bluuebunny/crossref_metadata_2025 huggingface dataset:
Reversible switching between two common protein folds in a designed system using only temperature
Authors: Solomon Tsega L. , He Yanan , Sari Nese , Chen Yihong , Gallagher D. Travis , Bryan Philip N. , Orban John
Published: January 2023

Naturally occurring metamorphic proteins have the ability to interconvert from one folded state to another through either a limited set of mutations or by way of a change in the local environment. Here, we show in a designed system that it is possible to switch reversibly between two of the most common monomeric folds employing only temperature changes. We demonstrate that a latent 3α state can be unmasked from an α/β-plait topology with a single V90T amino acid substitution, populating both forms simultaneously. The equilibrium between these two states exhibits temperature dependence, such that the 3α state is predominant (>90%) at 5 °C, while the α/β-plait fold is the major species (>90%) at 30 °C. We describe the structure and dynamics of these topologies, how mutational changes affect the temperature dependence, and the energetics and kinetics of interconversion. Additionally, we demonstrate how ligand-binding function can be tightly regulated by large amplitude changes in protein structure over a relatively narrow temperature range that is relevant to biology. The 3α/αβ switch thus represents a potentially useful approach for designing proteins that alter their fold topologies in response to environmental triggers. It may also serve as a model for computational studies of temperature-dependent protein stability and fold switching.
Cell survival following direct executioner-caspase activation
Authors: Nano Maddalena , Mondo James A. , Harwood Jacob , Balasanyan Varuzhan , Montell Denise J.
Published: January 2023

Executioner-caspase activation has been considered a point-of-no-return in apoptosis. However, numerous studies report survival from caspase activation after treatment with drugs or radiation. An open question is whether cells can recover from direct caspase activation without pro-survival stress responses induced by drugs. To address this question, we engineered a HeLa cell line to express caspase-3 inducibly and combined it with a quantitative caspase activity reporter. While high caspase activity levels killed all cells and very low levels allowed all cells to live, doses of caspase activity sufficient to kill 15 to 30% of cells nevertheless allowed 70 to 85% to survive. At these doses, neither the rate, nor the peak level, nor the total amount of caspase activity could accurately predict cell death versus survival. Thus, cells can survive direct executioner-caspase activation, and variations in cellular state modify the outcome of potentially lethal caspase activity. Such heterogeneities may underlie incomplete tumor cell killing in response to apoptosis-inducing cancer treatments.
Nonequilibrium Green’s function approach to multi-band Cooper-pair transport: linear magnetoresistance effect due to nonunitary superconductivity
Authors: Tkachov G
Published: January 2023

Many-body transport has emerged as an efficient tool for understanding interaction effects in quantum materials with a multi-band electronic structure. This paper proposes a formula for the two-particle transmission coefficient for Cooper-pair transport between multi-band normal and superconducting materials. The approach employs a tight-binding nonequilibrium Green’s function technique, allowing a direct calculation of the two-particle current, without invoking the paradigm of Andreev reflection. As an application of the theory, we demonstrate a low-field linear magnetoresistance effect for superconductors with an induced nonunitary order parameter. These results uncover an unexplored route for detecting unconventional nonunitary superconductivity in quantum materials of current theoretical and experimental interest.
Environmental sensitivity of GaN nanofins grown by selective area molecular beam epitaxy
Authors: Pantle Florian , Wörle Simon , Karlinger Monika , Rauh Felix , Kraut Max , Stutzmann Martin
Published: January 2023

Nanostructures exhibit a large surface-to-volume ratio, which makes them sensitive to their ambient conditions. In particular, GaN nanowires and nanofins react to their environment as adsorbates influence their (opto-) electronic properties. Charge transfer between the semiconductor surface and adsorbed species changes the surface band bending of the nanostructures, and the adsorbates can alter the rate of non-radiative recombination in GaN. Despite the importance of these interactions with the ambient environment, the detailed adsorption mechanisms are still not fully understood. In this article, we present a systematic study concerning the environmental sensitivity of the electrical conductivity of GaN nanofins. We identify oxygen- and water-based adsorbates to be responsible for a quenching of the electrical current through GaN nanofins due to an increased surface band bending. Complementary contact potential difference measurements in controlled atmospheres on bulk m- and c-plane GaN reveal additional complexity with regard to water adsorption, for which surface dipoles might play an important role besides an increased surface depletion width. The sensitive reaction of the electrical parameters to the environment and surface condition underlines the necessity of a reproducible pre-treatment and/or surface passivation. The presented results help to further understand the complex adsorption mechanisms at GaN surfaces. Due to the sensitivity of the nanofin conductivity on the environment, such structures could perform well as sensing devices.
Lipschitz and Hölder stable determination of nonlinear terms for elliptic equations
Authors: Kian Yavar
Published: January 2023

We consider the inverse problem of determining some class of nonlinear terms appearing in an elliptic equation from boundary measurements. More precisely, we study the stability issue for this class of inverse problems. Under suitable assumptions, we prove a Lipschitz and a Hölder stability estimate associated with the determination of quasilinear and semilinear terms appearing in this class of elliptic equations from measurements restricted to an arbitrary part of the boundary of the domain. Besides their mathematical interest, our stability estimates can be useful for improving numerical reconstruction of this class of nonlinear terms. Our approach combines the linearization technique with applications of suitable class of singular solutions.
Simulations of lithium impurity transport with a liquid lithium divertor using EMC3-EIRENE and ITCD
Authors: Gao G D , Liu B , Dai S Y , Chen Y T , Liu L Z , Feng Y , Wang D Z
Published: January 2023

