Efficacy of SARS-CoV-2 Vaccine Doses in Allogeneic Hemopoietic Stem Cell Recipients: A Systematic Review and Meta-Analysis.

OBJECTIVE: Recipients of allogeneic hematopoietic cell transplantation (alloHCT) are at increased risk of morbidity and mortality due to COVID-19. Immune responses to SARS-CoV-2 vaccines are blunted in these profoundly immunocompromised patients. As a result, novel strategies for protection, such as additional vaccine doses (boosters), are being explored. However, data regarding the efficacy of a third dose of SARS-CoV-2 vaccine in alloHCT recipients are limited and conflicting. METHODS: In this systematic review and meta-analysis, we investigated the efficacy of a third dose of SARS-CoV-2 vaccine in alloHCT recipients. The review was conducted following PRISMA guidelines, and 7 studies with 385 alloHCT recipients who received 3 vaccine doses were included. The primary outcomes assessed were the rate of seroconversion following the third dose of vaccine and the rate of seroconversion in patients who did not respond to the initial 2-dose vaccination series. RESULTS: The pooled humoral response rate after 3 doses of SARS-CoV-2 vaccine in alloHCT recipients was 74%. In a subgroup analysis of patients who did not respond to the initial 2-dose series, the seroconversion rate following the third vaccine dose was 49%. Notably, male patients and those with a shorter interval between alloHCT and the first vaccine dose were more likely to not respond to the third dose. CONCLUSION: In conclusion, the pooled humoral response rate of 74% following three doses of SARS-CoV-2 vaccine in alloHCT recipients highlights the potential for protection in this immunosuppressed population. Additionally, encouraging responses in nearly half of the patients who did not seroconvert with the initial 2-dose series suggest the continued utilization of additional vaccine doses until results from large prospective studies become available. These findings are critical for informing vaccination strategies in alloHCT recipients to mitigate the high mortality risk associated with COVID-19.

Multicenter Study of Long-Term Outcomes and Quality of Life in PHACE Syndrome after Age 10.

OBJECTIVE: To characterize long-term outcomes of PHACE syndrome. STUDY DESIGN: Multicenter study with cross-sectional interviews and chart review of individuals with definite PHACE syndrome ≥10 years of age. Data from charts were collected across multiple PHACE-related topics. Data not available in charts were collected from patients directly. Likert scales were used to assess the impact of specific findings. Patient-Reported Outcomes Measurement Information System (PROMIS) scales were used to assess quality of life domains. RESULTS: A total of 104/153 (68%) individuals contacted participated in the study at a median of 14 years of age (range 10-77 years). There were infantile hemangioma (IH) residua in 94.1%. Approximately one-half had received laser treatment for residual IH, and the majority (89.5%) of participants were satisfied or very satisfied with the appearance. Neurocognitive manifestations were common including headaches/migraines (72.1%), participant-reported learning differences (45.1%), and need for individualized education plans (39.4%). Cerebrovascular arteriopathy was present in 91.3%, with progression identified in 20/68 (29.4%) of those with available follow-up imaging reports. Among these, 6/68 (8.8%) developed moyamoya vasculopathy or progressive stenoocclusion, leading to isolated circulation at or above the level of the circle of Willis. Despite the prevalence of cerebrovascular arteriopathy, the proportion of those with ischemic stroke was low (2/104; 1.9%). PROMIS global health scores were lower than population norms by at least 1 SD. CONCLUSIONS: PHACE syndrome is associated with long-term, mild to severe morbidities including IH residua, headaches, learning differences, and progressive arteriopathy. Primary and specialty follow-up care is critical for PHACE patients into adulthood.

Disruption of DNA methylation-mediated cranial neural crest proliferation and differentiation causes orofacial clefts in mice.

