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BACKGROUND: The emergence of SARS-CoV-2 variants and COVID-19 vaccination have resulted in complex exposure histories. Rapid assessment of the effects of these exposures on neutralising antibodies against SARS-CoV-2 infection is crucial for informing vaccine strategy and epidemic management. We aimed to investigate heterogeneity in individual-level and population-level antibody kinetics to emerging variants by previous SARS-CoV-2 exposure history, to examine implications for real-time estimation, and to examine the effects of vaccine-campaign timing. METHODS: Our Bayesian hierarchical model of antibody kinetics estimated neutralising-antibody trajectories against a panel of SARS-CoV-2 variants quantified with a live virus microneutralisation assay and informed by individual-level COVID-19 vaccination and SARS-CoV-2 infection histories. Antibody titre trajectories were modelled with a piecewise linear function that depended on the key biological quantities of an initial titre value, time the peak titre is reached, set-point time, and corresponding rates of increase and decrease for gradients between two timing parameters. All process parameters were estimated at both the individual level and the population level. We analysed data from participants in the University College London Hospitals-Francis Crick Institute Legacy study cohort (NCT04750356) who underwent surveillance for SARS-CoV-2 either through asymptomatic mandatory occupational health screening once per week between April 1, 2020, and May 31, 2022, or symptom-based testing between April 1, 2020, and Feb 1, 2023. People included in the Legacy study were either Crick employees or health-care workers at three London hospitals, older than 18 years, and gave written informed consent. Legacy excluded people who were unable or unwilling to give informed consent and those not employed by a qualifying institution. We segmented data to include vaccination events occurring up to 150 days before the emergence of three variants of concern: delta, BA.2, and XBB 1.5. We split the data for each wave into two categories: real-time and retrospective. The real-time dataset contained neutralising-antibody titres collected up to the date of emergence in each wave; the retrospective dataset contained all samples until the next SARS-CoV-2 exposure of each individual, whether vaccination or infection. FINDINGS: We included data from 335 participants in the delta wave analysis, 223 (67%) of whom were female and 112 (33%) of whom were male (median age 40 years, IQR 22-58); data from 385 participants in the BA.2 wave analysis, 271 (70%) of whom were female and 114 (30%) of whom were male (41 years, 22-60); and data from 248 participants in the XBB 1.5 wave analysis, 191 (77%) of whom were female, 56 (23%) of whom were male, and one (<1%) of whom preferred not to say (40 years, 21-59). Overall, we included 968 exposures (vaccinations) across 1895 serum samples in the model. For the delta wave, we estimated peak titre values as 490·0 IC50 (95% credible interval 224·3-1515·9) for people with no previous infection and as 702·4 IC50 (300·8-2322·7) for people with a previous infection before omicron; the delta wave did not include people with a previous omicron infection. For the BA.2 wave, we estimated peak titre values as 858·1 IC50 (689·8-1363·2) for people with no previous infection, 1020·7 IC50 (725·9-1722·6) for people with a previous infection before omicron, and 1422·0 IC50 (679·2-3027·3) for people with a previous omicron infection. For the XBB 1.5 wave, we estimated peak titre values as 703·2 IC50 (415·0-3197·8) for people with no previous infection, 1215·9 IC50 (511·6-7338·7) for people with a previous infection before omicron, and 1556·3 IC50 (757·2-7907·9) for people with a previous omicron infection. INTERPRETATION: Our study shows the feasibility of real-time estimation of antibody kinetics before SARS-CoV-2 variant emergence. This estimation is valuable for understanding how specific combinations of SARS-CoV-2 exposures influence antibody kinetics and for examining how COVID-19 vaccination-campaign timing could affect population-level immunity to emerging variants. FUNDING: Wellcome Trust, National Institute for Health Research University College London Hospitals Biomedical Research Centre, UK Research and Innovation, UK Medical Research Council, Francis Crick Institute, and Genotype-to-Phenotype National Virology Consortium.

