Ustekinumab for the treatment of moderate‐to‐severe plaque psoriasis in paediatric patients (≥ 6 to < 12 years of age): efficacy, safety, pharmacokinetic and biomarker results from the open‐label CADMUS Jr study

Background Limited options are available for treatment of paediatric psoriasis. Objectives To evaluate the efficacy and safety of ustekinumab in paediatric patients with psoriasis (>= 6 to = 60 to 100 kg: 90 mg) administered by subcutaneous injection at weeks 0 and 4, then every 12 weeks through week 40. Study endpoints (all at week 12) included the proportions of patients achieving a Physician's Global Assessment score of cleared/minimal (PGA 0/1) and >= 75%/90% improvement in Psoriasis Area and Severity Index (PASI 75/90), and change in Children's Dermatology Life Quality Index (CDLQI). Serum ustekinumab concentrations, antidrug antibodies and cytokine levels were measured through week 52. Safety was evaluated through week 56. Results In total, 44 patients (median age 9 center dot 5 years) received at least one dose of ustekinumab. Three patients discontinued the study agent through week 40. At week 12, 77% of patients achieved PGA 0/1, 84% achieved PASI 75 and 64% achieved PASI 90 response. The mean change in CDLQI was -6 center dot 3. Trough serum ustekinumab concentrations reached steady state at weeks 28-52. The incidence of antidrug antibodies was 10% (n = 4). Mean serum concentrations of interleukin-17A/F and interleukin-22 were significantly reduced at weeks 12 and 52. Overall, 34 patients (77%) had at least one adverse event and three (7%) had a serious adverse event. Conclusions Ustekinumab effectively treated moderate-to-severe psoriasis in paediatric patients, and no new safety concerns were identified. What is already known about this topic? Ustekinumab is approved for use in adolescents (>= 12 to = 18 years) with moderate-to-severe psoriasis. What does this study add? Ustekinumab effectively treats moderate-to-severe psoriasis in paediatric patients (>= 6 to < 12 years of age), with no new safety concerns

Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma

Supplemental Data Supplemental Data include five figures and three tables and can be found with this article online at http://dx.doi.org/10.1016/j.ajhg.2017.05.003. Supplemental Data Document S1. Figures S1–S5 and Tables S1–S3 Download Document S2. Article plus Supplemental Data Download Web Resources 1000 Genomes, http://www.internationalgenome.org/ ANNOVAR, http://annovar.openbioinformatics.org/en/latest/ BWA-MEM, http://bio-bwa.sourceforge.net/index.shtml Database of Genomic Variants, http://dgv.tcag.ca/dgv/app/home dbSNP, https://www.ncbi.nlm.nih.gov/projects/SNP/ Exome Aggregation Consortium (ExAC) Browser, http://exac.broadinstitute.org/ ExonPrimer, https://ihg.helmholtz-muenchen.de/ihg/ExonPrimer.html GenBank, https://www.ncbi.nlm.nih.gov/genbank/ Genome Analysis Toolkit (GATK), https://software.broadinstitute.org/gatk/ Integrative Genomics Viewer (IGV), http://software.broadinstitute.org/software/igv/ OMIM, https://www.omim.org/ SNPmasker, http://bioinfo.ebc.ee/snpmasker/ UCSC Genome Browser, https://genome.ucsc.edu/index.html Variant Effect Predictor, http://useast.ensembl.org/info/docs/tools/vep/index.html The discovery of new genetic determinants of inherited skin disorders has been instrumental to the understanding of epidermal function, differentiation, and renewal. Here, we show that mutations in KDSR (3-ketodihydrosphingosine reductase), encoding an enzyme in the ceramide synthesis pathway, lead to a previously undescribed recessive Mendelian disorder in the progressive symmetric erythrokeratoderma spectrum. This disorder is characterized by severe lesions of thick scaly skin on the face and genitals and thickened, red, and scaly skin on the hands and feet. Although exome sequencing revealed several of the KDSR mutations, we employed genome sequencing to discover a pathogenic 346 kb inversion in multiple probands, and cDNA sequencing and a splicing assay established that two mutations, including a recurrent silent third base change, cause exon skipping. Immunohistochemistry and yeast complementation studies demonstrated that the mutations cause defects in KDSR function. Systemic isotretinoin therapy has achieved nearly complete resolution in the two probands in whom it has been applied, consistent with the effects of retinoic acid on alternative pathways for ceramide generation

Physician-Industry Collaboration: Organizational Considerations for the Future of Innovation and Growth in Dermatology

The U.S. medical environment continues to evolve with issues from Privacy to EMR, Insurance regulations, Physician Access and Healthcare Reform, and MACRA (Medicare Access and CHIP Reauthorization Act) on the discussion table. Not since the advent of Medicare and Medicaid in the mid 1960’s, have we seen such widespread changes in the medical healthcare environment (Centers for Medicare and Medicaid Services). Physicians, industry, patients and consumers are affected by the changes. These four groups have historically worked as separate entities, but are now key stakeholders in the future of dermatology. As stakeholders collaborating in building a future together, the dermatologists/physicians will help to ensure and preserve the quality of patient care and best patient outcomes. In the Executive Forum, leaders from the Women’s Dermatologic Society and Industry, explored five important areas: 1) A five-year outlook of Dermatology and Medicine; 2) Access of Industry to Dermatologists and Trainees; 3) The New Practice Environment; 4) Doing Things Differently; and 5) Unmet Specialty Needs. The collaborative group explored solutions for our specialty and the patients we serve