Orofacial clefts of the lip and palate are widely recognized to result from complex gene-environment interactions, but inadequate understanding of environmental risk factors has stymied development of prevention strategies. We interrogated the role of DNA methylation, an environmentally malleable epigenetic mechanism, in orofacial development. Expression of the key DNA methyltransferase enzyme DNMT1 was detected throughout palate morphogenesis in the epithelium and underlying cranial neural crest cell (cNCC) mesenchyme, a highly proliferative multipotent stem cell population that forms orofacial connective tissue. Genetic and pharmacologic manipulations of DNMT activity were then applied to define the tissue- and timing-dependent requirement of DNA methylation in orofacial development. cNCC-specific Dnmt1 inactivation targeting initial palate outgrowth resulted in OFCs, while later targeting during palatal shelf elevation and elongation did not. Conditional Dnmt1 deletion reduced cNCC proliferation and subsequent differentiation trajectory, resulting in attenuated outgrowth of the palatal shelves and altered development of cNCC-derived skeletal elements. Finally, we found that the cellular mechanisms of cleft pathogenesis observed in vivo can be recapitulated by pharmacologically reducing DNA methylation in multipotent cNCCs cultured in vitro. These findings demonstrate that DNA methylation is a crucial epigenetic regulator of cNCC biology, define a critical period of development in which its disruption directly causes OFCs, and provide opportunities to identify environmental influences that contribute to OFC risk.

Intralesional measles, mumps, and rubella vaccine after failure of intralesional Candida antigen for the treatment of recalcitrant pediatric warts.

Numerous studies have investigated the efficacy of intralesional immunotherapy for warts, but there are a lack of studies investigating the efficacy of alternative intralesional immunotherapies following failure of initial intralesional immunotherapy. In this retrospective study, we aimed to investigate the efficacy of intralesional measles, mumps, and rubella vaccine for the treatment of pediatric warts following failure of intralesional therapy with Candida antigen. Following intralesional measles, mumps, and rubella vaccine administration, 8/51 (15.5%) patients had complete resolution of their warts, 6/51 (12%) had near complete resolution, 19/51 (37%) had partial improvement, 12/51 (23.5%) had no change, and 6/51 (12%) had worsening. Although limited by retrospective nature and low sample size, our results demonstrate that intralesional immunotherapy with measles, mumps, and rubella vaccine provides an alternative therapeutic option for the treatment of recalcitrant pediatric warts in patients who fail to respond to intralesional Candida antigen.

Lipofibromatosis-like neural tumors: Report of a case and review of 73 reported cases.

Lipofibromatosis-like neural tumors (LPF-NTs) are a recently discovered group of spindle cell tumors defined by the presence of a lipofibromatosis-like pattern, CD34 and/or S100 reactivity, and frequent neurotrophic receptor tyrosine kinase 1 (NTRK1) gene rearrangements. As new cases emerge, the spectrum of features observed in LPF-NTs continues to evolve. Here we describe the case of an 11-year-old with LPF-NT with a dermatofibrosarcoma protuberans-like honeycomb pattern, CD34 and S100 co-expression, and an NTRK1 rearrangement. We also review the clinical and molecular features of the 73 cases of LPF-NT previously described in the literature.

African American race is a risk factor for severe hidradenitis suppurativa.