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Rare germline variation in regulator of telomere elongation helicase 1 (RTEL1) is associated with telomere biology disorders (TBDs). Biallelic RTEL1 variants result in childhood onset dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome whereas heterozygous individuals usually present later in life with pulmonary fibrosis or bone marrow failure. We compiled all TBD-associated RTEL1 variants in the literature and assessed phenotypes and outcomes of 44 individuals from 14 families with mono- or biallelic RTEL1 variants enrolled in clinical trial NCT00027274. Variants were classified by adapting ACMG-AMP guidelines using clinical information, telomere length, and variant allele frequency data. Compared with heterozygotes, individuals with biallelic RTEL1 variants had an earlier age at diagnosis (median age 35.5 vs. 5.1 years, p < 0.01) and worse overall survival (median age 66.5 vs. 22.9 years, p < 0.001). There were 257 unique RTEL1 variants reported in 47 publications, and 209 had a gnomAD minor allele frequency <1%. Only 38.3% (80/209) met pathogenic/likely pathogenic criteria. Notably, 8 of 209 reported disease-associated variants were benign or likely benign and the rest were variants of uncertain significance. Given the considerable differences in outcomes of TBDs associated with RTEL1 germline variants and the extent of variation in the gene, systematic functional studies and standardization of variant curation are urgently needed to inform clinical management.

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BACKGROUND: The relationship between fetal fraction and birth weight in twin gestations is poorly understood. OBJECTIVE: To investigate the relationship between first trimester cfDNA fetal fraction and birth weight < 10th percentile in twin gestations. STUDY DESIGN: This is a planned secondary analysis of the Twin cfDNA Study, a 17-center retrospective cohort of twin pregnancies screened for aneuploidy using cfDNA in the first trimester from 12/2011 - 2/2022, excluding those with positive screen results for chromosomal aneuploidy. CfDNA testing was performed by a single lab using massively parallel sequencing (MPSS). Baseline characteristics and birth weight of pregnancies with normal fetal fraction were compared to those with low (<5%) and high (>95%) fetal fraction using univariable analyses and multivariable regression. RESULTS: A total of 1041 twin pregnancies were included. Chronic hypertension, elevated BMI, and self-identified Black race were associated with fetal fraction <5th percentile. There was no difference in median fetal fraction between those with birth weight <10th percentile in at least one twin (median [IQR] fetal fraction 12.2% [9.8, 14.8] versus those with normal birth weight (10th percentile) in both twins (median [IQR] fetal fraction 12.3% [9.7, 15.2] for normal birth weight, p = 0.49). There was no association between high or low fetal fraction and birth weight <10th percentile for one (p=0.45) or both (p=0.81) twins, and there was no association between high or low fetal fraction and birth weight <5th percentile for one (p=0.44) or both (p=0.74) twins. The results were unchanged after adjustment for potential confounders. CONCLUSION: In this large cohort, there was no association between the extremes of cfDNA fetal fraction and birthweight < 10th percentile, suggesting that first trimester fetal fraction may not predict impaired fetal growth in twin gestations.

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BACKGROUND: The extent to which individuals can flexibly allocate their attention towards adaptive cues in the social environment may play an important role in the maintenance of social anxiety. Attentional control (AC) describes the top-down ability to regulate one's attention and cognitive resources. Although low AC has been linked to psychopathology broadly, the specific relation between AC and social anxiety disorder (SAD) remains poorly understood. The present study aimed to clarify the role of AC in SAD by examining unique associations between AC and several facets of social anxiety, above and beyond general psychological distress. METHODS: Adults endorsing elevated SAD symptoms (n = 123) were assessed for levels of AC, inhibitory control, social anxiety severity, social anxiety sensitivity, social avoidance/safety behaviors, stress, and depression. RESULTS: Partial correlations revealed that self-reported AC was negatively associated with all dimensions of SAD (rs = -0.20 to -0.29, ps < 0.05) after controlling for symptoms of stress and depression. Similarly, structural equation models showed that latent AC negatively predicted latent social anxiety (ß = -0.21, p < .05), even after controlling for latent psychological distress. LIMITATIONS: The study used a cross-sectional design, an analogue sample, and solely self-report measures in structural equation models. CONCLUSIONS: Results converge to suggest that subjective (but not objective) deficits in AC have a unique relation with several mechanisms involved in the development and maintenance of SAD. These findings partially support the applicability of Attentional Control Theory to SAD and point to AC as a potential treatment target.

