Structural and Dynamic Analyses of Pathogenic Variants in PIK3R1 Reveal a Shared Mechanism Associated among Cancer, Undergrowth, and Overgrowth Syndromes.

The PI3K enzymes modify phospholipids to regulate cell growth and differentiation. Somatic variants in PI3K are recurrent in cancer and drive a proliferative phenotype. Somatic mosaicism of PIK3R1 and PIK3CA are associated with vascular anomalies and overgrowth syndromes. Germline PIK3R1 variants are associated with varying phenotypes, including immunodeficiency or facial dysmorphism with growth delay, lipoatrophy, and insulin resistance associated with SHORT syndrome. There has been limited study of the molecular mechanism to unify our understanding of how variants in PIK3R1 drive both undergrowth and overgrowth phenotypes. Thus, we compiled genomic variants from cancer and rare vascular anomalies and sought to interpret their effects using an unbiased physics-based simulation approach for the protein complex. We applied molecular dynamics simulations to mechanistically understand how genetic variants affect PIK3R1 and its interactions with PIK3CA. Notably, iSH2 genetic variants associated with undergrowth destabilize molecular interactions with the PIK3CA receptor binding domain in simulations, which is expected to decrease activity. On the other hand, overgrowth and cancer variants lead to loss of inhibitory interactions in simulations, which is expected to increase activity. We find that all disease variants display dysfunctions on either structural characteristics or intermolecular interaction energy. Thus, this comprehensive characterization of novel mosaic somatic variants associated with two opposing phenotypes has mechanistic importance and biomedical relevance and may aid in future therapeutic developments.

Looking back, looking forward: lessons from COVID-19 communication measurement, evaluation and learning (MEL).

Problem: Communication is an integral component of an emergency response, including to the coronavirus disease (COVID-19) pandemic. Designing effective communication requires systematic measurement, evaluation and learning. Context: In the Western Pacific Region, the World Health Organization (WHO) responded to the COVID-19 pandemic by using the Communication for Health (C4H) approach. This included the development and application of a robust measurement, evaluation and learning (MEL) framework to assess the effectiveness of COVID-19 communication, and to share and apply lessons in real time to continuously strengthen the pandemic response. Action: MEL was applied during the planning, implementation and summative evaluation phases of COVID-19 communication, with evidence-based insights and recommendations continuously integrated in succeeding phases of the COVID-19 response. Lessons learned: This article captures good practices that helped WHO to implement MEL during the COVID-19 pandemic. It focuses on lessons from the evaluation process, including the importance of planning, data integration, collaboration, partnerships, piggybacking, using existing data and leveraging digital media. Discussion: Despite some limitations, the systematic application of MEL to COVID-19 communication shows its value in the planning and implementation of effective, evidence-based communication to address public health challenges. It enables the evaluation of outcomes and reflection on lessons identified to strengthen the response to the current pandemic and future emergencies.

Methotrexate for inflammatory skin disease in pediatric patients: Consensus treatment guidelines.

Methotrexate (MTX) is a readily accessible drug, first used in 1948 and employed for a wide variety of indications since then. However, despite widespread off-label use, FDA labeling does not include approved indications for the use of MTX for many inflammatory skin diseases in pediatric patients, including morphea, psoriasis, atopic dermatitis, and alopecia areata, among others. Without published treatment guidelines, some clinicians may be hesitant to use MTX off-label, or uncomfortable prescribing MTX in this population. To address this unmet need, an expert consensus committee was convened to develop evidence- and consensus-based guidelines for use of MTX to treat pediatric inflammatory skin disease. Clinicians with experience and expertise in clinical research, drug development, and treating inflammatory skin disease in pediatric patients with MTX were recruited. Five committees were created based on major topic areas: (1) indications and contraindications, (2) dosing, (3) interactions with immunizations and medications, (4) adverse effects (potential for and management of), and (5) monitoring needs. Pertinent questions were generated and addressed by the relevant committee. The entire group participated in a modified Delphi process to establish agreement on recommendations for each question. The committee developed 46 evidence- and consensus-based recommendations, each with >70% agreement among members, across all five topics. These are presented in tables and text, along with a discussion of supporting literature, and level of evidence. These evidence- and consensus-based recommendations will support safe and effective use of MTX for the underserved population of pediatric patients who may benefit from this valuable, time-honored medication.

