University of Pennsylvania

Autistic girls are often diagnosed late, missed, or misdiagnosed, which can negatively impact quality of life and mental health. Although research shows the social profiles of autistic girls differ from boys in systematic ways that might explain gaps in diagnosis, little is known about how autistic girls' social language compares to their same-sex non-autistic peers. This study investigated social words-words that make reference to other people-produced by 138 age- and IQ-matched autistic and non-autistic youth (ages 6-15) during one Autism Diagnostic Observation Schedule, Second Edition task. Girls used significantly more social words than boys across both diagnostic groups. There was a larger gap in social word production between autistic girls and non-autistic girls than autistic boys and non-autistic boys, with non-autistic girls using the most social words. Non-autistic girls' social language behavior-including their social word production-sets an especially high bar for autistic girls, who often report trying to blend in with other girls. Growing evidence of the distinct social language profiles of autistic and non-autistic girls versus boys should guide researchers and clinicians to assess autism in ways that are sensitive to sex-associated differences and develop interventions that consider the norms of youth's target social circles.Lay AbstractAutism is often diagnosed later in girls and women as compared to boys and men. More research is needed to understand how autism presents differently in girls. This study investigates how autistic and non-autistic youth aged 6 to 15 years use social words (e.g. "friend," "mom," "help," "talk") during an interview about friends, relationships, and marriage as part of an autism diagnostic assessment. Overall, girls used more social words compared to boys and talked more about friends. Specifically, non-autistic girls used the most social words in comparison with other groups. Highly social language produced by non-autistic girls may make it especially hard for autistic girls to blend in with other girls and could lead them to engage in more camouflaging behaviors to hide their autistic characteristics. With such different average social language behavior from girls and boys, researchers should consider adapting autism assessments and interventions to support the unique needs of autistic girls.

Postpartum pain, a common symptom after a cesarean birth, is influenced by psychosocial factors. This exploratory qualitative study examined patient perspectives on social support and healthcare communication behaviors in the postpartum setting in relation to the pain experience. In-depth, semi-structured, qualitative interviews about postpartum pain experiences were conducted 2-3 days and 2-6 weeks postpartum with individuals who underwent a cesarean birth (2020-2021). Data were analyzed using the constant comparative method. Among 49 postpartum individuals, themes related to social support and healthcare communication were identified in relation to postpartum pain. Participants discussed the impact of non-healthcare social support (e.g., partners, extended family, other children) on postpartum pain, highlighting emotional and practical assistance. Most commonly mentioned were the positive impacts of emotional and logistical support with household activities and childcare on postpartum pain recovery. The second theme covered individuals' views on how healthcare support and communication affected postpartum pain, with themes of both positive and negative experiences. Some participants discussed positive experiences of shared decision-making and responsiveness of the healthcare team, whereas others recounted negative experiences of lack of counseling and poor outpatient communication. Social support and healthcare communication are integral influences on pain recovery after a cesarean birth. These findings highlight the need for interventions to address psychosocial support and healthcare team communication in the immediate postpartum period.

