Herpes zoster (HZ) results from reactivation of latent varicella-zoster virus. Recent observations have suggested that HZ is associated with vaccination against COVID-19. To investigate the association between the vaccine and HZ severity, a single-centre, crosssectional study of all patients diagnosed with HZ and 2 control diagnoses (cellulitis and bone fractures), between 2017 and 2021, was performed. Hospital visits and hospitalization rates were compared. All medical records of patients diagnosed with HZ in the first year after the COVID-19 vaccination campaign began were reviewed, in order to generate a retrospective cohort comparing vaccinated and unvaccinated patients with HZ. All participants had received the Pfizer-BioNTech COVID-19 (BNT162b2) vaccine. During the study period, 2,413 patients were diagnosed with HZ, and when normalized to control diagnoses the number of cases remained stable. The retrospective cohort included 365 patients. A multivariate analysis controlling for sex, age, autoimmune diseases, malignancies, and immunosuppressive therapy showed higher admission rates in vaccinated compared with unvaccinated individuals (odds ratio (OR) 2.75, 95% CI 1.27-5.96, p =0.01). However, matching techniques and stratification by age, used to better control for confounders, invalidated these findings. No differences were observed in other variables indicative of disease severity (hospital stay length and complications). In conclusion, COVID-19 vaccination was not found to be associated with an increased risk of HZ-related admission and complications.

Previous research highlights the adverse effects of visual impairment (VI) on academic achievement in children, yet its impact on cognitive performance among adolescents and young adults remains under-studied. Therefore, this investigation aimed to analyse this association in a nationwide sample of Israeli adolescents. A retrospective population-based cross-sectional study was conducted among 1,410,616 Israeli-born adolescents aged 16–19 years, who were assessed before mandatory military service between 1993 and 2017. The definition of VI was based on best-corrected visual acuity (BCVA) measurements using a standard Snellen chart. Adolescents with BCVA worse than 6/9 in either or both eyes were classified as having unilateral or bilateral VI, respectively. Cognitive performance was measured using the General Intelligence Score (GIS), based on a validated four-domain test. Relationships were analysed using regression models yielding adjusted odds ratios (ORs) for low (<−1 standard deviation [SD]) and high (≥1 SD) cognitive Z-scores. Of 1,410,616 adolescents (56.1

Epidermal differentiation is ultimately aimed at the formation of a functional barrier capable of protecting the organism from the environment while preventing loss of biologically vital elements. Epidermal differentiation entails a delicately regulated process of cell-cell junction formation and dissolution to enable upward cell migration and desquamation. Over the past two decades, the deciphering of the genetic basis of a number of inherited conditions has delineated the pivotal role played in this process by a series of proteases and protease inhibitors, including serpins, cathepsins, and cystatins, suggesting novel avenues for therapeutic intervention in both rare and common disorders of cornification.

Drug-associated bullous pemphigoid has been shown to follow long-term gliptin (dipeptidyl-peptidase 4 inhibitors) intake. This study aimed at identifying risk factors for gliptin-associated bullous pemphigoid among patients with type 2 diabetes. A retrospective study was conducted in a tertiary centre among diabetic patients exposed to gliptins between the years 2008–2021. Data including demographics, comorbidities, medications, and laboratory results were collected using the MDClone platform. Seventy-six patients with type 2 diabetes treated with dipeptidyl-peptidase 4 inhibitors who subsequently developed bullous pemphigoid were compared with a cohort of 8,060 diabetic patients exposed to dipeptidyl-peptidase 4 inhibitors who did not develop bullous pemphigoid. Based on a multivariable analysis adjusted for age and other covariates, Alzheimer’s disease and other dementias were significantly more prevalent in patients with bullous pemphigoid (p = 0.0013). Concomitant use of either thiazide or loop diuretics and gliptin therapy was associated with drug-associated bullous pemphigoid (p < 0.0001 for both). While compared with sitagliptin, exposure to linagliptin and vildagliptin were associated with bullous pemphigoid with an odds ratio of 5.68 and 6.61 (p < 0.0001 for both), respectively. These results suggest gliptins should be prescribed with caution to patients with type 2 diabetes with coexisting Alzheimer’s and other dementias, or patients receiving long-term use of thiazides and loop diuretics. The use of sitagliptin over linagliptin and vildagliptin should be preferred in these patients.

