Investigations on T cell transmigration in a human skin-on-chip (SoC) model.

A microfluidics-based three-dimensional skin-on-chip (SoC) model is developed in this study to enable quantitative studies of transendothelial and transepithelial migration of human T lymphocytes in mimicked skin inflammatory microenvironments and to test new drug candidates. The keys results include 1) CCL20-dependent T cell transmigration is significantly inhibited by an engineered CCL20 locked dimer (CCL20LD), supporting the potential immunotherapeutic use of CCL20LD for treating skin diseases such as psoriasis; 2) transepithelial migration of T cells in response to a CXCL12 gradient mimicking T cell egress from the skin is significantly reduced by a sphingosine-1-phosphate (S1P) background, suggesting the role of S1P for T cell retention in inflamed skin tissues; and 3) T cell transmigration is induced by inflammatory cytokine stimulated epithelial cells in the SoC model. Collectively, the developed SoC model recreates a dynamic multi-cellular micro-environment that enables quantitative studies of T cell transmigration at a single cell level in response to physiological cutaneous inflammatory mediators and potential drugs.

Incidence of nonarteritic ischemic optic neuropathy following topical clear corneal cataract surgery: survey and meta-analysis.

OBJECTIVE: We estimate the incidence and characteristics of post-cataract-surgery nonarteritic ischemic optic neuropathy (PCNAION) after topical clear corneal cataract extraction (CCCE) in Canada. DESIGN: Canada-wide internet survey and meta-analysis PARTICIPANTS: All certified Canadian ophthalmologists in the Canadian Ophthalmological Society directory, or belonging to a provincial ophthalmology internet group. METHODS: Identical surveys were distributed to 5 regions in Canada. CCCE surgeons were asked to estimate the number of CCCE they had performed in their career, and the number of PCNAION events that occurred within 1 year after CCCE. The results were analyzed using a random effects meta-analysis of proportions for rare events. RESULTS: The estimated survey response rate was 18%-32%. The 182 survey respondents performed a total of 1 499 694 CCCE with 107 events of PCNAION. Twenty-six percent of surgeons had at least one patient with PCNAION. Meta-analysis revealed a pooled estimate incidence of 2.8 PCNAION events (95% confidence interval 1.6-4.7) per 100 000 cataract procedures during the year after cataract surgery. Seventy-seven percent (82/107) of the PCNAION cases occurred within 3 weeks of surgery, and 7 patients had bilateral PCNAION. CONCLUSIONS: PCNAION is a rare complication after topical CCCE. Its incidence is important to estimate for patient care and epidemiologic reasons.

One year effectiveness study of intravitreal aflibercept in neovascular age-related macular degeneration: a meta-analysis.

The current body of evidence on the efficacy and safety of aflibercept for age-related macular degeneration (AMD) is steadily growing as large clinical trials and observational studies are continually completed. Our aim was to analyse 1-year visual acuity (VA) outcomes in response to aflibercept therapy and identify factors affecting treatment response using evidence generated from a pooled analysis of current studies. A literature review of multiple electronic databases (EMBASE, MEDLINE, MedMEME) revealed 12 studies meeting inclusion and exclusion criteria for statistical analysis. Treatment posology, baseline patient characteristics, study type, sample size and 12-month change in VA were pooled in a meta-analysis with VA change as the main outcome. Data were then stratified by study design and posology in subgroup analyses. A meta-regression was conducted to regress 12-month VA change against posology, baseline VA and age. Users of aflibercept experienced an overall increase of 7.37 letters (95% confidence interval: 6.27-8.48, p heterogeneity: <0.001) in VA at 12 months of follow-up. In subgroup analyses, mean VA change was higher for randomized control trials and cohorts following regular posology (>7 injections/year) compared to observational studies and irregular posology. The meta-regression showed larger VA gains with regular posology compared to an irregular posology, and decreased effect size as age increased. This meta-analysis strongly suggests improved VA outcomes at 12 months in patients with wet AMD for 2.0 mg aflibercept, comparable to but slightly lower than landmark trials. Increased injection frequency and younger age demonstrates a trend with improved outcomes.

Therapeutic Use of Stem Cells in Treatment of Burn Injuries.