Simulations of lithium (Li) impurity transport behaviour with a liquid lithium divertor on the EAST tokamak have been performed using the fluid code EMC3-EIRENE and the Monte Carlo code ITCD. The interactions between particles and the wall surface, like the gyration-induced scrape-off effect, sheath acceleration, kinetic self-sputtering and reflection, are typically ignored or simplified in fluid models. In order to uncover the impacts of the scrape-off effect, sheath acceleration, kinetic self-sputtering and reflection on Li distribution, detailed analysis of the density distributions of Li1+ and Li2+ ions at the divertor region have been carried out by ITCD modelling. The newly-upgraded ITCD code can principally reproduce the distribution patterns of Li ions as well as EMC3-EIRENE under identical plasma conditions on EAST. However, due to the scrape-off effect and sheath acceleration, the densities of Li1+ and Li2+ ions simulated by ITCD are evidently reduced compared to the EMC3-EIRENE simulations. The kinetic self-sputtering by redeposited Li particles in ITCD can increase the densities of the Li ions. Moreover, the kinetic reflection database calculated by SRIM code has been employed by ITCD, which leads to an increase in the Li densities compared to the reflection approach used in EMC3-EIRENE. Overall, by adding the aforesaid physical effects in ITCD, the total number of Li ions shows an obvious reduction compared to the EMC3-EIRENE modelling.
The effect of impurity kinds and content on phase constituent and the microstructure of LaSi alloy
Authors: Wang Shuang , Chen Dehong , Zhong Jiamin , Zhang Xiaowei , Wang Zhiqiang , Lia Xin , Yang Zikun , Liu Dezhong
Published: January 2023

LaSi alloy with 1:1 atomic ratio was prepared by vacuum arc melting process, and different content impurities of Fe, Ni and Cu were added into the LaSi alloy. The phase constituent and microstructure of LaSi alloy with different impurities were studied using XRD and SEM, respectively. Experimental results showed that the LaSi alloy exhibited a new phase LaSi2-x when the added Fe content reached more than 300ppm. And the main diffraction peak of LaSi phase was shifted to a lower angle with the increase of Fe content. Similar to the effect of Fe impurities, the phase LaSi2-x appeared when the Ni impurity was added into LaSi alloy, while the diffraction intensity of main peak reduced by about 5 times compared to high-pure LaSi alloy. There was no LaSi2-x phase when the Cu was added into LaSi alloy, and the diffraction intensity of the main peak of LaSi increased by 2 times compared to the high-purity LaSi alloy. The microstructure of LaSi with Fe and Ni impurities displayed dark grey network. The LaSi alloy exhibited almost single-phase microstructure when the Cu impurity content reached 1526ppm. The Fe and Ni impurities exerted an obvious effect on phase and microstructure of LaSi alloy, while the Cu impurities played little effect on the phase and microstructure of LaSi alloy.
Spectral Properties of Ruelle Transfer Operators for Regular Gibbs Measures and Decay of Correlations for Contact Anosov Flows
Authors: Stoyanov Luchezar
Published: January 2023

In this work we study strong spectral properties of Ruelle transfer operators related to a large family of Gibbs measures for contact Anosov flows. The ultimate aim is to establish exponential decay of correlations for Hölder observables with respect to a very general class of Gibbs measures. The approach invented in 1997 by Dolgopyat in “On decay of correlations in Anosov flows” and further developed in Stoyanov (2011) is substantially refined here, allowing to deal with much more general situations than before, although we still restrict ourselves to the uniformly hyperbolic case. A rather general procedure is established which produces the desired estimates whenever the Gibbs measure admits a Pesin set with exponentially small tails, that is a Pesin set whose preimages along the flow have measures decaying exponentially fast. We call such Gibbs measures regular. Recent results in Gouëzel and Stoyanov (2019) prove existence of such Pesin sets for hyperbolic diffeomorphisms and flows for a large variety of Gibbs measures determined by Hölder continuous potentials. The strong spectral estimates for Ruelle operators and well-established techniques lead to exponential decay of correlations for Hölder continuous observables, as well as to some other consequences such as: (a) existence of a non-zero analytic continuation of the Ruelle zeta function with a pole at the entropy in a vertical strip containing the entropy in its interior; (b) a Prime Orbit Theorem with an exponentially small error.
Phosphorus availability and planting patterns regulate soil microbial effects on plant performance in a semiarid steppe
Authors: Li Yawen , Lu Xiaoming , Su Jishuai , Bai Yongfei
Published: January 2023

Background and Aims

Growing evidence has suggested that plant responses to model soil microorganisms are context dependent; however, few studies have investigated the effects of whole soil microbial communities on plant performance in different abiotic and biotic conditions. To address this, we examined how soil phosphorus (P) availability and different planting patterns regulate soil microbial effects on the growth of two native plant species in a semiarid steppe.

Methods

We carried out a glasshouse experiment to explore the effects of the whole indigenous soil microbiota on the growth and performance of Leymus chinensis and Cleistogenes squarrosa using soil sterilization with different soil P availabilities and planting patterns (monoculture and mixture). Transcriptome sequencing (RNA-seq) was used to explain the potential molecular mechanisms of the soil microbial effects on C. squarrosa.