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PURPOSE: Sleep disturbances are common in patients with breast cancer, but comprehensive evaluations with patient-reported outcomes (PRO) and sleep evaluation with polysomnography (PSG) are lacking. This study describes sleep disruption using PROs and PSG to identify underlying sleep disorders. METHODS: A retrospective review of patients with breast cancer undergoing formal sleep evaluation from 4/1/2009 to 7/31/2014 was performed. Clinical characteristics, PROs using Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS), and PSG data were reviewed. RESULTS: 404 patients were identified with 43% early, 30% locally advanced and 17% metastatic disease. PSQI revealed poor sleep in 75%, and ESS demonstrated daytime sleepiness in 55%. Sleep aid use was reported by 39%, and pain medication use in 22%. Most patients (50.2%) had multiple sleep disorders. Insomnia (54.5%) was the most frequent sleep disorder, followed closely by obstructive sleep apnea (OSA) (53.7%). PSG was performed in 74%. Multivariate analysis linked poor sleep to use of sleep aids [OR 7.7, 95% CI 3.9 to 15.2], anxiety disorder [OR 4.8, 95% CI 1.7 to 14.0], and metastatic disease [OR 2.8, 95% CI 1.1 to 6.6]. Daytime sleepiness correlated with known diagnosis of OSA [OR 1.9, 95% CI 1.0 to 3.3] and sleep aid use [OR 0.6, 95% CI 0.4 to 0.9]. CONCLUSIONS: Poor sleep was associated with sleep aid use, anxiety disorder and metastatic disease. Insomnia was the most common sleep disorder, followed by OSA (mostly mild). Education about sleep health and proactive screening for sleep symptoms would be beneficial in patients with breast cancer.

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To identify cancer-associated gene regulatory changes, we generated single-cell chromatin accessibility landscapes across eight tumor types as part of The Cancer Genome Atlas. Tumor chromatin accessibility is strongly influenced by copy number alterations that can be used to identify subclones, yet underlying cis-regulatory landscapes retain cancer type-specific features. Using organ-matched healthy tissues, we identified the "nearest healthy" cell types in diverse cancers, demonstrating that the chromatin signature of basal-like-subtype breast cancer is most similar to secretory-type luminal epithelial cells. Neural network models trained to learn regulatory programs in cancer revealed enrichment of model-prioritized somatic noncoding mutations near cancer-associated genes, suggesting that dispersed, nonrecurrent, noncoding mutations in cancer are functional. Overall, these data and interpretable gene regulatory models for cancer and healthy tissue provide a framework for understanding cancer-specific gene regulation.

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Outline a quality initiative establishing an institutional service line for neonatal transcatheter device closure of the patent ductus arteriosus (TDC-PDA). A retrospective descriptive observational study surrounds programmatic approach to TDC-PDA in premature neonates with process measure spanning education, implementation, referral, and post-procedural care. Metrics tracked pre- and post-program creation with statistical analyses performed. Neonatal TDC-PDA referrals increased exponentially since program inception (n = 13 in year prior; n = 42 year 1; n = 74 year 2), especially in patients weighing less than 1.3 kg (12.5%; 55%; 50%), and were associated with an increased procedural success rate (81%; 95%; 99%). Procedural checklist creation decreased procedural "out of isolette" time (median 93 min; 59; 52), and procedural-related complication or clinical sequelae (19%; 12%; 4%). A multidisciplinary service line and program dedicated to neonatal TDC-PDA can result in a significant increase in referrals as well as procedural efficacy and safety for this medically fragile population.