Burn injuries are one of the most common sources of trauma globally that comprise a significant drain on long-term personal and healthcare cost. Large surface area burn wounds are difficult to manage and may result in significant physiologic and psychologic sequelae. The goal of burn wound healing research is to fully repair and restore skin's original structure and functionality while minimizing problems such as hypertrophic scarring and contracture. One of the ways this can be achieved is through augmentation of the skin's natural healing process using the regenerative capability of stem cells. In this review, the authors highlight some recent developments in treatment of burn wounds employing stem cells. We compare and contrast the benefits and drawbacks to various sources of stem cells and techniques of delivery into damaged tissues that have been the focus of established and ongoing research, and avenues of exploration this burgeoning arena offers for the future.

One-Year Effectiveness Study of Intravitreous Ranibizumab in Wet (Neovascular) Age-Related Macular Degeneration: A Meta-Analysis.

PURPOSE: The clinical efficacy of ranibizumab has been examined by a large number of prospective and retrospective studies to date. This meta-analysis was conducted to summarize the current body of evidence on visual acuity (VA) changes with use of ranibizumab in the treatment of wet (neovascular) age-related macular degeneration (wAMD). METHODS: A literature review of multiple electronic databases (EMBASE, MEDLINE, MedMEME) was conducted to find randomized controlled trials (RCTs) and observational studies that reported changes in VA while patients with wAMD were on ranibizumab. Study factors analyzed were baseline patient characteristics, study type, sample size, and 12-month change in VA. Data were pooled in a meta-analysis with VA change as the main outcome. Data were then stratified by study design and a meta-regression was conducted to assess 12-month VA change against baseline VA and age. RESULTS: A total of 42 studies were included for analysis. An overall increase of 5.58 letters (95% confidence interval [CI]: 4.42-6.75; p heterogeneity, < 0.001) was shown with use of ranibizumab compared to baseline. Improvements in VA were larger for RCTs, at 7.71 letters (95% CI: 6.66-8.76; p heterogeneity, 0.013), compared to observational studies, at 4.85 letters (95% CI: 3.32-6.38; p heterogeneity, < 0.001). The meta-regression showed a significant decrease in effect size between baseline VA and 12-month VA change. CONCLUSION: This meta-analysis suggests visual improvements at 12 months of 0.5-mg ranibizumab use in patients with wAMD. A higher gain in VA was observed when pooling results from RCTs compared to those in observational studies.

Cough is less common and less severe in systemic sclerosis-associated interstitial lung disease compared to other fibrotic interstitial lung diseases.

BACKGROUND AND OBJECTIVE: The objectives of this study were to determine the prevalence and characteristics of cough in idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis (HP) and systemic sclerosis-associated interstitial lung disease (SSc-ILD). METHODS: Cough severity was measured in consecutive patients with IPF (n = 77), HP (n = 32) and SSc-ILD (n = 67) using a 10-cm visual analogue scale (VAS). Dyspnoea and quality of life were measured using established questionnaires. Cough severity was compared across ILD subtypes and predictors of cough severity were determined using multivariate analysis. RESULTS: Cough was more common in IPF and chronic HP compared to SSc-ILD (87% and 83% vs 68%, P = 0.02). The median (interquartile range) VAS score was 39 (17-65) in the IPF cohort, 29 (11-48) in HP and 18 (0-33) in SSc-ILD (P < 0.0001). Cough was more often productive in chronic HP and IPF (63% and 43% vs 21%, P < 0.001). Cough severity was independently predicted only by ILD diagnosis and higher dyspnoea score. Cough severity was not associated with other common causes of cough. Cough was a significant predictor of quality of life in IPF and SSc-ILD with adjustment for age, sex, dyspnoea and ILD severity; however, cough was not associated with quality of life in chronic HP. CONCLUSION: Cough is more frequent, more severe and more often productive in IPF and chronic HP compared to SSc-ILD, despite similar ILD severity in these cohorts. Cough severity is strongly and independently associated with dyspnoea and pulmonary function, and is a significant contributor to reduced quality of life in both IPF and SSc-ILD.

Fluoroquinolone Use and Risk of Carpal Tunnel Syndrome: A Pharmacoepidemiologic Study.