Key Results

The soil sterilization treatment significantly increased the biomass of L. chinensis and C. squarrosa in both monoculture and mixture conditions, which indicated that the soil microbiota had negative growth effects on both plants. The addition of P neutralized the negative microbial effects for both L. chinensis and C. squarrosa, whereas the mixture treatment amplified the negative microbial effects on L. chinensis but alleviated them on C. squarrosa. Transcriptomic analysis from C. squarrosa roots underscored that the negative soil microbial effects were induced by the upregulation of defence genes. The P addition treatment resulted in significant decreases in the number of differentially expressed genes attributable to the soil microbiota, and some defence genes were downregulated.

Conclusions

Our results underline that indigenous soil microbiota have negative effects on the growth of two dominant plant species from a semiarid steppe, but their effects are highly dependent on the soil P availability and planting patterns. They also indicate that defence genes might play a key role in controlling plant growth responses to the soil microbiota.
A cooking pot lit by fire
Authors: Gasper Giles E M , Tanner Brian K
Published: January 2023

Giles E M Gasper and Brian K Tanner discuss a newly-identified 12th century report by an English chronicler which appears to describe solar prominences.
Efficacy and safety of Oleogel-S10 (birch triterpenes) for epidermolysis bullosa: results from the phase III randomized double-blind phase of the EASE study
Authors: Kern Johannes S , Sprecher Eli , Fernandez Maria Florencia , Schauer Franziska , Bodemer Christine  , Cunningham Tracy , Löwe Sandra , Davis Charles , Sumeray Mark , Bruckner Anna L , Murrell Dédée F ,   for the EASE investigators
Published: January 2023

Background

Epidermolysis bullosa (EB) is a heterogeneous group of rare, difficult-to-treat, inherited multisystem diseases affecting epithelial integrity. Patients with EB are affected by mechanical fragility of epithelial surfaces including the skin and, as a result, extensive recurrent blistering is a characteristic of the condition. Chronic wounds predispose patients with EB to the development of squamous cell carcinoma, which is a major cause of premature death.

Objectives

EASE was a double-blind, randomized, vehicle-controlled, phase III study to determine the efficacy and safety of the topical gel Oleogel-S10 (birch triterpenes) in EB. EASE was funded by Amryt Research Limited.

Methods

Patients with dystrophic EB, junctional EB or Kindler EB and a target partial-thickness wound lasting ≥ 21 days and < 9 months that was 10–50 cm2, were enrolled and randomized via computer-generated allocation tables 1 : 1 to Oleogel-S10 or control gel – both with standard-of-care dressings. Study gel was applied to all wounds at least every 4 days. The primary endpoint was the proportion of patients with first complete closure of target wound within 45 days.

Results

A total of 223 patients were enrolled and treated (109 treated with Oleogel-S10, 114 with control gel). The primary endpoint was met; Oleogel-S10 resulted in 41·3% of patients with first complete target wound closure within 45 days, compared with 28·9% in the control gel arm (relative risk 1·44, 95% confidence interval (CI) 1·01–2·05; P = 0·013). Adverse events (AEs) occurred with similar frequency for Oleogel-S10 (81·7%) compared with control gel (80·7%). AEs were predominantly of mild-to-moderate intensity (4·6% were severe).

Conclusions

Oleogel-S10 is the first therapy to demonstrate accelerated wound healing in EB. Oleogel-S10 was well ­tolerated.
The perspectives of 606 US dermatologists on active surveillance for low-risk basal cell carcinoma
Authors: van Egmond Sven , de Vere Hunt Isabella , Cai Zhuo Ran , Rizk Nada , Wakkee Marlies , Chren Mary-Margaret , Goldfarb Noah , Simard Julia F , Linos Eleni
Published: January 2023

In this survey study of over 600 US dermatologists, identical clinical scenarios (10mm primary asymptomatic BCC) were presented except for randomly varied patient characteristics including age, life expectancy, and tumor location. Most dermatologists (62%) recommended active surveillance for patients with advanced age (91 years) and a 1-year life expectancy. The odds ratio for choosing active surveillance was 20.31 (95% CI 14.10-35.30) comparing a patient with a 1-year life expectancy to a healthy patient.
Interleukin-13 inhibition by tralokinumab reduces inducible T-cell costimulator-positive innate lymphoid cells in skin lesions of atopic dermatitis
Authors: Kogame Toshiaki , Yonekura Satoru , Lovato Paola , Hirata Masahiro , Takimoto-ito Riko , Takegami Tomoya , Komatsu-Fujii Takayoshi , Kambe Naotomo , Nomura Takashi , Røpke Mads A , Kabashima Kenji
Published: January 2023

Despite the low frequency of skin ILCs and the limited number of samples analyzed in this study, our data indicate that ICOS+ ILCs express IL-13Rα1 and that the density of ICOS+ ILCs decreased four weeks after initiation of treatment with tralokinumab.
Burden of disease: assessing quality-of-life impacts in hyperhidrosis
Authors: Gabes Michaela , Donhauser Theresa , Kann Gesina , Masur Clarissa , Apfelbacher Christian
Published: January 2023

With this study it can be concluded that a substantial number of severe axillary HH patients suffers from a tremendous impairment in their QoL. In comparison to other dermatological conditions, the burden of disease in hyperhidrosis is quite high.
Near complete responses to concurrent brentuximab vedotin and ultra-hypofractionated low-dose total skin electron beam radiation in advanced cutaneous T-cell lymphoma
Authors: Oymanns Mathias , Daum-Marzian Michael , Bellm Aliyah , Elsayad Khaled , Eich Hans T , Assaf Chalid
Published: January 2023

