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This study analyzed the association between adolescent BMI and myopia severity.This cross-sectional study comprised 1,359,153 adolescents who were medically examined before mandatory military service. Mild-to-moderate and high myopia were defined based on right-eye refractive data. BMI was categorized based on the US age- and sex-matched percentiles. Logistic regression models were applied separately for women and men to estimate odds ratios (ORs) for myopia per BMI category.A total of 318,712 adolescents had mild-to-moderate myopia and 23,569 had high myopia. Compared with low-normal BMI (reference group), adjusted ORs for mild-to-moderate and high myopia increased with increasing BMI status, reaching 1.39 (95% CI: 1.23-1.57) and 1.73 (95% CI: 1.19-2.51) for men with severe obesity, respectively, and 1.19 (95% CI: 1.12-1.27) and 1.38 (95% CI: 1.14-1.65) for women with mild obesity, respectively. ORs for mild-to-moderate and high myopia were also higher in men with underweight (OR = 1.20; 95% CI: 1.18-1.23 and OR = 1.39; 95% CI: 1.30-1.47) and women with underweight (OR = 1.06; 95% CI: 1.03-1.09 and OR = 1.12; 95% CI: 1.04-1.22). The overall size effect was greater for men than women (pBMI was associated with myopia in a J-shaped pattern, with the size effect being greater for adolescent men than women. This study indicates that both low BMI and high BMI are associated with mild-to-moderate and severe myopia.

Objective To characterize the association between prolonged supine postoperative positioning of patients undergoing Descemet-stripping automated endothelial keratoplasty (DSAEK) and graft dislocation rate. Methods In this retrospective cohort study, medical records of patients who underwent uncomplicated DSAEK surgery at Yitzhak Shamir Medical Center between 2010 and 2019 were reviewed. Nursing documentation of patients’ adherence to supine positioning during the postoperative hospitalization period was collected. A patient was considered compliant if he or she was documented as cooperative with supine positioning throughout the first 24 hours. Results A total of 170 eyes of 138 patients were found eligible. Main indications for surgery were pseudophakic bullous keratopathy (50.6%), previous graft failure (25.9%), and Fuch's endothelial dystrophy (FED; 20.6%). Twelve surgeries were combined with cataract extraction. Postoperative graft detachment occurred in 26 eyes (15.3%) after an average period of 1 day (range, 0–20 days). Compliance with supine positioning was documented in 84.1% (n = 143 patients). Noncompliance rates during the first 24 hours in the detached and nondetached groups were 26.9% (n = 7) and 14.4% (n = 20), respectively; after adjustment for possible confounders, the odds ratio (OR) was 1.44 (p = 0.249). Graft dislocation was observed in 13.3% (19 of 143) and 25.9% (7 of 27) of cooperative and noncooperative patients, respectively (p = 0.17). Subanalysis of 120 eyes with either BPK or FED for which it was the first transplantation demonstrated a protective effect of supine positioning (OR 3.42, confidence interval 1.095–10.700; p = 0.034). Findings for both groups remained unchanged in multivariate analysis. Conclusions We found a statistically significant protective effect of 24 hours of postoperative supine positioning against graft detachment after DSAEK in eyes with no prior transplantations.

Palmoplantar keratodermas (PPKs) form a group of disorders characterized by thickening of palm and sole skin. Over the past 2 decades, many types of inherited PPKs have been found to result from abnormal expression, processing, or function of adhesion proteins.We used exome and direct sequencing to detect causative pathogenic variants. Functional analysis of these variants was conducted using reverse transcription quantitative polymerase chain reaction, immunofluorescence confocal microscopy, immunoblotting, a promoter reporter assay, and chromatin immunoprecipitation.We identified 2 heterozygous variants (c.1226AG and c.633_634dupGT) in KLF4 in 3 individuals from 2 different unrelated families affected by a dominant form of PPK. Immunofluorescence staining for a number of functional markers revealed reduced epidermal DSG1 expression in patients harboring heterozygous KLF4 variants. Accordingly, human keratinocytes either transfected with constructs expressing these variants or downregulated for KLF4 displayed reduced DSG1 expression, which in turn has previously been found to be associated with PPK. A chromatin immunoprecipitation assay confirmed direct binding of KLF4 to the DSG1 promoter region. The ability of mutant KLF4 to transactivate the DSG1 promoter was significantly decreased when compared with wild-type KLF4.Loss-of-function variants in KLF4 cause a novel form of dominant PPK and show its importance in the regulation of epidermal differentiation.

