCL3, which recruited neutrophils, CD8 T cells, and natural killer cells to the epidermis. Keratinocytes were the dominant source of tumour necrosis factor-α and interleukin (IL)-6 in HS lesions with little to no contribution from underlying dermal immune cells. In the presence of IFN-γ, which is dependent on immune cell infiltrate in vivo, keratinocytes expressed increased levels of additional cytokines including IL-1ß, IL-12, IL-23 and IL-36γ. The JAK inhibitor ruxolitinib mitigated the expression of inflammatory cytokines and chemokines in HS lesional keratinocytes, thus providing a rationale for future study as a topical treatment for HS. CONCLUSIONS: This study demonstrates that keratinocytes actively recruit immune cells to HS epidermis and interactions between these cells drive a broad inflammatory profile in HS epidermis. Targeting epidermal inflammation in HS with novel topical formulations may be highly efficacious with reduced systemic side-effects.

Evolution of the facial skin microbiome during puberty in normal and acne skin.

BACKGROUND: The composition of the skin microbiome varies from infancy to adulthood and becomes most stable in adulthood. Adult acne patients harbour an 'acne microbiome' dominated by specific strains of Cutibacterium acnes. However, the precise timing of skin microbiome evolution, the development of the acne microbiome, and the shift to virulent C. acnes strain composition during puberty is unknown. OBJECTIVES: We performed a cross-sectional pilot study in a paediatric population to understand how and when the skin microbiome composition transitions during puberty and whether a distinct 'acne microbiome' emerges in paediatric subjects. METHODS: Forty-eight volunteers including males and females, ages 7-17 years, with and without acne were enrolled and evaluated for pubertal development using the Tanner staging criteria. Sebum levels were measured, and skin microbiota were collected by sterile swab on the subject's forehead. DNA was sequenced by whole genome shotgun sequencing. RESULTS: A significant shift in microbial diversity emerged between early (T1-T2) and late (T3-T5) stages of puberty, coinciding with increased sebum production on the face. The overall relative abundance of C. acnes in both normal and acne skin increased during puberty and individual C. acnes strains were uniquely affected by pubertal stage and the presence of acne. Further, an acne microbiome signature associated with unique C. acnes strain composition and metabolic activity emerges in late puberty in those with acne. This unique C. acnes strain composition is predicted to have increased porphyrin production, which may contribute to skin inflammation. CONCLUSIONS: Our data suggest that the stage of pubertal development influences skin microbiome composition. As children mature, a distinct acne microbiome composition emerges in those with acne. Understanding how both puberty and acne influence the microbiome may support novel therapeutic strategies to combat acne in the paediatric population.

Parametric Acne Severity (PAS) Score and Lesion Counts From Multi-Modality Facial Image Analysis Correlates Strongly with Investigator Assessment.

Variability in acne lesion counting and assessing global severity necessitates large sample sizes that increase trial costs. Lack of standardized measures for these outcomes precludes the conduct of meta-analyses needed to compare efficacy of acne treatments. The goal of this study was to evaluate objective measures of lesion counts and global severity using analysis of multimodal photography. An algorithm for counting lesions was trained and validated in 30 acne subjects and compared to parallel assessments by 2 expert raters. A composite of photographic data representative of acne lesion topography, erythema, and C Acnes fluorescence was used to generate a Parametric Acne Severity (PAS) score. No relationship was identified between lesion counts and IGA. The correlation coefficients between raters and the algorithm when compared per view for the inflammatory and non-inflammatory lesion counts were 0.77 (P=0.001) and 0.85 (P=0.001), respectively. The correlation coefficient between the raters’ IGA grades and the PAS score was 0.82 (P<0.05). These data demonstrate that the lesion counting, and PAS are objective measures that strongly correlate with investigator assessments. Inclusion of these measure in clinical trials may reduce variability, standardize outcomes, and provide insights into treatment effects on photographic parameters associated with acne. J Drugs Dermatol. 2021;20(6):642-647. doi:10.36849/JDD.6165.