Patients with advanced stage mycosis fungoides (MF) or Sézary syndrome (SS) have a poor prognosis. Despite many available active single agents for CTCL treatment, high remission rates and long-lasting responses are rarely achieved in advanced CTCL [1]. Therefore, it is important to find more effective strategies, e.g. combination therapy, which could enhance efficacy by targeting key pathways in a synergistic or additive manner. We report on three patients with tumor stage MF (IIB) with fast response and very good partial remission due to induction with BV with 1.8 mg/kg dose concurrently in combination with ultra-hypofractionated low dose TSEBT.
Semi-virtual patch testing: the future?
Authors: Vincent Rosie , Ormerod Emma , Gollins Charlotte E , Rai Nabina , Conduit-Turner Karen , Sinha Aparna , Sansom Jane
Published: January 2023

A review of 181 patients that underwent ‘semi-virtual’ patch testing using virtual day 2 readings. Results highlight that most patients are able to remove patches and take high quality images via smart phone technology, with very limited adverse clinical impact. A notable reduction in travel was required, with subsequent positive environmental impacts.
Pain experiences among those living with hidradenitis suppurativa: a qualitative study
Authors: Orenstein Lauren A V , Salame Nicole , Siira Meron R , Urbanski Megan , Flowers Nyla I , Echuri Harika , Garg Amit , McKenzie-Brown Anne Marie , Curseen Kimberly A , Patzer Rachel E , Kavalieratos Dio , Chen Suephy C
Published: January 2023

Background

Pain is rated by patients with hidradenitis suppurativa (HS) as the disease’s most impactful symptom. HS therapies are often insufficient to control inflammatory disease activity and pain. A better understanding of patient experiences with pain may improve patient–provider relationships and help identify strategies for addressing HS pain.

Objectives

This qualitative study sought to characterize lived pain experiences of those with HS.

Methods

English-speaking patients ≥ 18 years old with a dermatologist-confirmed diagnosis of HS and an average numerical rating scale pain score of ≥ 1 over the preceding week were recruited from a single academic medical centre in Atlanta, Georgia, USA. Semistructured interviews were conducted from November 2019 to March 2020 to explore participants’ HS pain experiences and the subsequent impact on their lives. Thematic saturation was reached after interviewing 21 participants. Interviews were audio recorded, transcribed, and analysed using thematic analysis.

Results

Among 21 study participants, the median 7-day average pain score was 6 (interquartile range 3–7; scale ranges from 0 to 10, with 10 being most pain). Participants’ descriptions of pain were consistent with nociceptive pain, neuropathic pain and itch. Pain impacted multiple life domains, including physical limitations (decreased mobility and impaired sleep), decreased psychological wellbeing (irritability, depression, loss of control, and difficulty communicating pain experiences) and impaired social relationships (social isolation, intimacy problems and difficulty fulfilling social responsibilities). Although participants reported chronic discomfort, acutely painful and unpredictable HS disease flares caused more distress and quality-of-life (QoL) burden. Participants frequently treated their pain without input from the medical team, sometimes with unsafe medication doses or combinations. Factors contributing to self-management of pain included difficulty accessing timely outpatient care during disease flares and fear of stigma from healthcare providers.

Conclusions

When present, HS-related pain may impact not only physical wellbeing but also mental health and relationships. In addition to therapies that target the inflammatory disease burden, treating the symptom of pain may improve patients’ QoL and wellbeing. Because patients with HS have difficulty explaining their pain, proactively asking them about pain may identify unmet needs, facilitate better pain control and improve QoL. Further, the influence of HS-related pain on numerous aspects of QoL suggests the need for multidisciplinary, patient-centred approaches to HS pain management.
Pathogenic variants in the SPTLC1 gene cause hyperkeratosis lenticularis perstans
Authors: Jägle Sabine , Hsu Hao-Hsiang , Juratli Hazem A , Zimmer Andreas D , Prieschl Amelie , Alter Svenja , Wiedenhofer Bernhard , Metze Dieter , Emmert Steffen , Fischer Judith
Published: January 2023

Background

Hyperkeratosis lenticularis perstans (HLP), also known as Flegel disease, is a rare skin disease presenting with asymptomatic small hyperkeratotic papules. The lesions often appear on the dorsal feet and lower legs, and typically develop after the fourth decade of life. A genetic basis for HLP is suspected; however, so far no gene defect linked to the development of HLP has been identified.

Objectives

We aimed to identify the genetic cause of HLP.

Methods

For mutational analysis we studied a cohort of five patients with HLP using next-generation sequencing (NGS). We used DNA ­extracted from fresh skin biopsies alongside ethylenediamine tetraacetic acid (EDTA) blood samples from two patients, and formalin-fixed ­paraffin-embedded skin biopsy material from three patients. In addition, immunofluorescence staining of HLP lesions from four patients was investigated.

Results

In all samples from the five patients with HLP we identified by NGS rare variants in the SPTLC1 gene. In four patients we detected small deletions/frameshift variants and in one patient a splicing variant, predicted to disturb the splicing process. In blood samples the detected variants were heterozygous with an allele frequency of 49% and 50%, respectively. In skin biopsies the allele frequency was within the range of 46–62%. Immunofluorescence staining revealed reduced SPTLC1 protein levels in skin of patients.