The application of myopia definition varies considerably within the literature. The purpose of this study was to examine the relationship between different myopia and high myopia definitions and resultant prevalence estimates. A population-based cross-sectional study of 1,588,508 Israeli adolescents assessed for medical fitness before mandatory military service at the age of 17 years between 1993 through 2015. Participants underwent non-cycloplegic autorefraction. Nine definitions of myopia and seven definitions of high myopia were examined. Prevalence estimates for each definition were calculated and compared with the reference definition (right eye spherical equivalent (SE)≤-0.50D and ≤-6.00D for myopia and high myopia, respectively), to yield a rate ratio (RR) across definitions. Applying the right eye SE≤-0.50D reference definition yielded 31.0% myopia prevalence. While some definitions resulted in similar prevalence estimates, using the right eye SE of ≤-0.75D; ≤-1.00D or least minus meridian of ≤-0.75D definitions yielded 28.8%, 26.3%, and 26.9% myopia prevalence, respectively, which corresponded to a 7.1%, 15.1% and 13.4% reduction in myopia RR, respectively. The prevalence of high myopia demonstrated considerable alternations, with a 1.7-fold increase in prevalence for the narrower threshold of SE≤-5.00D compared with SE≤-6.00D reference definition (4.2% and 2.4%, respectively). The prevalence of myopia and especially high myopia varies between frequently applied definitions, considering diverse thresholds, eye lateralization, and spherical vs. astigmatic refractive components. This variability highlights the pressing need for standardization of myopia definition in ophthalmic research. The results of this study provide crude estimates of a “conversion rate” across data, allowing comparisons between studies that utilize different myopia definitions.

Lupus erythematosus (LE) is an autoimmune disorder commonly affecting the skin; cutaneous lesions may indicate systemic involvement, warranting further evaluation. Photosensitivity, which may result in hyperpigmentation, is a well-known feature of the disease. In contrast, the prevalence of primary hyperpigmentation as a presenting sign of LE is not well established. Here, we compare 3 unique cases of diffuse facial hyperpigmentation as the primary manifestation of LE (cutaneous or systemic) and review previously reported cases. Our data highlight the need for considering LE in the differential diagnosis of facial hyperpigmentation and substantiate the importance of this unique lupus variant in early diagnosis and patient evaluation.

Background A broad spectrum of adverse reactions associated with the use of tumor necrosis factor alpha (TNFα) antagonists has been recognized over the past years. Induction of scalp psoriasis is a less known undesirable consequence of the use of these drugs and is not well characterized. Objective To characterize TNFα inhibitors-induced psoriatic alopecia. Methods We studied 6 patients with TNF-inhibitor induced psoriatic alopecia and reviewed 28 patients with this condition reported in the literature to date. Results In addition to severe scalp psoriasis, we report hair follicle pathologies ranging from alopecia areata to scarring alopecia. Prognosis was good, but discontinuation of TNFα inhibitors was required in more than half of the cases in order to achieve a favourable outcome. Conclusion TNFα inhibitors-associated psoriatic alopecia is rarely reported but requires a high index of suspicion and prompt diagnosis, as timely intervention may prevent irreversible damage.

Background Pemphigus vulgaris (PV) is a life-threatening mucocutaneous autoimmune blistering disease. We previously showed that genetic variants within the ST18 gene promoter area confer a sixfold increase in the propensity to develop PV. ST18, a transcription factor, was found to be overexpressed in the epidermis of patients with PV. In addition, it was found to promote autoantibody-mediated abnormal epidermal cell-cell adhesion and secretion of proinflammatory mediators by keratinocytes. Objectives To delineate the mechanism through which ST18 contributes to destabilization of cell-cell adhesion. Methods We used quantitative reverse-transcriptase polymerase chain reaction, immunofluorescence microscopy, a luciferase reporter system, site-directed mutagenesis, chromatin immunoprecipitation (ChIP) and the dispase dissociation assay. Results The ChIP and luciferase reporter assays showed that ST18 directly binds and activates the TNF promoter. Accordingly, increased ST18 expression contributes to PV pathogenesis by destabilizing cell-cell adhesion in a tumour necrosis factor (TNF)-α-dependent fashion. In addition, dual immunofluorescence staining showed increased expression of both ST18 and TNF-α in the skin of patients with PV carrying an ST18-associated PV risk variant, which was found to be associated with a more extensive PV phenotype. Conclusions Our findings suggest a role for TNF-α in mediating the deleterious effect of increased ST18 expression in PV skin.