BACKGROUND: African Americans face a disproportionate incidence and prevalence of hidradenitis suppurativa (HS) in the United States, but HS severity and outcomes across racial and ethnic groups have not been well-established while controlling for potentially confounding factors. In this retrospective cohort study, we investigated the associations of race and ethnicity with HS severity, emergency department (ED) visits, hospitalizations, and surgeries for HS while controlling for age, sex, body mass index (BMI), tobacco use, and insurance type. METHODS: We reviewed 1190 patients seen at the Medical College of Wisconsin with ≥3 encounters for HS between 1/1/2002 and 3/19/2019, excluding those without race data or an encounter in which HS was treated. RESULTS: A total of 953 patients were included; 470 patients were Black or African American non-Hispanic (49%), 39 Hispanic (4%), 418 White non-Hispanic (44%), and 26 other race or ethnicity (3%). Controlling for age, sex, BMI, tobacco use, and insurance type, Black patients had 2.8 times the odds of having Hurley stage III disease (95% CI 1.76-4.45, P < 0.001), 2.86 times the risk for experiencing an ED visit for HS (95% CI 2.12-3.88, P < 0.001), 2.25 times the risk for experiencing a hospitalization for HS (95% CI 1.42-3.56, P < 0.001), and 1.61 times the risk for experiencing a surgical encounter for HS (95% CI 1.34-1.95, P < 0.001) when compared to White patients. CONCLUSIONS: African Americans face significant disparities in HS severity, ED visits, hospitalizations, and surgeries. The causes of these disparities must be further investigated and addressed.

Racial disparities of delay in diagnosis and dermatologic care for hidradenitis suppurativa.

Hidradenitis suppurativa is a chronic, debilitating skin disease that disproportionately affects African Americans, and care-related factors may contribute to this disparity. In this study, we investigated delay in diagnosis and dermatologic care for HS at an urban Midwestern Academic Center. A retrospective chart review of 1,190 patients with 3 or more encounters for HS between 1/1/2002 and 3/19/2019 was conducted. A total of 953 patients were included in statistical analysis. A mean (standard deviation) delay in diagnosis was 4.1 ± 7.0 years. For white patients the delay in diagnosis was 3.2 ± 6.3 years, for Black patients 4.8 ± 7.0 years, for Hispanic patients 4.7 ± 5.8 years, and for other races 4.9 ± 7.4 years (p <0.001). Among the 932 patients with known specialist visit types, 500 (53.6%) had seen dermatology including 222 (47.8%) of Black patients, 242 (59.5%) of white patients, 24 (64.9%) of Hispanic patients, and 12 (50%) patients of other races (p=0.003).White patients and Hispanic patients saw a dermatologist an average of 3.0 years after first presentation of HS and Black patients saw a dermatologist on average 5.0 years after first presentation (p=0.004). Of the patients who did see dermatology, 44.9% of Black patients, 31.6% of white patients, 23.1% of Hispanic patients, and 30.8% of other races saw surgery before dermatology (p<.001). Our results indicate that non-white patients have a longer delay in diagnosis than their white counterparts and that Black patients do not see dermatology as early in their disease course as other racial groups. Black patients also see surgery more often than white patients before seeing dermatology, which could suggest greater disease severity at presentation and diagnosis or difficult access to dermatology.

Anti-IL 23 biologics for the treatment of plaque psoriasis.

INTRODUCTION: Psoriasis is a chronic inflammatory disease that can drastically affect a patient's quality-of-life and is associated with multiple comorbid conditions. The most common form of psoriasis is plaque psoriasis, commonly presenting as sharply demarcated, erythematous plaques with overlying silvery scale on the trunk, extensor surfaces, limbs, and scalp. Although initially limited to oral therapies, the choices in systemic therapies for moderate-to-severe plaque psoriasis have evolved with biologic immunotherapies being the main focus. AREAS COVERED: In this review, we describe the IL-23/Th17 axis and IL-23 inhibitors as targets for a growing family of biologics. This family includes the FDA-approved medications ustekinumab, guselkumab, tildrakizumab, and risankizumab. We will review the safety and efficacy of these medications throughout various Phase 1,2, and 3, trials for moderate-to-severe psoriasis. A literature search of PubMed was utilized for the following terms: 'psoriasis and IL-23,' 'ustekinumab,' 'guselkumab,' 'tildrakizumab,' and 'risankizumab.' We also searched for clinical trials involving IL-23 inhibitors registered at ClinicalTrials.gov. EXPERT OPINION: Anti-IL 23 therapy, especially anti-p19 monoclonal antibodies, should be considered first-line therapy for moderate-to-severe plaque psoriasis due to their efficacy and relative safety. More research is required to expand the scope of anti-p19 therapy to pediatric populations and additional indications such as psoriatic arthritis.