Fluoroquinolone-induced peripheral neuropathies and tendinopathies are well documented, but there are no epidemiologic studies on the risk of carpal tunnel syndrome (CTS). We conducted a case-control study of >6 million patients. Fluoroquinolone use is associated with increased risk of CTS (rate ratio, 1.34 [95% confidence interval, 1.31-1.37]).

Vitamin D pathway regulatory genes encoding 1α-hydroxylase and 24-hydroxylase are dysregulated in sinonasal tissue during chronic rhinosinusitis.

BACKGROUND: Vitamin D deficiency is associated with many inflammatory respiratory disease states. However, serum vitamin D concentrations may not reflect tissue-specific availability. In this study we sought to assess the local expression of genes essential in vitamin D regulation in chronic rhinosinusitis (CRS). METHODS: A cross-sectional study of adult patients undergoing endoscopic sinus surgery was performed. Patients were defined as having CRS with polyps (CRSwNP) or without polyps (CRSsNP), or normal sinus mucosa. Sinus mucosal biopsies were assessed using quantitative polymerase chain reaction to determine expression of genes encoding the vitamin D receptor (VDR), 25-hydroxylase (CYP2R1), 1α-hydroxylase (CYP27B1), and 24-hydroxylase (CYP24A1). Expression levels correlated with serum 25(OH)D [sum 25(OH)D2  and 25(OH)D3 ], the 22-item Sinonasal Outcome Test (SNOT-22), and Nasal Symptom Score (NSS). Separate analyses were performed for patients grouped by tissue eosinophilia. RESULTS: Thirty-one patients were assessed (age 49.47 ± 18.14 years, 48.4% female), including 8 CRSsNP, 10 CRSwNP, and 13 controls. CRSsNP and CRSwNP mucosa exhibited decreased CYP27B1 compared with controls (0.0437 [Interquartile range (IQR) 0.0999] vs 0.3260 [IQR 2.9384] vs 0.6557 [IQR 1.1005], p = 0.039), whereas CYP24A1 was upregulated (0.8522 [IQR 1.3170] vs 1.2239 [IQR 4.4197] vs 0.1076 [IQR 0.1791], p = 0.025). CYP24A1 was upregulated in both non-eosinophilic CRS and eosinophilic CRS (1.1337 [IQR 2.3790] vs 0.9555 [IQR 3.2811] vs 0.1076 [IQR 0.1791], p = 0.033). Significant correlations were observed between NSS and CYP2R1 (r = -0.432, p = 0.022), CYP24A1 (r = 0.420, P = 0.026), and VDR (r = 0.425, p = 0.024), although no correlations with serum 25(OH)D were observed. CONCLUSIONS: The local regulation of vitamin D in sinonasal tissue during CRS may be independent of serum 25(OH)D levels. Vitamin D may be dysregulated at multiple levels, with decreased transcription of the metabolic gene CYP27B1 and increased transcription of the catabolic gene CYP24A1 observed.

Shifts in Lachnospira and Clostridium sp. in the 3-month stool microbiome are associated with preschool age asthma.

Asthma is a chronic disease of the airways affecting one in ten children in Westernized countries. Recently, our group showed that specific bacterial genera in early life are associated with atopy and wheezing in 1-year-old children. However, little is known about the link between the early life gut microbiome and the diagnosis of asthma in preschool age children. To determine the role of the gut microbiota in preschool age asthma, children up to 4 years of age enrolled in the Canadian Healthy Infant Longitudinal Development (CHILD) study were classified as asthmatic (n=39) or matched healthy controls (n=37). 16S rRNA sequencing and quantitative PCR (qPCR) were used to analyse the composition of the 3-month and 1-year gut microbiome of these children. At 3 months the abundance of the genus, Lachnospira (L), was decreased (P=0.008), whereas the abundance of the species, Clostridium neonatale (C), was increased (P=0.07) in asthmatics. Quartile analysis of stool composition at 3-months revealed a negative association between the ratio of these two bacteria (L/C) and asthma risk by 4 years of age [quartile 1: odds ratio (OR)=15, P=0.02, CI (confidence interval)= 1.8-124.7; quartile 2: OR=1.0, ns; quartile 3: OR=0.37, ns]. We conclude that opposing shifts in the relative abundances of Lachnospira and C. neonatale in the first 3 months of life are associated with preschool age asthma, and that the L/C ratio may serve as a potential early life biomarker to predict asthma development.