Antibody responses to influenza A viruses are strongly focused on immunodominant antigenic sites within the haemagglutinin (HA) head domain. Although immunodominance hierarchies have been described for H1 and H3 subtypes in adults, it remains unclear whether these patterns are shaped by first early-life exposure or by cumulative influenza infections or vaccinations over time. We evaluated HA antigenic site immunodominance using haemagglutination inhibition (HI) assays with panels of H1 and H3 mutant viruses lacking individual classical antigenic sites. Sera from two human cohorts with different exposure histories were analysed: adults from New York City with mixed exposures through vaccination and infection, as well as children and adults living in rural Zambia exposed only through infection. Analyses of children with presumed first exposure were conducted to assess how initial influenza exposure shapes immunodominance hierarchies. Across both cohorts, H1-specific antibody responses were consistently dominated by antigenic sites Sb and Ca2, regardless of age, geography, or exposure history. For H3, sites A and B shared immunodominance. The first influenza A infection in children was associated with the establishment of these hierarchies. Importantly, influenza B infection did not alter the immunodominance profiles of influenza A H1 or H3 haemagglutinin. Immunodominance hierarchies of influenza A haemagglutinin antigenic sites are established early in life following first exposure and appear not to be substantially affected by diverse exposure histories. This project was financially supported by Center for Excellence on Influenza Research and Response, the Center of Excellence for Influenza Research and Surveillance, the Collaborative Influenza Vaccine Innovation Centers programme as well as institutional funds from the Center for Vaccine Research and Pandemic Preparedness, and the National Institute of Allergy and Infectious Diseases.
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Sturge-Weber syndrome (SWS) brain involvement has been associated with impairments in the blood-brain barrier (BBB) and microglial activation within involved cortical regions. Acute neurological crises, including seizures, stroke-like episodes, and/or significant headaches, are common in these patients. This report describes in detail an adolescent with SWS and acute drug-resistant status epilepticus, headache, and stroke-like episode who improved clinically when treated with high-dose steroids. Review of medical records identified two other patients previously treated with steroids for acute neurological symptoms. A 13-year-old boy with SWS brain involvement presented with fever, headache, seizures, and right-sided weakness. Brain magnetic resonance imaging (MRI) revealed characteristic findings of SWS. The patient was placed on continuous electroencephalogram that showed findings consistent with electrographic status epilepticus. Seizures were refractory to multiple anti-seizure medications as well as to an intravenous midazolam drip. A repeat MRI of the brain documented a significant increase in leptomeningeal enhancement with associated gyral edema and sulcal effacement. Steroid therapy with methylprednisolone and prednisone improved his status epilepticus and stroke-like symptoms, including resolution of seizures and marked improvement in his hemiparesis. This patient suggests a potential role for inflammation-targeted therapies in individuals with SWS brain involvement who present with prolonged neurological crises. Two other patients with SWS brain involvement who were treated with high-dose steroids in the context of acute neurological episodes also support the need for future clinical and preclinical research to validate this approach.
Two decades after the Human Genome Project, we finally have the ability to read the complete genome of any human and (nearly) any species. These sequences provide the ideal foundation for training predictive models of the genome that will accelerate basic research, enable accurate diagnostics, and guide precision medicine.
ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). In this review, we explore the possibility of using ivermectin to slow ALS progression. Ivermectin's ability to modulate neuroinflammation and excitotoxicity give it plausible mechanisms for treating ALS, though it does not get into the brain very well. One preclinical study demonstrated that ivermectin lengthened lifespan within a mouse model of mSOD1 genetic ALS. This finding has not been replicated. The 2 PALS we found who had data comparing ALSFRS-R progression on and off ivermectin appeared to have no benefit from it. We found no trials of ivermectin in PALS. Ivermectin is low cost and generally well tolerated with most adverse effects being mild and transient, but serious side effects can rarely occur, and it has not been carefully studied in PALS. We cannot at present endorse ivermectin as an ALS treatment.
To investigate the link between continuous glucose monitoring (CGM) metrics and risk of severe hypoglycemia and diabetic ketoacidosis (DKA) in individuals of type 1 diabetes. We pooled individual-level data from 10 studies of type 1 diabetes. From a 14-day baseline period, we derived CGM metrics (time in range [TIR] 70-180 mg/dL, time above range [TAR], time below range [TBR], sensor mean glucose, SD, and percent coefficient of variation [%CV]) and CGM-defined hypo- and hyperglycemic episodes. We used Cox regression to evaluate associations with severe hypoglycemia and diabetic ketoacidosis, with and without adjustment for HbA1c. Among 1,550 participants, 65 severe hypoglycemia and 163 DKA events occurred over a median follow-up of 16 weeks. Higher TBR <70 and <54 mg/dL, SD, %CV, and CGM-defined hypoglycemic episodes were associated with greater risk of severe hypoglycemia independent of HbA1c (e.g., hazard ratio [HR] 1.52 [1.29-1.79] per 1-SD higher TBR <70). Lower TIR and higher mean glucose, SD, %CV, TAR, and hyperglycemic episodes were associated with higher DKA risk; these associations were attenuated after HbA1c adjustment, but TIR, sensor mean glucose, and SD remained statistically and clinically significant (e.g., HR 0.76, 95% CI 0.60-0.97 per 1-SD higher TIR). CGM hypoglycemic and glycemic variability metrics were associated with severe hypoglycemia risk independent of HbA1c, whereas TIR, mean glucose, and SD provided information for DKA risk beyond HbA1c. This supports the complementary value of CGM and HbA1c in risk assessment for severe hypoglycemia and DKA.