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PURPOSE: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have improved patient survival in hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) in clinical trials and real-world studies. However, investigations of survival gains in broader HR+/HER2- mBC populations using epidemiological approaches are limited. METHODS: This retrospective study used SEER registry data to assess breast cancer-specific survival (BCSS) in patients diagnosed with HR+/HER2- de novo mBC from 2010 to 2019. Kaplan-Meier and Cox proportional hazards models were used to compare BCSS in patients diagnosed before (2010‒2013 with follow-up to 2014) and after (2015‒2018 with follow-up to 2019) the 2015 guideline recommendations for CDK4/6i use. A comparison was made to patients with HR+/HER2-positive (HER2+) de novo mBC, for which no major guideline changes occurred during 2015-2018. RESULTS: Data from 11,467 women with HR+/HER2- mBC and 3260 women with HR+/HER2+ mBC were included. After baseline characteristic adjustment, patients with HR+/HER2- mBC diagnosed post-2015 (n = 6163), had an approximately 10% reduction in risk of BC-specific death compared with patients diagnosed pre-2015 (n = 5304; HR = 0.895, p < 0.0001). Conversely, no significant change was observed in HR+/HER2+ BCSS post-2015 (n = 1798) versus pre-2015 (n = 1462). Similar results were found in patients aged ≥ 65 years. CONCLUSION: Using one of the largest US population-based longitudinal cancer databases, significant improvements in BCSS were noted in patients with HR+/HER2- mBC post-2015 versus pre-2015, potentially due to the introduction of CDK4/6i post-2015. No significant improvement in BCSS was observed in patients with HR+/HER2+ mBC post-2015 versus pre-2015, likely due to the availability of HER2-directed therapies in both time periods.

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BACKGROUND: Artificial intelligence (AI) and large language models (LLMs) transform how patients inform themselves. LLMs offer potential as educational tools, but their quality depends upon the information generated. Current literature examining AI as an informational tool in dermatology has been limited in evaluating AI's multifaceted roles and diversity of opinions. Here, we evaluate LLMs as a patient-educational tool for Mohs micrographic surgery (MMS) in and out of the clinic utilizing an international expert panel. METHODS: The most common patient MMS questions were extracted from Google and transposed into two LLMs and Google's search engine. 15 MMS surgeons evaluated the generated responses, examining their appropriateness as a patient-facing informational platform, sufficiency of response in a clinical environment, and accuracy of content generated. Validated scales were employed to assess the comprehensibility of each response. RESULTS: The majority of reviewers deemed all LLM responses appropriate. 75% of responses were rated as mostly accurate or higher. ChatGPT had the highest mean accuracy. The majority of the panel deemed 33% of responses sufficient for clinical practice. The mean comprehensibility scores for all platforms indicated a required 10th-grade reading level. CONCLUSIONS: LLM-generated responses were rated as appropriate patient informational sources and mostly accurate in their content. However, these platforms may not provide sufficient information to function in a clinical environment, and complex comprehensibility may represent a barrier to utilization. As the popularity of these platforms increases, it is important for dermatologists to be aware of these limitations.

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OBJECTIVE: Maternal obesity (MO) increases the risk of later-life liver disease in offspring, especially in males. This may be due to impaired cytochrome P450 (CYP) enzyme activity driven by an altered maternal-fetal hormonal milieu. MO increases fetal cortisol concentrations that may increase CYP activity; however, glucocorticoid receptor (GR)-mediated signaling can be modulated by alternative GR isoform expression. We hypothesized that MO induces sex-specific changes in GR isoform expression and localization that contribute to reduced hepatic CYP activity. METHODS: Nonpregnant, nulliparous female baboons were assigned to either an ad libitum control diet or a high-fat, high-energy diet (HF-HED) at 9 months pre pregnancy. At 165 days' gestation (term = 180 days), fetal liver samples were collected (n = 6/sex/group). CYP activity was quantified using functional assays, and GR was measured using quantitative RT-PCR and Western blot. RESULTS: CYP3A activity was reduced in the HF-HED group, whereas CYP2B6 activity was reduced in HF-HED males only. Total GR expression was increased in the HF-HED group. Relative nuclear expression of the antagonistic GR isoform GRß was increased in HF-HED males only. CONCLUSIONS: Reduced CYP activity in HF-HED males may be driven in part by dampened hepatic-specific glucocorticoid signaling via altered GR isoform expression. These findings highlight targetable mechanisms that may reduce later-life sex-specific disease risk.