Mpox in Young Woman with No Epidemiologic Risk Factors, Massachusetts, USA.

We describe a case of mpox characterized by a circularly distributed facial rash but no identified risk factors. Fomite transmission of monkeypox virus from contaminated linen at a massage spa was suspected. Clinicians should consider mpox in patients with consistent clinical syndromes, even in the absence of epidemiologic risk factors.

PTPN11 Mosaicism Causes a Spectrum of Pigmentary and Vascular Neurocutaneous Disorders and Predisposes to Melanoma.

Phakomatosis pigmentovascularis is a diagnosis that denotes the coexistence of pigmentary and vascular birthmarks of specific types, accompanied by variable multisystem involvement, including CNS disease, asymmetrical growth, and a predisposition to malignancy. Using a tight phenotypic group and high-depth next-generation sequencing of affected tissues, we discover here clonal mosaic variants in gene PTPN11 encoding SHP2 phosphatase as a cause of phakomatosis pigmentovascularis type III or spilorosea. Within an individual, the same variant is found in distinct pigmentary and vascular birthmarks and is undetectable in blood. We go on to show that the same variants can cause either the pigmentary or vascular phenotypes alone, and drive melanoma development within pigmentary lesions. Protein structure modeling highlights that although variants lead to loss of function at the level of the phosphatase domain, resultant conformational changes promote longer ligand binding. In vitro modeling of the missense variants confirms downstream MAPK pathway overactivation and widespread disruption of human endothelial cell angiogenesis. Importantly, patients with PTPN11 mosaicism theoretically risk passing on the variant to their children as the germline RASopathy Noonan syndrome with lentigines. These findings improve our understanding of the pathogenesis and biology of nevus spilus and capillary malformation syndromes, paving the way for better clinical management.

Early-onset hypertension associated with extensive cutaneous capillary malformations harboring postzygotic variants in GNAQ and GNA11.

BACKGROUND AND OBJECTIVES: Cutaneous capillary malformations (CMs) describe a group of vascular birthmarks with heterogeneous presentations. CMs may present as an isolated finding or with other associations, including glaucoma and leptomeningeal angiomatosis (i.e., Sturge-Weber syndrome) or pigmentary birthmarks (i.e., phakomatosis pigmentovascularis). The use of targeted genetic sequencing has revealed that postzygotic somatic variations in GNAQ and GNA11 at codon 183 are associated with CMs. We report five patients with early-onset hypertension and discuss possible pathogenesis of hypertension. METHODS: Twenty-nine patients with CMs, confirmed GNAQ/11 postzygotic variants, and documented past medical history were identified from a multi-institutional vascular anomalies study. Early-onset hypertension was defined as hypertension before the age of 55 years. Clinical data were reviewed for evidence of hypertension, such as documentation of diagnosis or elevated blood pressure measurements. RESULTS: Five of the 29 patients identified as having GNAQ/11 postzygotic variants had documented early-onset hypertension. Three individuals harbored a GNAQ p.R183Q variant, and two individuals harbored a GNA11 p.R183C variant. All individuals had extensive cutaneous CMs involving the trunk and covering 9%-56% of their body surface area. The median age of hypertension diagnosis was 15 years (range 11-24 years), with three individuals having renal abnormalities on imaging. CONCLUSIONS: Early-onset hypertension is associated with extensive CMs harboring somatic variations in GNAQ/11. Here, we expand on the GNAQ/11 phenotype and hypothesize potential mechanisms driving hypertension. We recommend serial blood pressure measurements in patients with extensive CMs on the trunk and extremities to screen for early-onset hypertension.