Diaper dermatitis prevalence and severity : global perspective on the impact of caregiver behavior

Objectives To compare prevalence and severity of diaper dermatitis (DD) in infants and toddlers (babies) across three countries (China, USA, and Germany), including diapered skin measures and caregiver practices. Methods A cross‐sectional study of 1791 babies (~600 from each country) was recruited at each clinical site. Based on regional toilet‐training habits, exclusively diaper‐wearing infants were recruited between ages 2‐8 months in China and 2‐18 months in the USA and Germany. DD was measured, as well as skin pH, transepidermal water loss (TEWL), and relative humidity (RH) in the diapered region. Caregiver habits were collected via a questionnaire and included information on hygienic practices. Results Diaper dermatitis was highest in the perianal area, followed by the intertriginous, genital, and buttock regions. In general, DD was significantly lower in babies in China, highest in Germany, and intermediate in the USA. This rank ordering of DD by geography was also observed in baby age 2‐8 months. The lower DD observed in China was associated with lower skin pH and TEWL on diapered skin and decreased RH in the diaper. Chinese caregivers had the highest rate of prophylactic topical product usage, the most robust cleaning of the diapered area, lack of cleansing after urine‐only diaper changes, and Chinese infants spent the least time in an overnight diaper. Conclusions These data suggest caregiver behaviors including prophylactic use of topical products, thorough cleaning after stooling and reduced time in an overnight diaper are associated with less DD, lower superficial skin pH, and enhanced skin barrier

Atopic dermatitis: A global health perspective

The International Society of AD (ISAD) organized a roundtable on global aspects of AD at the WCD 2023 in Singapore. According to the Global Burden of Disease (GBD) consortium, at least 171 million individuals were affected with AD in 2019, corresponding to 2.23% of the world population, with age‐standardized prevalence and incidence rates that were relatively stable from 1990 to 2019. Based on the panel experience, most AD cases are mild‐to‐moderate. Without parallel data on disease prevalence and severity, the GBD data are difficult to interpret in many regions. This gap is particularly important in countries with limited medical infrastructure, but indirect evidence suggests a significant burden of AD in low‐and‐medium resource settings, especially urban areas. The Singapore roundtable was an opportunity to compare experiences in World Bank category 1 (Madagascar and Mali), 3 (Brazil, China) and 4 (Australia, Germany, Qatar, USA, Singapore, Japan) countries. The panel concluded that current AD guidelines are not adapted for low resource settings and a more pragmatic approach, as developed by WHO for skin NTDs, would be advisable for minimal access to moisturizers and topical corticosteroids. The panel also recommended prioritizing prevention studies, regardless of the level of existing resources. For disease long‐term control in World Bank category 3 and most category 4 countries, the main problem is not access to drugs for most mild‐to‐moderate cases, but rather poor compliance due to insufficient time at visits. Collaboration with WHO, patient advocacy groups and industry may promote global change, improve capacity training and fight current inequalities. Finally, optimizing management of AD and its comorbidities needs more action at the primary care level, because reaching specialist care is merely aspirational in most settings. Primary care empowerment with store and forward telemedicine and algorithms based on augmented intelligence is a future goal

Neuroelectric Evidence for Cognitive Association Formation: An Event-Related Potential Investigation

Although many types of learning require associations to be formed, little is known about the brain mechanisms engaged in association formation. In the present study, we measured event-related potentials (ERPs) while participants studied pairs of semantically related words, with each word of a pair presented sequentially. To narrow in on the associative component of the signal, the ERP difference between the first and second words of a pair (Word2-Word1) was derived separately for subsequently recalled and subsequently not-recalled pairs. When the resulting difference waveforms were contrasted, a parietal positivity was observed for subsequently recalled pairs around 460 ms after the word presentation onset, followed by a positive slow wave that lasted until around 845 ms. Together these results suggest that associations formed between semantically related words are correlated with a specific neural signature that is reflected in scalp recordings over the parietal region

The role of reperfusion injury in photodynamic therapy with 5-aminolaevulinic acid – a study on normal rat colon

Reperfusion injury can occur when blood flow is restored after a transient period of ischaemia. The resulting cascade of reactive oxygen species damages tissue. This mechanism may contribute to the tissue damage produced by 5-aminolaevulinic acid-induced photodynamic therapy, if this treatment temporarily depletes oxygen in an area that is subsequently reoxygenated. This was investigated in the normal colon of female Wistar rats. All animals received 200 mg kg−1 5-aminolaevulinic acid intravenously 2 h prior to 25 J (100 mW) of 628 nm light, which was delivered continuously or fractionated (5 J/150 second dark interval/20 J). Animals were recovered following surgery, killed 3 days later and the photodynamic therapy lesion measured macroscopically. The effects of reperfusion injury were removed from the experiments either through the administration of free radical scavengers (superoxide dismutase (10 mg kg−1) and catalase (7.5 mg kg−1) in combination) or allopurinol (an inhibitor of xanthine oxidase (50 mg kg−1)). Prior administration of the free radical scavengers and allopurinol abolished the macroscopic damage produced by 5-aminolaevulinic acid photodynamic therapy in this model, regardless of the light regime employed. As the specific inhibitor of xanthine oxidase (allopurinol) protected against photodynamic therapy damage, it is concluded that reperfusion injury is involved in the mechanism of photodynamic therapy in the rat colon