Epidermodysplasia verruciformis (EV) was described as a congenital skin disease and later as a Mendelian disorder in 1922 and 1946, respectively [1]. For decades, EV was considered a monogenic entity and was also interchangeably referred to as Treeman syndrome (TMS). However, recent advancements in next-generation sequencing (NGS) have revealed that the pathogenesis of EV is distinct from TMS [2]. In fact, a recent study showed that TMS, in some cases, is caused by biallelic loss-of-function CD28 mutations and that TMS warts are driven by α-human papillomavirus (HPV) [2]. Furthermore, at least 21 genes have been implicated in EV pathogenesis. Persistent disseminated flat-like warts in EV patients are derived, for the most part, from weakly virulent, E5- and E8-deficient β-HPVs, which exclusively reside within keratinocytes. However, these β-HPVs, lacking the E5 and E8 genes that are expressed in other genera of more pathogenic HPVs, typically cause only asymptomatic infections in the general population [1]. It is noteworthy that, in addition to β-HPVs, non-β-HPVs (including α- and γ-HPVs) are occasionally associated with the EV phenotype [3]. Mechanistic insights gained from studies of single-gene disorders with EV manifestations suggest dual contributions of keratinocyte-intrinsic immunity and adaptive T-cell immunity to β-HPV clearance. Ultrarare and private mutations in genes governing either keratinocyte-intrinsic immunity or adaptive T-cell immunity, at the priming or effector level, confer predisposition to severe β-HPV infections (Figure 1). These observations led Shen et al., in this issue of the International Journal of Dermatology, and other research groups to categorize EV into classic (TMC6, TMC8, and CIB1), nonclassic (e.g., DOCK8, STK4), and acquired forms [4, 5]. A total of 439 EV patients, comprising 137 classic (typical) EV patients, 46 nonclassic (atypical) EV patients, and 256 acquired EV (AEV) patients, were reviewed. The most commonly reported genes were TMC6, CIB1, TMC8, STK4, and DOCK8. A total of 31 distinct HPVs, belonging to the α-, γ-, and β-HPV genera, were associated with the EV phenotype, with β-HPV-5, -8, and -20 identified as the most common types. Collectively, these genomics-driven advances in EV understanding herald a paradigm shift in the diagnosis, prognosis, and monitoring of EV in the era of precision dermatology. While single-gene EV is a pediatric clinical condition (with an age of onset before 12 years in 89% of cases), most AEV patients are adults, and the disease is prevalent among HIV and transplant populations [5]. The phenocopy in AEV patients underscores the effective suppression of the same surveillance pathways for HPV clearance that are disrupted in hereditary forms [4, 5]. A review of oncologic data in EV patients offers clinically actionable insight into the age of onset and extent of cancer risk. The majority (56%) of monogenic EV patients develop malignancy, occurring decades earlier than in the general population. Moreover, the distinction between isolated and syndromic EV has implications for cancer management: cutaneous malignancies predominate in isolated EV, while extracutaneous malignancies are more common in syndromic forms. These results support genotype-informed cancer surveillance strategies in EV patients. Furthermore, they indicate that EV should be integrated into broader hereditary cancer predisposition frameworks [5]. In sum, EV offers a unique human knockout model for the study of host–virus co-evolution, tissue-specific immunity, and early carcinogenesis. Furthermore, recent genomic advances shift the paradigm of EV from a mere dermatologic curiosity to a prototype for precision dermatology. The authors employed large language models to refine manuscript grammar and phrasing, then reviewed, edited, and accepted full responsibility for the final content. The LEO Foundation (grant LF-OC-22-000965) and the US NIH (grant R01AI143810) supported the authors' studies. The authors declare no conflicts of interest. Clinical and Molecular Perspectives on Epidermodysplasia Verruciformis, https://doi.org/10.1111/ijd.70295. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

BackgroundBrepocitinib is a first-in-class, oral, selective TYK2–JAK1 inhibitor that blocks cytokine signaling, which has been implicated in dermatomyositis.MethodsIn this phase 3, double-blind, randomized, placebo-controlled trial, adults with dermatomyositis were assigned in a 1:1:1 ratio to receive once-daily oral brepocitinib at a dose of 30 mg, brepocitinib at a dose of 15 mg, or placebo for 52 weeks. Standard therapies were continued, and glucocorticoids were tapered. The primary end point was the Total Improvement Score, a validated composite myositis index (with scores ranging from 0 to 100 and higher scores indicating greater improvement) at week 52. Key secondary end points, including skin disease activity, glucocorticoid tapering, and physical function, were tested in a multiplicity-controlled sequence.ResultsA total of 241 patients underwent randomization: 81 to receive brepocitinib 30 mg, 81 to receive brepocitinib 15 mg, and 79 to receive placebo. At week 52, the mean Total Improvement Score was 46.5, 37.5, and 31.2, respectively (difference with brepocitinib 30 mg vs. placebo, 15.3; 95% confidence interval [CI], 6.7 to 24.0; P<0.001; difference with brepocitinib 15 mg vs. placebo, 6.3; 95% CI, −2.4 to 14.9). Brepocitinib 30 mg was superior to placebo across all nine key secondary end points, including skin disease activity, systemic glucocorticoid tapering, and functional disability, with improvements observed as early as week 4. Serious infections were more frequent in the brepocitinib 30-mg group than in the placebo group (10% vs. 1%). No deaths occurred during the trial.ConclusionsIn adults with dermatomyositis that was resistant to previous therapy, the use of brepocitinib at a dose of 30 mg (but not at a dose of 15 mg) resulted in significant benefits with respect to a composite myositis index, skin disease severity, glucocorticoid tapering, and functional disability. (Funded by Priovant Therapeutics; ClinicalTrials.gov number, NCT05437263.)