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SUMMARYThe human microbiota encompasses the diverse communities of microorganisms that reside in, on, and around various parts of the human body, such as the skin, nasal passages, and gastrointestinal tract. Although research is ongoing, it is well established that the microbiota exert a substantial influence on the body through the production and modification of metabolites and small molecules. Disruptions in the composition of the microbiota-dysbiosis-have also been linked to various negative health outcomes. As humans embark upon longer-duration space missions, it is important to understand how the conditions of space travel impact the microbiota and, consequently, astronaut health. This article will first characterize the main taxa of the human gut microbiota and their associated metabolites, before discussing potential dysbiosis and negative health consequences. It will also detail the microbial changes observed in astronauts during spaceflight, focusing on gut microbiota composition and pathogenic virulence and survival. Analysis will then turn to how astronaut health may be protected from adverse microbial changes via diet, exercise, and antibiotics before concluding with a discussion of the microbiota of spacecraft and microbial culturing methods in space. The implications of this review are critical, particularly with NASA's ongoing implementation of the Moon to Mars Architecture, which will include weeks or months of living in space and new habitats.

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We present a case of a vein of Galen aneurysmal malformation (VGAM), a rare congenital arteriovenous malformation, in one fetus of a monochorionic-diamniotic twin pregnancy. The diagnosis was made with color Doppler ultrasonography at 28 weeks and the affected fetus was found to have worsening cardiomegaly on subsequent fetal echocardiograms. She was emergently delivered at 32 weeks for abnormal fetal heart rate tracing of the affected twin. Magnetic resonance imaging of the brain findings after delivery demonstrated severe neurological injury; therefore, postnatal embolization was not performed. The neonate died on day of life 9. The cotwin survived without neurological complications. This is the first case in the literature of a VGAM diagnosed prenatally in a monochorionic-diamniotic twin pregnancy and demonstrates the challenge of delivery timing with prenatal diagnosis in a twin pregnancy.

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The consumption of high fat-high energy diets (HF-HEDs) continues to rise worldwide and parallels the rise in maternal obesity (MO) that predisposes offspring to cardiometabolic disorders. Although the underlying mechanisms are unclear, thyroid hormones (TH) modulate cardiac maturation in utero. Therefore, we aimed to determine the impact of a high fat-high energy diet (HF-HED) on the hormonal, metabolic and contractility profile of the non-human primate (NHP) fetal heart. At ∼9 months preconception, female baboons (Papio hamadryas) were randomly assigned to either a control diet or HF-HED. At 165 days gestational age (term = 184 days), fetuses were delivered by Caesarean section under anaesthesia, humanely killed, and left ventricular cardiac tissue (Control (n = 6 female, 6 male); HF-HED (n = 6 F, 6 M)) was collected. Maternal HF-HED decreased the concentration of active cardiac TH (i.e. triiodothyronine (T3)), and type 1 iodothyronine deiodinase (DIO1) mRNA expression. Maternal HF-HED decreased the abundance of cardiac markers of insulin-mediated glucose uptake phosphorylated insulin receptor substrate 1 (Ser789) and glucose transporter 4, and increased protein abundance of key oxidative phosphorylation complexes (I, III, IV) and mitochondrial abundance in both sexes. Maternal HF-HED alters cardiac TH status, which may induce early signs of cardiac insulin resistance. This may increase the risk of cardiometabolic disorders in later life in offspring born to these pregnancies. KEY POINTS: Babies born to mothers who consume a high fat-high energy diet (HF-HED) prior to and during pregnancy are predisposed to an increased risk of cardiometabolic disorders across the life course. Maternal HF-HED prior to and during pregnancy decreased thyroid hormone triiodothyronine (T3) concentrations and type 1 iodothyronine deiodinase DIO1 mRNA expression in the non-human primate fetal heart. Maternal HF-HED decreased markers of insulin-dependent glucose uptake, phosphorylated insulin receptor substrate 1 and glucose transporter 4 in the fetal heart. Maternal HF-HED increased mitochondrial abundance and mitochondrial OXPHOS complex I, III and IV in the fetal heart. Fetuses from HF-HED pregnancies are predisposed to cardiometabolic disorders that may be mediated by changes in T3, placing them on a poor lifetime cardiovascular health trajectory.