Conclusions

Our findings suggest that pathogenic variants in the SPTLC1 gene are the underlying genetic cause of HLP. Of note, the identified variants were either frameshift- or splicing variants probably leading to nonsense-mediated mRNA decay and thus reduced SPTLC1 protein levels. We conclude that diminished SPTLC1, the key enzyme in sphingolipid biosynthesis, leads to the development of HLP, which highlights the sphingolipid pathway as a new therapeutic target.
The impact of hidradenitis suppurativa on professional life
Authors: Schneider-Burrus Sylke , Kalus Stefanie , Fritz Björn , Wolk Kerstin , Gomis-Kleindienst Susana , Sabat Robert
Published: January 2023

Background

Hidradenitis suppurativa (HS) is a chronic inflammatory disease that affects intertriginous skin.

Objectives

To determine the extent of work ability and productivity impairment as a result of HS in Germany.

Methods

A prospective, multicentre, epidemiological, noninterventional study of patients with HS was conducted. Medical history, medical examination performed by dermatologists and patient-reported outcomes [Work Ability Index (WAI) and Work Productivity and Activity Impairment (WPAI)] were collected.

Results

Of the 481 patients with HS included in the study, 99% were below the current statutory retirement age. In total, 53·3% of patients were working full time, 16·8% part time and 7·3% had retired. The unemployment rate was 12·6%, two times higher than in the general German population. Medical leave because of HS, within the last 6 months, was reported in 41·4% [95% confidence interval (CI) 36·9–46·0], with a duration of 39·3 days on average (95% CI 32·4–46·1). The mean HS-related WPAI absenteeism was 13.3% (95% CI 9·7–16·8), and the loss in productivity because of HS during working hours (WPAI presenteeism) was 25.2% (95% CI 21·8–28·6). Presenteeism was associated with HS disease severity. Overall work impairment because of HS was 33·4% (95% CI 29·3–37·6). The WAI score for patients was 32·2, ∼20% lower than for the average German employee. Only 62·8% of patients were relatively certain that they would be able to perform their work in the coming 2 years. Being more depressed and having more severe pain were associated with lower work ability and overall work impairment. The estimated annual loss of gross value added because of HS for Germany was ∼€12.6 billion (€3.3 billion related to a lower employment rate, €3.5 billion related to absenteeism and €5.8 billion related to presenteeism).

Conclusions

HS leads to a substantial decrease in work ability and productivity and considerable loss of gross value added. Impairment during working hours correlates with disease severity, underlining the socioeconomic importance of early and adequate treatment. Furthermore, decreased work ability and productivity is linked to depressed mood and severe pain, aspects that need more attention in patient care.
Variants in KLK11, affecting signal peptide cleavage of kallikrein-related peptidase 11, cause an autosomal-dominant cornification disorder
Authors: Gong Zhuoqing , Dai Shangzhi , Jiang Xingyuan , Lee Mingyang , Zhu Xuejun , Wang Huijun , Lin Zhimiao
Published: January 2023

Background

Mendelian disorders of cornification (MeDOC) are a group of heterogeneous genodermatoses with different genetic bases. The pathogenesis of a substantial group of MeDOC remains to be elucidated.

Objectives

To identify a new causative gene and the pathogenesis of a previously undescribed autosomal-dominant cornification disorder.

Methods

Whole-exome sequencing was performed in three families with the novel cornification disorder to identify the disease-causing variants. As the variants were located around the signal peptide (SP) cleavage site of a kallikrein-related peptidase, SP cleavage, subcellular localization and extracellular secretion of the variants were evaluated in eukaryotic overexpression systems by Western blotting or immunocytochemistry. Then the trypsin-like and chymotrypsin-like proteolytic activity of the peptidase and degradation of its catalytic substrate were assayed using the patients’ stratum corneum (SC) samples. The morphology of the lamellar bodies and corneodesmosomes (CDs) in the patients’ SC was ultrastructurally examined. A mouse model harbouring the equivalent variant was constructed and evaluated histologically.

Results

We identified two heterozygous variants affecting Gly50 in kallikrein-related peptidase (KLK)11 in a familial case and two sporadic cases with the new disorder, which is characterized by early-onset ichthyosiform erythroderma or erythrokeratoderma. KLK11 belongs to the family of kallikrein-related peptidases participating in skin desquamation by decomposing CDs, a process essential for shedding of the SC. In vitro experiments demonstrated that the variants perturbed the SP cleavage of KLK11, leading to subcellular mislocalization and impaired extracellular secretion of the KLK11 Gly50Glu variant. Both trypsin-like and chymotrypsin-like proteolytic activities were significantly decreased in the patients’ SC samples. Reduced proteolysis of desmoglein 1 and delayed degeneration of CDs were detected in patients’ SC, indicating delayed skin desquamation. Consistently, the patients showed a thickened, dense SC, indicating abnormal skin desquamation. Mice harbouring the homozygous c.131G>A (p.Gly44Glu) Klk11 variant, which is equivalent to KLK11 c.149G>A (p.Gly50Glu) in humans, exhibited hyperkeratosis and abnormal desquamation, partially recapitulating the phenotype.