Developmental Toxicity Assessment of Piperonyl Butoxide Exposure Targeting Sonic Hedgehog Signaling and Forebrain and Face Morphogenesis in the Mouse: An in Vitro and in Vivo Study.

BACKGROUND: Piperonyl butoxide (PBO) is a pesticide synergist used in residential, commercial, and agricultural settings. PBO was recently found to inhibit Sonic hedgehog (Shh) signaling, a key developmental regulatory pathway. Disruption of Shh signaling is linked to birth defects, including holoprosencephaly (HPE), a malformation of the forebrain and face thought to result from complex gene-environment interactions. OBJECTIVES: The impact of PBO on Shh signaling in vitro and forebrain and face development in vivo was examined. METHODS: The influence of PBO on Shh pathway transduction was assayed in mouse and human cell lines. To examine its teratogenic potential, a single dose of PBO (22-1,800mg/kg) was administered by oral gavage to C57BL/6J mice at gestational day 7.75, targeting the critical period for HPE. Gene-environment interactions were investigated using Shh+/- mice, which model human HPE-associated genetic mutations. RESULTS: PBO attenuated Shh signaling in vitro through a mechanism similar to that of the known teratogen cyclopamine. In utero PBO exposure caused characteristic HPE facial dysmorphology including dose-dependent midface hypoplasia and hypotelorism, with a lowest observable effect level of 67mg/kg. Median forebrain deficiency characteristic of HPE was observed in severely affected animals, whereas all effective doses disrupted development of Shh-dependent transient forebrain structures that generate cortical interneurons. Normally silent heterozygous Shh null mutations exacerbated PBO teratogenicity at all doses tested, including 33mg/kg. DISCUSSION: These findings demonstrate that prenatal PBO exposure can cause overt forebrain and face malformations or neurodevelopmental disruptions with subtle or no craniofacial dysmorphology in mice. By targeting Shh signaling as a sensitive mechanism of action and examining gene-environment interactions, this study defined a lowest observable effect level for PBO developmental toxicity in mice more than 30-fold lower than previously recognized. Human exposure to PBO and its potential contribution to etiologically complex birth defects should be rigorously examined. https://doi.org/10.1289/EHP5260.

Gli2 gene-environment interactions contribute to the etiological complexity of holoprosencephaly: evidence from a mouse model.

Holoprosencephaly (HPE) is a common and severe human developmental abnormality marked by malformations of the forebrain and face. Although several genetic mutations have been linked to HPE, phenotypic outcomes range dramatically, and most cases cannot be attributed to a specific cause. Gene-environment interaction has been invoked as a premise to explain the etiological complexity of HPE, but identification of interacting factors has been extremely limited. Here, we demonstrate that mutations in Gli2, which encodes a Hedgehog pathway transcription factor, can cause or predispose to HPE depending upon gene dosage. On the C57BL/6J background, homozygous GLI2 loss of function results in the characteristic brain and facial features seen in severe human HPE, including midfacial hypoplasia, hypotelorism and medial forebrain deficiency with loss of ventral neurospecification. Although normally indistinguishable from wild-type littermates, we demonstrate that mice with single-allele Gli2 mutations exhibit increased penetrance and severity of HPE in response to low-dose teratogen exposure. This genetic predisposition is associated with a Gli2 dosage-dependent attenuation of Hedgehog ligand responsiveness at the cellular level. In addition to revealing a causative role for GLI2 in HPE genesis, these studies demonstrate a mechanism by which normally silent genetic and environmental factors can interact to produce severe outcomes. Taken together, these findings provide a framework for the understanding of the extreme phenotypic variability observed in humans carrying GLI2 mutations and a paradigm for reducing the incidence of this morbid birth defect.