Cytokines dimerize two receptor chains to activate Janus kinases and STAT transcription factors that regulate immune cells but have therapeutic liabilities. We engineered “Trikines” to compel cis formation of three-chain cytokine receptor complexes at the cell surface that induce bespoke STAT transcriptional signaling programs optimized for therapeutic efficacy. Designed Trikines co-activated pSTAT5 and pSTAT3 signatures distinct from any natural cytokines, by assembling trimeric combinations of Interleukin-2 (IL-2), Interleukin-10 (IL-10), and Interleukin-21 (IL-21) receptors. An IL-2-based-Trikine restrained terminal differentiation of T cells, promoted stemness, and enhanced durability of tumor control without toxicity. Unexpectedly, an IL-10-based Trikine induced immune infiltration into poorly immunogenic tumors, showing striking efficacy in small cell lung cancer and pancreatic cancer models. Trikines obviate the need for cell engineering to customize STAT signatures for immunotherapy.

Polycomb group proteins maintain gene expression patterns established during early development, with Polycomb repressive complex 2 (PRC2) methyltransferase being a key regulator of cell differentiation, identity, and plasticity. Consequently, extensive somatic mutations in PRC2, including gain or loss of function (GOF or LOF), are observed in human cancers. The regulation of chromatin structure by PRC2 is critically dependent on its enhancer of zeste homolog 2 (EZH2) subunit, which catalyzes the methylation of histone H3 lysine 27 (H3K27). Recent structural studies of PRC2 revealed extensive conformational changes in the noncatalytic EZH2 N-terminal SANT1-binding domain (SBD) during PRC2 activation, though the functional significance remains unclear. Here, we investigated how the SBD regulates PRC2 function. The domain is highly conserved in metazoans and dispensable for PRC2 assembly and chromatin localization yet is required for genome-wide histone H3K27 methylation. Furthermore, we show that an intact SBD is necessary for the proliferation of EZH2-addicted lymphomas, and its deletion in the presence of EZH2 GOF mutations inhibits cancer cell growth. These observations provide new insights into the regulation of PRC2 activity in normal development and malignancy.

Understanding the origin, distribution, and biology of different cell populations in chimeric mice is critical for interpreting the pathological changes developed in these models. To this aim, the methodological work presented here illustrates the validation and application of a collection of labeling techniques to differentiate between specific mouse and human tissue/cell components in formalin-fixed paraffin-embedded samples from chimeric mice, especially those bearing human tumor and immune cells. First, broad approaches to identify cells of human origin using ubiquitous immunohistochemical targets such as HLA-A, Ku80, and human mitochondrial 60 kDa protein (hMito) were established using specimens from humanized mice and a human tissue microarray including both normal and neoplastic samples. Due to its crisp membranous immunoreactivity, HLA-A was the most useful marker for visual human cell identification; however, Ku80 and hMito may be suitable options when HLA-A is not expressed in the cells of interest. Importantly, using one or more of these markers provides a broad range of coverage for the vast majority of human-derived cells in chimeric mice. Second, tailored immunohistochemical or in situ hybridization methodologies to distinguish specific human or mouse cell subsets are presented, focusing on immune/inflammatory cells and human chimeric antigen receptor (CAR) T-cells. These diverse approaches are accompanied by descriptions of case examples highlighting practical diagnostic and experimental applications in the context of various humanized mouse models. While not comprehensive, this work represents a valuable starting reference for pathologists and investigators working with humanized mouse models and seeking to add spatial resolution to the complex landscape of chimeric tissues.