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Introduction: Many loci segregate alleles classified as "genetic diseases" due to their deleterious effects on health. However, some disease alleles have been reported to show beneficial effects under certain conditions or in certain populations. The beneficial effects of these antagonistically pleiotropic alleles may explain their continued prevalence, but the degree to which antagonistic pleiotropy is common or rare is unresolved. We surveyed the medical literature to identify examples of antagonistic pleiotropy to help determine whether antagonistic pleiotropy appears to be rare or common. Results: We identified ten examples of loci with polymorphisms for which the presence of antagonistic pleiotropy is well supported by detailed genetic or epidemiological information in humans. One additional locus was identified for which the supporting evidence comes from animal studies. These examples complement over 20 others reported in other reviews. Discussion: The existence of more than 30 identified antagonistically pleiotropic human disease alleles suggests that this phenomenon may be widespread. This poses important implications for both our understanding of human evolutionary genetics and our approaches to clinical treatment and disease prevention, especially therapies based on genetic modification.

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BACKGROUND: The frequency and significance of IDH mutations in glioma across age groups is incompletely understood. We performed a multi-center retrospective age-stratified comparison of patients with IDH-mutant gliomas to identify age-specific differences in clinico-genomic features, treatments, and outcomes. METHODS: Clinical, histologic, and sequencing data from patients with IDH-mutant, grade 2-4 gliomas, were collected from collaborating institutions between 2013-2019. Patients were categorized as pediatric (<19y), YA (19-39y) or older adult (≥40y). Clinical presentation, treatment, histologic, and molecular features were compared across age categories using Fisher's exact test or analysis-of-variance. Cox proportional-hazards regression was used to determine association of age and other covariates with overall (OS) and progression-free survival (PFS). RESULTS: We identified a cohort of 379 patients (204 YA) with IDH-mutant glioma with clinical data. There were 155 (41%) oligodendrogliomas and 224 (59%) astrocytomas. YA showed significantly shorter PFS and shorter median time-to-malignant transformation (MT) compared to pediatric and adult groups, but no significant OS difference. Adjusting for pathology type, extent of resection, and upfront therapy in multivariable analysis, the YA group was independently prognostic of shorter PFS than pediatric and adult groups. Among astrocytomas, CDK4/6 copy number amplifications were associated with both shorter PFS and shorter OS. Among oligodendrogliomas, PIK3CA and CDKN2A/2B alterations were associated with shorter OS. CONCLUSIONS: IDH-mutant glioma YA patients had significantly shorter PFS and time to MT but did not differ in OS compared to pediatric and adult groups. Treatment approach varied significantly by patient age and warrant further study as addressable age-associated outcome drivers.

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BACKGROUND: While inflammatory and immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in peripheral blood are extensively described, responses at the upper respiratory mucosal site of initial infection are relatively poorly defined. We sought to identify mucosal cytokine/chemokine signatures that distinguished coronavirus disease 2019 (COVID-19) severity categories, and relate these to disease progression and peripheral inflammation. METHODS: We measured 35 cytokines and chemokines in nasal samples from 274 patients hospitalized with COVID-19. Analysis considered the timing of sampling during disease, as either the early (0-5 days after symptom onset) or late (6-20 days after symptom onset) phase. RESULTS: Patients that survived severe COVID-19 showed interferon (IFN)-dominated mucosal immune responses (IFN-γ, CXCL10, and CXCL13) early in infection. These early mucosal responses were absent in patients who would progress to fatal disease despite equivalent SARS-CoV-2 viral load. Mucosal inflammation in later disease was dominated by interleukin 2 (IL-2), IL-10, IFN-γ, and IL-12p70, which scaled with severity but did not differentiate patients who would survive or succumb to disease. Cytokines and chemokines in the mucosa showed distinctions from responses evident in the peripheral blood, particularly during fatal disease. CONCLUSIONS: Defective early mucosal antiviral responses anticipate fatal COVID-19 but are not associated with viral load. Early mucosal immune responses may define the trajectory of severe COVID-19.