Background The coexistence of pachyonychia congenita (PC) and hidradenitis suppurativa (HS) has been described in case reports. However, the pathomechanism underlying this association and its true prevalence are unknown. Objectives To determine the genetic defect underlying the coexistence of PC and HS in a large kindred, to delineate a pathophysiological signalling defect jointly leading to both phenotypes, and to estimate the prevalence of HS in PC. Methods We used direct sequencing and a NOTCH luciferase reporter assay to characterize the pathophysiological basis of the familial coexistence of HS and PC. A questionnaire was distributed to patients with PC registered with the International Pachyonychia Congenita Research Registry (IPCRR) to assess the prevalence of HS among patients with PC. Results Direct sequencing of DNA samples obtained from family members displaying both PC and HS demonstrated a missense variant (c.275A>G) in KRT17, encoding keratin 17. Abnormal NOTCH signalling has been suggested to contribute to HS pathogenesis. Accordingly, the KRT17 c.275A>G variant resulted in a significant decrease in NOTCH activity. To ascertain the clinical importance of the association of HS with PC, we distributed a questionnaire to all patients with PC registered with the IPCRR. Seventy-two of 278 responders reported HS-associated clinical features (25·9%). Disease-causing mutations in KRT17 were most prevalent among patients with a dual phenotype of PC and HS (43%). Conclusions The coexistence of HS and KRT17-associated PC is more common than previously thought. Impaired NOTCH signalling as a result of KRT17 mutations may predispose patients with PC to HS. What is already known about this topic? The coexistence of pachyonychia congenita (PC) and hidradenitis suppurativa (HS) has been described in case reports. However, the pathomechanism underlying this association and its true prevalence are unknown. What does this study add? A dual phenotype consisting of PC and HS was found to be associated with a pathogenic variant in KRT17. This variant was found to affect NOTCH signalling, which has been previously implicated in HS pathogenesis. HS was found to be associated with PC in a large cohort of patients with PC, especially in patients carrying KRT17 variants, suggesting that KRT17 variants causing PC may also predispose to HS. What is the translational message? These findings suggest that patients with PC have a higher prevalence of HS than previously thought, and hence physicians should have a higher level of suspicion of HS diagnosis in patients with PC.

Autosomal recessive congenital ichthyosis (ARCI) manifests with generalized scaling often associated with generalized erythema. Mutations in at least 13 different genes have been reported to cause ARCI. Acral peeling skin syndrome (APSS) is a rare autosomal recessive disorder manifesting with peeling over the distal limbs and dorsal surfaces of hands and feet. APSS is mostly due to mutations in TGM5, encoding transglutaminase 5. Both ARCI and APSS are fully penetrant genetic traits. Here, we describe a consanguineous family in which one patient with mild ARCI was found to carry a homozygous mutation in ALOXE3 (c.1238G > A; p.Gly413Asp). The patient was also found to carry a known pathogenic homozygous mutation in TGM5 (c.1335G > C; p.Lys445Asn) but did not display acral peeling skin. Her uncle carried the same homozygous mutation in TGM5 but carried the ALOXE3 mutation in a heterozygous state and showed clinical features typical of APSS. Taken collectively, these observations suggested that the ALOXE3 mutation suppresses the clinical expression of the TGM5 variant. We hypothesized that ALOXE3 deficiency may affect the expression of a protein capable of compensating for the lack of TGM5 expression. Downregulation of ALOXE3 in primary human keratinocytes resulted in increased levels of corneodesmosin, which plays a critical role in the maintenance of cell-cell adhesion in the upper epidermal layers. Accordingly, ectopic corneodesmosin expression rescued the cell-cell adhesion defect caused by TGM5 deficiency in keratinocytes as ascertained by the dispase dissociation assay. The present data thus provide evidence for phenotypic suppression in a human hereditary skin disorder.