E-cadherin and p120ctn protein expression are lost in hidradenitis suppurativa lesions.

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease affecting the pilosebaceous units in the axilla, groin and buttocks. While the pathogenesis of HS is not clear, mechanical stress exacerbates HS. In this study, we aimed to determine whether intracellular adhesive junctions may be aberrant in HS patient skin. Strikingly, we observed loss of E-cadherin and p120ctn protein expression, two key adherens junction proteins, in ~85% of HS severe skin lesions. Moreover, loss of protein expression was apparent in non-lesional skin from HS patients and the degree of loss positively correlated with HS Hurley Stage of disease. E-cadherin expression was unaltered in other inflammatory skin conditions including chronic wound epithelium, atopic dermatitis, and acne vulgaris compared with healthy skin suggesting that its loss may be uniquely relevant to HS pathogenesis. A complete loss of α-catenin, ß-catenin and ZO-1 was not observed; however, some cytoplasmic staining of the catenins was noted in HS epithelium. We also demonstrated diminished desmosome size in HS lesional skin. Overall, our data suggested that loss of adherens junction proteins and diminished desmosome size in HS skin contributes to the skin's inability to withstand mechanical stress and provides rationale as to why mechanical stress exacerbates HS symptoms.

Urushiol Patch Test Using the T.R.U.E. TEST System.

BACKGROUND: Poison ivy, poison oak, and poison sumac are the most common causes of allergic contact dermatitis in North America. Although extensive efforts have been made to develop therapies that prevent and treat allergic contact dermatitis to these plants, there lacks an entirely effective method, besides complete avoidance. Efforts to develop a more effective preventive therapy, such as a vaccine, are ongoing. To accurately evaluate the efficacy of these new therapies, an appropriate assessment tool is needed. OBJECTIVE: The aim of this study was to evaluate the safety and appropriate doses of urushiol required for a patch test based on the hydrogel delivery system of the Thin-Layer Rapid Use Epicutaneous Patch Test. METHODS: Nine subjects were patch tested with various doses of urushiol and a negative control on day 0. Patch test sites were inspected for any local reaction on days 2, 4, 7, 14, and 21 after the initial exposure and graded by standard morphology. CONCLUSIONS: All 9 subjects did not have any significant adverse effects. The urushiol patch test using the hydrogel delivery method demonstrated urushiol sensitivity. All doses of urushiol resulted in a local reaction, and severity of reactions was correlated with dosage of urushiol used in the patch test.

Improving detection of adolescent hearing loss.

OBJECTIVES: To compare a protocol for pure-tone threshold testing, capable of detecting high-frequency hearing loss as indicated by notched audiometric configurations, with the current school rapid hearing screen and to determine typical adolescent noise exposures associated with notched audiometric configurations. DESIGN: In conjunction with required school rapid hearing screening, a pure-tone threshold testing protocol was administered, specifically to test hearing at high frequencies. A single audiologist reviewed the results. Students completed a survey assessing their noise exposures. SETTING: A public high school in Pennsylvania. PARTICIPANTS: Eleventh-grade students. MAIN OUTCOME MEASURE: Notched audiometric configurations on the pure-tone threshold test. RESULTS: Among 296 participants, 78 (26.4%) failed pure-tone threshold testing compared with 15 (5.1%) failing rapid hearing screening. Among those failing the pure-tone threshold testing, 67 (85.9%) failed due to notched audiometric configurations. Self-reported headphone use with an MP3 player was significantly associated with notched audiometric configurations compared with use of earbuds or stereo connection/docking systems. CONCLUSIONS: Pure-tone threshold testing incorporating high frequencies detects adolescent hearing loss more often than rapid hearing screens. Most state hearing screens omit high-frequency testing, potentially missing high-frequency losses, such as noise-induced hearing loss. Because noise-induced hearing loss in particular is preventable and hazardous noise exposures have increased, a reliable school hearing screen to detect high-frequency hearing loss in adolescents is warranted.