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BACKGROUND: Dogs with lymphoma that fail cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy (CHOP) before completion of their protocol are commonly thought to have poor long-term outcome, but no previous studies have evaluated the effect of early relapse on progression-free interval (PFI) or overall survival time (OST) for patients undergoing rescue chemotherapy. OBJECTIVE: Correlate rescue treatment outcomes in dogs with multicentric lymphoma with outcomes after 1st-line CHOP chemotherapy. METHODS: Data were collected from 6 previous retrospective or prospective studies in 187 dogs with multicentric lymphoma that received 1st-line CHOP chemotherapy and then received either lomustine (CCNU), L-asparaginase and prednisone (LAP), or rabacfosadine (RAB, Tanovea), with or without prednisone or L-asparaginase. RESULTS: The PFI after initiation of CHOP chemotherapy was significantly associated with response rate postprogression, PFI, and postrescue survival time (ST) for both rescue protocols. Immunophenotype (B- vs T-cell) was not significantly associated with response, PFI or OST for LAP but was significantly associated with response and PFI for RAB. CONCLUSION: Dogs that experience short PFI during or after 1st-line CHOP chemotherapy had lower response rates to rescue treatment, with shorter PFI and ST. Immunophenotype did not significantly affect outcome with LAP but was associated with PFI for RAB.

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While surgery, when possible, remains the mainstay of pediatric low-grade glioma (pLGG) management, adjuvant therapy has significantly evolved over time. Radiation therapy was commonly used in the late 1990s for tumors that could not be resected or recurred. This resulted in significant late morbidity in this population and mortality related to secondary malignancies and chronic health conditions. Chemotherapy became the mainstay of adjuvant therapy but children still experienced late morbidity secondary to exposure to multiple lines of treatment over time. Targeted therapies emerged after the identification of frequent genetic alterations in the mitogen activated protein kinase (MAPK) pathway including KIAA1549-BRAF fusions and BRAF-V600 mutations and the near universal upregulation of the MAPK pathway in these tumors. Both BRAF and MEK inhibitors have shown efficacy in the treatment of pLGG and have led to prolonged stability in some cases. Multiple phase III clinical trials are now comparing targeted therapy to standard-of-care chemotherapy regimens setting the stage for targeted therapy to replace chemotherapy as the first-line treatment in some cases. Targeted therapy, however, is not without its challenges. There are clear examples of resistance and mechanisms of resistance have not been fully elucidated. There is also no clear duration for these therapies and rebound growth is a well-known phenomenon especially in BRAF-V600 mutant tumors. Targeted therapies are also fairly recent developments and long-term toxicities and functional outcomes are still being monitored. Very young and adolescent/young adult LGGs also carry molecular features that may not be addressed by inhibition of the MAPK pathway. Adjuvant therapy for pLGG has evolved from radiation for all unresectable or residual tumors to molecularly driven targeted therapies with improved quality of life, late effects, and less off-target toxicities. While there is still much to learn in regard to newer targeted therapies for pLGG, the era of targeted therapies for pediatric LGG is upon us.

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Maintenance of astronaut health during spaceflight will require monitoring and potentially modulating their microbiomes. However, documenting microbial shifts during spaceflight has been difficult due to mission constraints that lead to limited sampling and profiling. Here we executed a six-month longitudinal study to quantify the high-resolution human microbiome response to three days in orbit for four individuals. Using paired metagenomics and metatranscriptomics alongside single-nuclei immune cell profiling, we characterized time-dependent, multikingdom microbiome changes across 750 samples and 10 body sites before, during and after spaceflight at eight timepoints. We found that most alterations were transient across body sites; for example, viruses increased in skin sites mostly during flight. However, longer-term shifts were observed in the oral microbiome, including increased plaque-associated bacteria (for example, Fusobacteriota), which correlated with immune cell gene expression. Further, microbial genes associated with phage activity, toxin-antitoxin systems and stress response were enriched across multiple body sites. In total, this study reveals in-depth characterization of microbiome and immune response shifts experienced by astronauts during short-term spaceflight and the associated changes to the living environment, which can help guide future missions, spacecraft design and space habitat planning.

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