Purpose Immigration studies can shed light on myopia development and reveal high-risk populations. To this end, we investigated the association among immigration, age at immigration, and myopia occurrence during adolescence. Design Population-based, retrospective, cross-sectional study. Participants Six hundred seven thousand eight hundred sixty-two adolescents, Israeli born and immigrants, with origins in the former Union of Soviet Socialist Republics (USSR), Ethiopia, or Israel, assessed for medical fitness for mandatory military service at 17 years of age between 1993 and 2016. Methods Myopia and high myopia were defined based on right eye refractive data. Age at immigration was categorized into 0 to 5 years of age, 6 to 11 years of age, and 12 to 19 years of age. Univariate and multivariate logistic regression models were created. Myopia odds ratios (ORs) were calculated according to immigration status, with Israeli-born natives as controls. Next, myopia ORs were calculated according to age at immigration, with Israeli-born of same origin as controls. Main Outcome Measures Myopia prevalence and ORs. Results Myopia was less prevalent among immigrants than Israeli-born controls. When stratified according to age at immigration, a decrease in myopia prevalence and ORs with increasing age at migration were observed, most prominent in immigrants arriving after 11 years of age, who also showed lower high-myopia ORs. The immigrants from the USSR and Ethiopia arriving after 11 years of age showed a myopia OR of 0.65 (95% confidence interval [CI], 0.63–0.67; P Conclusions Immigrants arriving after 11 years of age showed markedly lower ORs for myopia and high myopia relative to Israeli-born controls or those arriving during early childhood, likely because of environmental and lifestyle changes. Differences between immigrants arriving up to 5 years of age and those arriving between 6 and 11 years of age were relatively smaller, suggesting exposures at elementary school age play a greater role in this population.

Supplementary Material Supplementary table 1. The association between adolescent body mass index (BMI) and myopia for men– methodological sensitivity and subgroup analyses Supplementary table 2. The association between adolescent body mass index (BMI) and myopia for women– methodological sensitivity and subgroup analyses

Context A correlation between myopia and insulin resistance has been suggested. Objective We investigated the association between myopia in adolescence and type 2 diabetes (T2D) incidence in young adulthood. Methods This population-based, retrospective, cohort study comprised 1 329 705 adolescents (579 543 women, 43.6%) aged 16 to 19 years, who were medically examined before mandatory military service during 1993 to 2012, and whose data were linked to the Israel National Diabetes Registry. Myopia was defined based on right-eye refractive data. Cox proportional models were applied, separately for women and men, to estimate hazard ratios (HRs) for T2D incidence per person-years of follow-up. Results There was an interaction between myopia and sex with T2D (P Conclusion For women, myopia in adolescence was associated with a significantly increased risk for incident T2D in young adulthood, in a severity-dependent manner. This finding may support the role of insulin resistance in myopia pathogenesis.

OBJECTIVES: To compare the visual outcome of patients treated for non-arthritic central retinal artery occlusion (CRAO) in a medical centre that uses hyperbaric oxygen therapy (HBOT) as part of the standard of care (SOC) to medical centres that does not. METHODS: The study included data from two tertiary medical centres. The medical records of all patients diagnosed with non-arthritic CRAO without a patent cilioretinal artery between January 2010 and December 2018 in two tertiary medical centres were reviewed. RESULTS: One hundred and twenty-one patients were treated by HBOT and 23 patients received only SOC. In the HBOT group, best-corrected visual acuity (BCVA) improved from 2.89 ± 0.98 logMAR at presentation to 2.15 ± 1.07 logMAR upon the end of HBOT (P < 0.001), while the SOC group had no significant improvement, from 3.04 ± 0.82 logMAR at presentation to 2.80 ± 1.50 logMAR (P = 0.24). With adjustment for age, gender, and the duration of symptoms, final BCVA in the HBOT group was significantly better compared to the control group (P = 0.023). Rates of patients achieving vision of 20/200 or better were similar between groups (17.4% vs. 19.8%, P = 0.523). CONCLUSION: Utilizing HBOT as part of the SOC for CRAO improves the final visual outcome. HBOT is safe and can be implemented, if available, as part of SOC in all tertiary medical centres.