Conclusions

We provide evidence that variants at Gly50 affecting the SP cleavage of KLK11 cause a new autosomal-dominant cornification disorder with abnormal desquamation. Our findings highlight the essential role of KLKs in maintaining homeostasis of skin keratinization and desquamation.
Water and adult eczema: the hard truth?
Authors: Zhang Junfen , Schuttelaar Marie L A
Published: January 2023

This is an invited commentary letter for the publication entitled "The association between domestic hard water and eczema in adults from the UK Biobank cohort study" in the recent issue of BJD.
Trends in incidence, treatment and survival of Merkel cell carcinoma in England 2004–2018: a cohort study
Authors: Mistry Khaylen , Levell Nick J , Hollestein Loes , Wakkee Marlies , Nijsten Tamar , Knott Craig S , Steven Neil M , Craig Paul J , Venables Zoe C
Published: January 2023

Background

Merkel cell carcinoma (MCC) is a rare tumour with neuroendocrine differentiation and high associated mortality. Studies that describe the epidemiology of MCC are often limited by small sample size, short duration of follow-up, absence of nationwide data and paucity of data on different risk factors.

Objectives

To determine the incidence, demographics and survival for MCC in England between 2004 and 2018.

Methods

This national retrospective cohort study identified all cases of MCC in England from 2004 to 2018 using national population-based data from the National Disease Registration Service. Crude counts, European age-standardized incidence rates (EASRs) and joinpoint analysis were conducted. Patient demographics and treatments received were described. Multivariable Cox regression analysis was used to study risk factors for MCC-specific mortality, by including a priori defined demographic factors, tumour characteristics and immunosuppression. Treatment data were not included in the Cox regression analysis.

Results

A total of 3775 MCC tumours were registered. The median age at diagnosis was 81 years (interquartile range 74–87). Overall, 96·6% of patients identified as White ethnicity, and 8·3% of patients were immunosuppressed. The most common site was the face (27·4%). Patients most often presented with stage one disease (22·8%); however, stage was unknown in 31·0%. In total, 80·7% of patients underwent surgical excision, 43·5% radiotherapy and 9·2% systemic therapy. The EASR increased from 0·43 per 100 000 person-years (PYs) to 0·65 per 100 000 person-years between 2004 and 2018, representing a significant annual percentage change of 3·9%. The EASR was greater in men than in women for all years, with an overall male-to-female ratio of 1·41 : 1. The highest EASR was in South West England. Five-year disease-specific survival was 65·6% [95% confidence interval (CI) 63·8–67·4], with a median follow-up of 767 days. MCC-specific mortality increased with age [hazard ratio (HR) 1·02, 95% CI 1·02–1·03], deprivation (HR 1·43, 95% CI 1·16–1·76), immunosuppression (HR 2·80, 95% CI 2·34–3·34) and stage at diagnosis (HR 8·24, 95% CI 5·84–11·6).

Conclusions

This study presents the largest national MCC dataset in Europe, and the most complete reporting of MCC incidence and survival ever published. With the EASR of MCC increasing and high associated mortality, this study encourages further research into the pathology, diagnosis and therapeutic options for MCC to support management guidelines.
Strongyloides screening prior to dupilumab therapy in atopic dermatitis: a retrospective cohort study evaluating screening utility
Authors: Gill Kyra , Xu Jennifer , Kozera Emily , Stewart Thomas , Flora Akshay , Frew John W
Published: January 2023

The utility of Strongyloidiasis screening in the setting of Dupilumab therapy is unknown. Our retrospective cohort study identifies a low prevalence of Strongyloidiasis with no cases of disseminated disease in the setting of Dupilumab therapy. Baseline IgE and Eosinophil levels were not associated with Strongyloidiasis and screening is likely of low utility.
Atopic dermatitis across the life course
Authors: Abuabara Katrina , Langan Sinéad M
Published: January 2023

Atopic dermatitis, the most common chronic inflammatory skin disease, can occur at any age, and patterns of disease activity vary over time. Both prevalence and incidence are highest in infancy and early childhood, followed by a second peak in older adulthood. Birth cohort studies from European countries following children through adolescence have identified subgroups of patients with early-onset persistent disease, early-onset resolving disease, and later-onset disease. Parental history of atopy and genetic factors are among the most consistent predictors of more persistent disease. Studies have begun to examine whether molecular markers differ by age group, although longitudinal data are lacking. Breastfeeding, probiotics and skin-directed therapies such as emollients have been investigated as potential preventive measures, but randomized trials have not found consistent long-term benefit. Future research should focus on patterns of disease activity beyond early adulthood and the role of treatments on long-term disease activity.
Bimekizumab efficacy and safety in patients with moderate-to-severe plaque psoriasis who switched from adalimumab, ustekinumab or secukinumab: results from phase III/IIIb trials
Authors: Kokolakis Georgios , Warren Richard B , Strober Bruce , Blauvelt Andrew , Puig Luis , Morita Akimichi , Gooderham Melinda , Körber Andreas , Vanvoorden Veerle , Wang Maggie , de Cuyper Dirk , Madden Cynthia , Nunez Gomez Natalie , Lebwohl Mark
Published: January 2023

Background

Discontinuation of biologics is common among patients with psoriasis due to treatment failure or adverse events. To achieve improvements in disease management, patients and clinicians may choose to switch biologics.

Objectives

To evaluate the efficacy and safety of switching to bimekizumab from adalimumab, ustekinumab and secukinumab.

Methods

Data are reported for up to 80 weeks after patients switched to bimekizumab from adalimumab at week 24 in BE SURE, ustekinumab at week 52 in BE VIVID [upon entry into the BE BRIGHT open-label extension (OLE)] and secukinumab at week 48 in BE RADIANT (upon entry into the BE RADIANT OLE). Efficacy outcomes are reported by number of weeks after switching to bimekizumab and were split based on whether patients had achieved a ≥ 90% improvement from baseline in Psoriasis Area and Severity Index (PASI 90) at the time of switch. Treatment-emergent adverse events (TEAEs) are reported using exposure-adjusted incidence rates (EAIRs) per 100 patient-years. Trial registration: BE SURE (NCT03412747), BE VIVID (NCT03370133), BE BRIGHT (NCT03598790), BE RADIANT (NCT03536884).