[Box: see text]Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual. ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines. Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating clinician and do not account for individual variation among patients. See appendix for disclaimers and other important information (Appendix I and Appendix II). Updates are published regularly and can be found on the ASCO Publications website.
Standard of care RPT may result in dose-limiting side effects of the salivary glands include sialadenitis and xerostomia that are inconsistent with outcomes from external beam for equivalent ADs. This work develops a parametrizable 'Macro-to-Micro' (M2μ) model that demonstrates the consideration of small-scale dosimetry in comparison to conventional methods that typically assume uniform voxel or organ-level uptake. Anatomical features of the salivary gland are represented by annular structures (a centralized branching network of ducts, including excretory, lobar, interlobular) and small-scale voxels (intralobular ducts and acinar cells) with dimensions set to reproduce ex-vivo murine histopathology measurements and scaled up in size for extrapolation to humans. Simulations were performed by scoring and recording S-value histograms to the target ductal and acinar cells, for two beta emitters (177Lu, 131I) and one alpha emitter (225Ac). Four idealized activity distributions were created to assign activity to surface and volumes of the annuli, and GEANT4 v11 was used for radiation transport calculations. Comparisons against whole gland uniform spherical self-dose S-value calculations were conducted to validate the radiation transport and to highlight differences between M2μ and conventional dosimetry approaches. Analyses for both models showed greater S-value variation in comparison to the homogeneously distributed activity S-value calculation. The most notable result was that the calculated S-values differed between different branches, depending on the geometric size of the annuli. For the surrounding acinar cells, S-values from ductal cells decreased as a function of distance from the branching structures. High variability of S-values, depending on ductal cell dimensions as well as within the acinar cell distribution of the salivary gland highlights the potential clinical utility of small-scale approaches to RPT salivary gland dosimetry, contingent on clinical translation and validation. To this end, future work should further refine the model and incorporate small-scale activity distributions from pre-clinical and translational studies.
Centromeres ensure chromosome segregation, but their chromatin organization within repetitive alpha-satellite DNA has been difficult to resolve. To address this, we generated haplotype-resolved satellite DNA annotations for the complete diploid T2T-HG002 human genome assembly, then we mapped centromere protein A (CENP-A), H3K9me3, and CpG methylation on ultra-long, adaptively sampled nanopore reads using directed methylation with long-read sequencing (DiMeLo-seq). We find that CENP-A occupies multiple discrete subdomains within hypomethylated centromere dip regions (CDRs), with constrained aggregate size and balanced CENP-A dosage between homologous chromosomes despite extensive satellite array variation. We also show that extended lymphoblastoid cell culture and induced pluripotent stem cell (iPSC) reprogramming remodel DNA methylation and alter CENP-A abundance and CDR subdomain organization. These results define a single-molecule, haplotype-resolved framework for studying human centromere plasticity, epigenetic inheritance, and chromosomal instability in development and disease.
Centromere identity is specified by CENP-A, a histone H3 variant that epigenetically defines centromere position. How CENP-A is maintained at one location in rapidly evolving centromeric DNA is unknown. Using single-cell-derived clones of human cell lines, we demonstrate heterogeneity in CENP-A position within cell populations at neocentromeres and a native centromere. CENP-A heterogeneity is accompanied by heterogeneous DNA methylation patterns, with DNA methylation shifting according to CENP-A position. We demonstrate centromere epigenetic plasticity over extended proliferation, with native centromeres maintaining stable DNA methylation boundaries, but neocentromeres exhibiting DNA methylation instability, boundary loss, and increased missegregation. Finally, we show that neocentromeres are more sensitive to DNA methylation inhibition than native centromeres, and that this inhibition is accompanied by expanded CENP-A-enriched domains and increased missegregation. This study supports a role for DNA methylation boundaries in maintaining centromere position, stability, and function and highlights the intrinsic instability of DNA methylation at neocentromeres.