Unparalleled mitochondrial heteroplasmy and Wolbachia co-infection in the non-model bee, Amphylaeus morosus.

Mitochondrial heteroplasmy is the occurrence of more than one type of mitochondrial DNA within a single individual. Although generally reported to occur in a small subset of individuals within a species, there are some instances of widespread heteroplasmy across entire populations. Amphylaeus morosus is an Australian native bee species in the diverse and cosmopolitan bee family Colletidae. This species has an extensive geographical range along the eastern Australian coast, from southern Queensland to western Victoria, covering approximately 2,000 km. Seventy individuals were collected from five localities across this geographical range and sequenced using Sanger sequencing for the mitochondrial cytochrome c oxidase subunit I (COI) gene. These data indicate that every individual had the same consistent heteroplasmic sites but no other nucleotide variation, suggesting two conserved and widespread heteroplasmic mitogenomes. Ion Torrent shotgun sequencing revealed that heteroplasmy occurred across multiple mitochondrial protein-coding genes and is unlikely explained by transposition of mitochondrial genes into the nuclear genome (NUMTs). DNA sequence data also demonstrated a consistent co-infection of Wolbachia across the A. morosus distribution with every individual infected with both bacterial strains. Our data are consistent with the presence of two mitogenomes within all individuals examined in this species and suggest a major divergence from standard patterns of mitochondrial inheritance. Because the host's mitogenome and the Wolbachia genome are genetically linked through maternal inheritance, we propose three possible hypotheses that could explain maintenance of the widespread and conserved co-occurring bacterial and mitochondrial genomes in this species.

Extreme reproductive skew at the dawn of sociality is consistent with inclusive fitness theory but problematic for routes to eusociality.

To understand the earliest stages of social evolution, we need to identify species that are undergoing the initial steps into sociality. Amphylaeus morosus is the only unambiguously known social species in the bee family Colletidae and represents an independent origin of sociality within the Apoidea. This allows us to investigate the selective factors promoting the transition from solitary to social nesting. Using genome-wide SNP genotyping, we infer robust pedigree relationships to identify maternity of brood and intracolony relatedness for colonies at the end of the reproductive season. We show that A. morosus forms both matrifilial and full-sibling colonies, both involving complete or almost complete monopolization over reproduction. In social colonies, the reproductive primary was also the primary forager with the secondary female remaining in the nest, presumably as a guard. Social nesting provided significant protection against parasitism and increased brood survivorship in general. We show that secondary females gain large indirect fitness benefits from defensive outcomes, enough to satisfy the conditions of inclusive fitness theory, despite an over-production of males in social colonies. These results suggest an avenue to sociality that involves high relatedness and, very surprisingly, extreme reproductive skew in its earliest stages and raises important questions about the evolutionary steps in pathways to eusociality.

Cutaneous mosaic RASopathies associated with rhabdomyosarcoma.

Variants in RAS are known drivers of certain pediatric blood and solid cancers, including brain tumors. Though most RAS-driven cancers are thought to occur sporadically, genetic syndromes caused by germline RAS variants portend a slightly higher risk of rhabdomyosarcoma (RMS) development. Three new cases and a review of the literature demonstrate that in rare cases, certain somatic RAS variants are associated with an increased risk of RMS and that RMS development may be heralded by the presence of concomitant RAS-driven birthmarks. Further prospective studies are needed to establish incidence and recommend appropriate monitoring guidelines for patients at risk.

Continental risk assessment for understudied taxa post-catastrophic wildfire indicates severe impacts on the Australian bee fauna.