Results

Rapid and durable improvements in clinical responses and benefits in health-related quality of life were observed among PASI 90 nonresponders who switched to bimekizumab. Most PASI 90 nonresponders achieved PASI 90 4 weeks after switching to bimekizumab from adalimumab (67%), ustekinumab (79%) and secukinumab (53%). After 48 weeks of bimekizumab, 91%, 90% and 79% of PASI 90 nonresponders had achieved PASI 90 after switching from adalimumab, ustekinumab or secukinumab, respectively. Durable improvements were also observed for PASI 100, Investigator’s Global Assessment score 0/1, body surface area affected by psoriasis ≤ 1%, absolute PASI ≤ 2, and Dermatology Life Quality Index 0/1. Among PASI 90 responders, existing treatment responses were maintained or improved after switching to bimekizumab. The majority of TEAEs were mild or moderate. EAIRs were generally similar between active-comparator treatment periods and after switching to bimekizumab. EAIRs typically decreased with a longer duration of bimekizumab exposure.

Conclusions

High proportions of patients who did not adequately respond to adalimumab, ustekinumab or secukinumab achieved high levels of skin clearance after switching to bimekizumab. Bimekizumab was well tolerated and there were no new safety findings.
Clinical research: photo validation study using Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) scores in patients with dermatomyositis
Authors: Grinnell Madison , Concha Josef , Feng Rui , Keyes Emily , Okawa Joyce , Diaz DeAnna , Vazquez Thomas , Werth Victoria P
Published: January 2023

In this study, we evaluated Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) scores calculated from photos taken by trained clinic staff. We found excellent reliability between photographs and an in-person scoring of the CDASI activity portion in patients with dermatomyositis although the CDASI may be underestimated from photographs. More research is needed to determine if photographs taken outside the office setting may be used to assess clinical trials outcomes.
Cross-specialty identification of the JAK1 inhibitor trial agent filgotinib as a potential therapy for alopecia areata
Authors: Fagan Nicole , Doherty Glen A , Meah Nekma  , Sinclair Rodney , Wall Dmitri 
Published: January 2023

First report of alopecia areata responding to the selective JAK1 inhibitor filgotinib. This case is a patient with coinciding Crohn’s disease that had failed multiple biologics. It serves as a real-world example of how shared decision making between physicians can greatly improve patient outcomes. It highlights that sharing patient registry datasets between specialties will have great benefits, for example in repurposing of JAK inhibitors for other conditions.
Analysis of laser-generated plume concentration during in vivo laser hair reduction procedures in a tertiary referral laser dermatology unit
Authors: Jones Lewis C R , Britton Jason , McCartney Audrey , Kipling-Steels Paula , Urwin Rachel , Lloyd Daniel , Tyrer John R
Published: January 2023

Air particulate concentrations for a typical day of laser hair reduction procedures in a tertiary referral laser dermatology unit were measured, while all standard operating procedures were followed. Concentrations above the World Health Organisation PM2.5 Air Quality Guidance level were detected even following current guidance on room ventilation and local exhaust ventilation. This suggests that further analysis into this hazard is required to assess the use of current engineering and personal protective equipment controls for operators
The association between pilonidal sinus disease and hidradenitis suppurativa: a systematic review and meta-analysis
Authors: Wark Kirsty J L , Der Sarkissian Samuel A , Tatian Artiene , Woods Jane , Cains Geoffrey D
Published: January 2023

We performed a systematic review and meta-analysis examining the association between hidradenitis suppurativa (HS) and pilonidal sinus disease (PSD). We found a strong association between HS and PSD, with an increased occurrence of PSD in individuals with HS compared with unaffected controls. Given this strong association, patients with HS should be assessed for PSD.
Successful dose reduction of dupilumab in atopic dermatitis
Authors: Ardern-Jones Michael R , Buchanan Emily E , Njungu Samba , O’Driscoll Daniel
Published: January 2023

Current UK, European and USA atopic dermatitis guidelines do not currently advise on the possibility of dose reduction of dupilumab therapy below the licensed dose of 300 mg subcutaneously every 2 weeks for adults. Here, we report preliminary findings to suggest that in those who respond well to the licensed dose, dupilumab dosing can be reduced while maintaining good disease control. We propose a randomized controlled clinical trial to further analyse the cost effectiveness of this approach.
An enlarging nodule on the vertex of scalp in an elderly man
Authors: Winter Sarah Min Kyeong , Ali Faraz Mahmood , May Kenneth John , Motley Richard John
Published: January 2023

A 79-year-old man presented with a crusty yellow lesion on his scalp. Histological examination revealed ulceration of the epidermis with an underlying mass in the dermis. Immunohistochemistry showed positivity for p63, and focal positivity for AE1/AE3, CK5/6 and EMA.
A sinister case of alopecia in a middle-aged woman
Authors: Borg Grech Sarah , Pisani David , Degaetano James , Boffa Michael J
Published: January 2023