Tricho-dento-osseous syndrome (TDOS) is a rare ectodermal dysplasia caused by mutations in the DLX3 gene and it is not usually included as a cause of syndromic woolly hair. We present a new case of TDOS with a novel DLX3 variant and woolly hair.

Summary Background Previous research on the association between body mass index (BMI) and visual impairment (VI) in youth has reported inconsistent findings. We aimed to investigate this association in a national cohort of Israeli adolescents. Methods This retrospective, population‐based, cross‐sectional study included 1 697 060 adolescents (56.4% men; mean age 17 years) who underwent mandatory pre‐military service assessments from 1993 to 2017. BMI was classified based on the US age‐ and sex‐matched percentiles. Unilateral or bilateral VI was classified as best‐corrected visual acuity (BCVA) worse than 6/9 in either or both eyes, respectively. Sex‐stratified regression models adjusted for sociodemographic variables were used to analyse the BMI‐VI relationship. Results Overall, 17 871 (1.05%) and 5148 (0.30%) adolescents had unilateral and bilateral VI, respectively. Compared with high‐normal BMI (50th to 85th percentile), adjusted odds ratios (ORs) for unilateral and bilateral VI gradually increased with higher BMI, reaching 1.33 (1.13–1.55) and 1.80 (1.37–2.35) in men with severe obesity, and 1.51 (1.24–1.84) and 1.52 (1.08–2.14) in women with severe obesity, respectively. Men with underweight also had increased ORs for unilateral and bilateral VI (1.23; 1.14–1.33 and 1.59; 1.37–1.84, respectively), a pattern not observed in women (0.96; 0.86–1.07 and 1.02; 0.83–1.25, respectively). Results were maintained when the outcome was restricted to mild VI, as well as in subgroups of adolescents with unimpaired health and those without moderate‐to‐severe myopia. Conclusions Abnormal BMI, and particularly obesity, is associated with increased OR for VI in late adolescence.

Frontonasal dysplasia (FND) refers to a group of rare developmental disorders characterized by abnormal morphology of the craniofacial region. We studied a family manifesting with clinical features typical for FND2 including neurobehavioral abnormalities, hypotrichosis, hypodontia, and facial dysmorphism. Whole-exome sequencing analysis identified a novel heterozygous frameshift insertion in ALX4 (c.985_986insGTGC, p.Pro329Argfs*115), encoding aristaless homeobox 4. This and a previously reported dominant FND2-causing variant are predicted to result in the formation of a similar abnormally elongated protein tail domain. Using a reporter assay, we showed that the elongated ALX4 displays increased activity. ALX4 negatively regulates the Wnt/β-catenin pathway and accordingly, patient keratinocytes showed altered expression of genes associated with the WNT/β-catenin pathway, which in turn may underlie ectodermal manifestations in FND2. In conclusion, dominant FND2 with ectodermal dysplasia results from frameshift variants in ALX4 exerting a gain-of-function effect.

Cole disease (CD) is a rare genodermatosis featuring punctate palmoplantar keratosis and patchy hypopigmentation. This disorder results from pathogenic variants in ENPP1 which encodes ectonucleotide pyrophosphatase/ phosphodiesterase 1a. ENPP1 is responsible for the biosynthesis of an inhibitor of ectopic calcification. CD-causing variants affect a specific domain of the protein which may regulate response to insulin. We have previously shown that ENPP1 is expressed in keratinocytes. Downregulation of ENPP1 in organotypic skin cultures and MNT1 cells was associated with hyperproliferation and decreased melanin synthesis, respectively. We then aimed to investigate the pathomechanism by which CD-causing variants result in epidermal proliferation and decrease in melanin synthesis. Loss-of-function of ENPP1 in murine articular cartilage results in hedgehog pathway activation and overexpression of sonic hedgehog signaling in the skin causes epidermal basal proliferation and decrease in melanin synthesis as seen with ENPP1 downregulation, suggesting a mechanism underlying CD pathogenesis. A significant increase in luciferase activity was measured in HeLa cells transfected with a construct expressing the CD-causing c.530G>A ENPP1 variant along with a sonic hedgehog luciferase reporter as compared to cells transfected with wild-type ENPP1 cDNA. Similarly, downregulation of ENPP1 with specific siRNAs in the same system was also associated with a significant increase in luciferase activity as compared with cells transfected with a control siRNA, suggesting a loss-of-function effect. In summary, the present data substantiate the notion that ENPP1 regulates epidermal differentiation and melanogenesis by modulation of the hedgehog pathway activity.