The 2019-2020 Australian Black Summer wildfires demonstrated that single events can have widespread and catastrophic impacts on biodiversity, causing a sudden and marked reduction in population size for many species. In such circumstances, there is a need for conservation managers to respond rapidly to implement priority remedial management actions for the most-affected species to help prevent extinctions. To date, priority responses have been biased towards high-profile taxa with substantial information bases. Here, we demonstrate that sufficient data are available to model the extinction risk for many less well-known species, which could inform much broader and more effective ecological disaster responses. Using publicly available collection and GIS datasets, combined with life-history data, we modelled the extinction risk from the 2019-2020 catastrophic Australian wildfires for 553 Australian native bee species (33% of all described Australian bee taxa). We suggest that two species are now eligible for listing as Endangered and nine are eligible for listing as Vulnerable under IUCN criteria, on the basis of fire overlap, intensity, frequency, and life-history traits: this tally far exceeds the three Australian bee species listed as threatened prior to the wildfire. We demonstrate how to undertake a wide-scale assessment of wildfire impact on a poorly understood group to help to focus surveys and recovery efforts. We also provide the methods and the script required to make similar assessments for other taxa or in other regions.

Diversity in pediatric dermatology: A report from the Pediatric Dermatology Research Alliance and a call to action.

BACKGROUND/OBJECTIVES: The Pediatric Dermatology Research Alliance (PeDRA) connects pediatric dermatologists, trainees, basic scientists, allied health professionals, and patient advocates to improve the lives of children with skin disease through research. As a training pipeline for future pediatric dermatologists and steward of research in the field, PeDRA has a responsibility to examine its history and take actionable steps to diversify its membership, grant recipients, study leads, research priorities, and leadership. METHODS: In 2020, PeDRA formed an Equity, Diversity, and Inclusion Task Force to address this need. In an effort to assess PeDRA's past and plan for PeDRA's future, a review of PeDRA's membership, leadership, grant awardees, and research topics was conducted. RESULTS/CONCLUSIONS: Results demonstrated gaps in PeDRA's current operational efforts to diversify the pediatric dermatology workforce and identified areas for improvement. Recommendations are proposed as a call to action for the community.

Achieving equity and inclusion in pediatric dermatology research: Priorities and considerations.

As we increase our focus and energy on equity, diversity, and inclusion (EDI)-relevant research, we must consider the "what, why, and how" of our work. The goals of this paper are to highlight unique issues pediatric dermatologists face in providing equitable care, pose considerations when reporting data on race and ethnicity, and advocate for standardized classification of race and ethnicity in research.

Somatic PIK3R1 variation as a cause of vascular malformations and overgrowth.

PURPOSE: Somatic activating variants in the PI3K-AKT pathway cause vascular malformations with and without overgrowth. We previously reported an individual with capillary and lymphatic malformation harboring a pathogenic somatic variant in PIK3R1, which encodes three PI3K complex regulatory subunits. Here, we investigate PIK3R1 in a large cohort with vascular anomalies and identify an additional 16 individuals with somatic mosaic variants in PIK3R1. METHODS: Affected tissue from individuals with vascular lesions and overgrowth recruited from a multisite collaborative network was studied. Next-generation sequencing targeting coding regions of cell-signaling and cancer-associated genes was performed followed by assessment of variant pathogenicity. RESULTS: The phenotypic and variant spectrum associated with somatic variation in PIK3R1 is reported herein. Variants occurred in the inter-SH2 or N-terminal SH2 domains of all three PIK3R1 protein products. Phenotypic features overlapped those of the PIK3CA-related overgrowth spectrum (PROS). These overlapping features included mixed vascular malformations, sandal toe gap deformity with macrodactyly, lymphatic malformations, venous ectasias, and overgrowth of soft tissue or bone. CONCLUSION: Somatic PIK3R1 variants sharing attributes with cancer-associated variants cause complex vascular malformations and overgrowth. The PIK3R1-associated phenotypic spectrum overlaps with PROS. These data extend understanding of the diverse phenotypic spectrum attributable to genetic variation in the PI3K-AKT pathway.