We present the case of a middle-aged woman who presented with multiple indurated areas of hair loss on her scalp. Closer dermoscopic inspection of these patches revealed multiple arborizing vessels on an erythematous background. On further inspection nodules were also noted on the nape of the neck and right breast. Punch biopsies showed diffuse infiltration of the dermis by a neoplastic population of cells with moderate nuclear pleomorphism, abundant eosinophilic cytoplasm and brisk mitotic activity.
Unsolicited patient images and burnout in dermatology
Authors: Jiang Simon W , Flynn Seth M , Borre Ethan D , Nicholas Matilda W
Published: January 2023

Patient-submitted images can be helpful for medical decision-making when requested by dermatologists. However, unsolicited photographs may burden dermatologists and have variable clinical usefulness. In this survey study, we characterized dermatologists’ views on unsolicited patient photographs across various practice settings.
Sucralfate-based cream as a novel and cost-effective topical agent in poorly healing ulcers in junctional epidermolysis bullosa
Authors: Agrawal Akriti , Bhardwaj Abhishek
Published: January 2023

We describe successful use of sucralfate-based cream to treat poorly healing ulcers in junctional epidermolysis bullosa (JEB). This can be used as an economical, easily available and effective therapy for JEB.
Successful management of ulceration associated with diffuse dermal angiomatosis of the breasts with topical glyceryl trinitrate spray
Authors: Pearce J , Al-Wahab Y , Natkunarajah J
Published: January 2023

We report the successful use of topical glyceryl trinitrate spray in managing ulceration associated with diffuse dermal angiomatosis of the breasts.
Bridging knowledge gaps in paediatric chronic urticaria through a video-based educational tool
Authors: Karim Jumanah , Gabrielli Sofianne , Mule Pasquale , Torabi Bahar , Byrne Adam , De Schryver Sarah , Gadoury-Lévesque Vanessa , Alizadehfar Reza , McCusker Christine , Zhang Xun , Ben-Shoshan Moshe
Published: January 2023

Background

There is a lack of patient educational resources about chronic urticaria (CU).

Aims

To develop and test the effectiveness of an education tool to help paediatric patients and their families better understand CU and its management.

Methods

From July 2020 to May 2022, paediatric patients with a history of CU who presented to the allergy outpatient clinics at our institution were recruited. Consenting families and patients were asked to complete five questions related to the definition, causes and management of CU at the time of presentation to the clinic. Participants were shown a 5-min animated video addressing the main knowledge gaps about CU. At the end of the video, participants were redirected to the same five questions to respond again. The scores were recorded as a proportion of correct answers (range 0·0–1·0).

Results

In total, 53 patients [30 girls (56·6%), 23 boys (43·4%); mean age 9·7 ± 5·1 years, range 1·4–18·5 years] were recruited. The mean baseline pre-video education questionnaire score was 0·67 ± 0·2 (range 0·2–1·0), while the mean post-video score was 0·94 ± 0·1 (range 0·4–1·0), a mean score difference of 0·27, which was statistically significant (P < 0·001). At the 1-year follow-up, 14 (26·4%) patients answered the questionnaire again to assess retention of knowledge; the mean score was 0·83 ± 0·2 (range 0·2–1·0).

Conclusions

Our educational video was successful in educating patients and their families to better understand urticaria. Future studies should aim to optimize patient education through nontraditional tools such as videos, and compare knowledge gain using different methods of education.
Nonhealing exuberant red ulcers on the genitalia in an immunocompromised patient
Authors: Agrawal Akriti , Budania Anil , Thirunavukkarasu Balamurugan , Verma Vikrant , Kaur Maninder
Published: January 2023

We report a case of atypical exuberant ulcers on the genitals, groin and lower abdomen in an HIV-positive patient. Histopathology of the lesion revealed hyperkeratosis, acanthosis and intraepidermal bulla formation.
Patient-captured images in the triage of skin lesions: ‘Project Skin Selfie’
Authors: Muna Abdul Gafoor Shafiah , Adityani Btari , Nelson Toby
Published: January 2023

Dermatology services are overwhelmed with 2-week wait (2WW) skin cancer referrals. We outline a triage system using patient-captured images, taken by dermoscopic smartphone attachments.
Onset of epidermolysis bullosa acquisita under therapy with ustekinumab for the treatment of Crohn disease
Authors: Gambichler Thilo , Schmidt E , Scheel Christina H , Chatzipantazi Maria
Published: January 2023

A 32-year-old man with a long history of Crohn disease was put on ustekinumab, and after about 1 year of treatment, developed blisters and inflammatory lesions. He was diagnosed with epidermolysis bullosa acquisita and treated with dapsone.
Mental health burden of patients with activity-limiting skin conditions: a national analysis
Authors: Yang Kevin , Kaundinya Trisha , Kassamali Bina , Pan Catherina X , Zhou Guohai , Nambudiri Vinod E
Published: January 2023

Cutaneous diseases are the fourth leading cause of nonfatal disease burden globally. In this study, we aimed to investigate the psychological symptom burden in patients with chronic activity-limiting cutaneous diseases. Our findings suggest that this patient population experience a wide range of interference with their daily lives and exhibit higher psychological burdens and lower quality of life. This study also identified that patients with activity-limiting skin conditions do not seem to seek more professional help or take more medications, which may suggest a potential gap in adequate mental health support and resources.
A nodular lesion on a finger: an unusual site for a cyst
Authors: Vargas-Mora Pablo , González-Godoy Daniela , Lobos-Guede Nelson , Andreani Sebastián , Carreño Laura
Published: January 2023

We report a greyish nodule on the pad of the second finger of the right hand. High-resolution ultrasound showed a predominantly cystic lesion with an intralesional peripheral solid component with a mamelonated pseudonodular appearance.