PurposeThe 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.MethodsA 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.ResultsApplying 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).ConclusionsThe 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.

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: Gain-of-function mutations in CARD14 have recently been shown to be involved in the pathogenesis of psoriasis and pityriasis rubra pilaris (PRP). Those mutations were found to activate the NF-kB signaling pathway. Objective: Zebrafish is often used to model human diseases in general, and in skin disorders more particularly. In the present study, we aimed to examine the effect of CARD14 overexpression in zebrafish with the aim to validate this model for future translational applications. Methods: We used light microscopy, scanning electron microscopy, histological analysis and whole mount in situ hybridization as well as real-time PCR to ascertain the effect of CARD14 overexpression in the developing zebrafish. Results: Overexpression of human CARD14 had a marked morphological and developmental effect on the embryos. Light microscopy demonstrated a characteristic cutaneous pattern including a granular surface and a spiky pigment pattern. In situ hybridization revealed keratinocytes of uneven size and shape. Scanning electron microscopy showed aberrant production of actin microridges and a rugged keratinocyte cell surface, reminiscent of the human hyperkeratotic phenotype. Developmentally, overexpression of CARD14 had a variable effect on anterior-posterior axis symmetry. Similar to what has been observed in humans with psoriasis or PRP, NF-kB expression was higher in CARD14-overexpressing embryos compared to controls. Conclusions: Overexpression of CARD14 results in a distinct cutaneous pattern accompanied by hyperactivation of the NF-kB pathway, suggesting that the zebrafish represents a useful system to model CARD14-associated papulosquamous diseases.

A steadily growing number of hereditary palmoplantar keratodermas (PPKs) have been found to result from defective function of epidermal adhesion proteins such as desmoglein 1 (DSG1), a critical component of desmosomes which has been implicated in the pathogenesis of striate, diffuse and focal PPKs. Here we aimed at delineating the genetic basis of a novel dominant form of PPK. We studied three patients from two families diagnosed with PPK. Whole exome sequencing revealed causative pathogenic heterozygous variants in KLF4 gene in the three affected individuals. Immunofluorescence staining revealed reduced epidermal desmoglein 1 (DSG1) expression in patients harboring heterozygous KLF4 variants. Accordingly, human keratinocytes either transfected with constructs expressing these variants or down-regulated for KLF4, displayed reduced DSG1 expression, which has previously been found to be associated with PPK. A ChIP assay confirmed direct binding of KLF4 to the DSG1 promoter region. The ability of mutant KLF4 to trans-activate the DSG1 promoter was significantly decreased. In Conclusion, Loss-of-function variants in KLF4 cause a novel form of dominant PPK and demonstrate its importance in the regulation of epidermal differentiation.

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<.001). For women, T2D incidence rates (per 100 000 person-years) were 16.6, 19.2, and 25.1 for those without myopia, and with mild-to-moderate and high myopia, respectively. These corresponded to HRs of 1.29 (95% CI, 1.14-1.45) and 1.63 (1.21-2.18) for women with mild-to-moderate and high myopia, respectively, compared to those without myopia, after adjustment for age at study entry, birth year, adolescent body mass index, cognitive performance, socioeconomic status, and immigration status. Results persisted in extensive sensitivity and subgroup analyses. When managed as a continuous variable, every 1-diopter lower spherical equivalent yielded a 6.5% higher adjusted HR for T2D incidence (P= .003). There was no significant association among men. 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.

PURPOSE: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.METHODS: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.RESULTS:We identified 2 heterozygous variants (c.1226A>G 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.CONCLUSION:Loss-of-function variants in KLF4 cause a novel form of dominant PPK and show its importance in the regulation of epidermal differentiation.

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.

Objective This study analyzed the association between adolescent BMI and myopia severity. Methods 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. Results 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 (p(interaction) < 0.001), in whom the group with severe obesity did not reach statistical significance. Conclusions BMI 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.