High-quality reference genomes are critical for studying the biology of the genome, but current methods often leave gaps and errors, especially in repetitive regions. These issues arise from challenges in genome graph curation and are not fully resolvable by standard polishing approaches. To address this, we developed Verkko-Fillet, a Python-based interactive framework for inspecting, editing, and refining genome assembly graphs. It integrates multiple data sources and provides tools for visualization, gap filling, and structural correction. Applied to a giraffe and the benchmark human genome, Verkko-Fillet improves a draft assembly (Q61.5) to a complete telomere-to-telomere genome (Q73.6), increasing both contiguity and accuracy. This work highlights the importance of graph-based curation for producing a finished, gapless genome assembly suitable for downstream analyses.
A 14 +6 year-old (bone age 13 +0 years) genetically 46, XX, phenotypic female patient underwent distal femur and proximal tibia screw epiphysiodesis for a leg length discrepancy related to overgrowth following juvenile ACL reconstruction. The patient was considering, but had not committed to, gender affirmation treatment (internally the patient felt male). The patient later started testosterone, which altered predictions of height and leg length discrepancy at maturity. Screws were removed to minimize overshortening of the previously long leg. Upon screw removal, modest growth of the operative limb resumed. Following removal of transphyseal screws in skeletally immature patients, growth may resume.
The landscape of pediatric ataxia is diverse, encompassing acute, subacute, episodic, and chronic/progressive presentations. We review the typical diagnostic strategy for chronic and progressive ataxias. We then provide an overview of emerging treatments and the pipeline for disease-modifying therapies. Unfortunately, the needle has not yet substantially shifted on survivorship in pediatric ataxia, so the focus remains on management of longer-term complications and emphasizing the importance of a multidisciplinary team and the role of palliative care.
Musculoskeletal injuries such as patellofemoral pain syndrome (PFPS) result in loss of readiness in military warfighters, underscoring the importance of therapies to accelerate recovery for rapid return-to-duty. Non-pharmacologic interventions, including exercise, neuromuscular electrical stimulation (NMES), and blood flow restriction (BFR), may be beneficial in garrison and far-forward settings. However, since the electrical currents used in NMES and the restriction of blood flow during NMES and BFR therapies cause pain and discomfort that may be intensified when combined, there is concern that these therapies could lead to heightened physical and psychological difficulties. Thus, the present secondary analysis examined whether the combined use of BFR, NMES, and exercise affected pain intensity, functional abilities, and the physical (PCS) and mental (MCS) components summary scores of the Health-Related Quality of Life (HRQoL) questionnaire. This randomized controlled trial entailed the random assignment of 84 service members with PFPS to 1 of 2 groups: sham with application of 20 mmHg pressure or BFR pressure to 80% occlusion. BFR-NMES was performed in clinic 2 times per week, while NMES with exercise and exercise alone were performed at home on alternating days and omitted on in-clinic days. The outcome measures included the 12-item Short Form Health Survey v.2 (SF-12v2) MCS and PCS scales. Pain levels were measured using the Anterior Knee Pain Scale (AKPS) and Visual Analog Scale (VAS). Over the 9-week intervention, both groups demonstrated similar improvements in pain as measured by the AKPS and VAS scales. Both groups also showed similar improvements on the SF-12v2 PCS, progressing from well below normal to almost normal over the 9 weeks. However, a significant difference in the MCS scores between the 2 groups was observed over time, as evidenced by a notable group-by-time interaction (P = .01). At baseline, both groups scored above the average "normal" score of 50 (SD = 10) on the MCS. By week 9, the MCS score for the sham BFR group remained essentially unchanged, while that of the high BFR group declined below average. Mental health is as important as physical health in optimizing the recovery of injured military warfighters. The balanced use of non-pharmacologic interventions such as exercise, NMES, and BFR therapy is essential for promoting mental and physical readiness. The observed decline in mental scores over time highlights the potential need for integrating pain management techniques, behavioral strategies, and social support into future rehabilitation protocols to enhance overall outcomes. By addressing these elements comprehensively, military warfighters can develop the resilience required for a successful return-to-duty in both resource-rich clinical settings and demanding far-forward environments. The Blood Flow Restriction trial was registered in ClinicalTrials.gov (Identifier: NCT04086615), first posted on September 11, 2019.
Retinal vasculitis is a sight-threatening condition associated with diverse ocular and systemic diseases. Variability in terminology and definitions across clinical practice and research has limited diagnostic consistency, communication among specialists, and comparability of studies. To develop standardized, consensus-based definitions for retinal vasculitis and related terms to improve diagnostic clarity and harmonize communication among ophthalmologists and other medical specialties. This was an international modified Delphi consensus study conducted using a structured consensus process guided by a comprehensive literature review, including systematic reviews and meta-analyses. Two rounds of Delphi surveys were performed, and consensus was predefined as at least 75% agreement. Included was an international expert panel of 27 specialists in ophthalmology, rheumatology, pathology, imaging, and research methodology. The specialists had recognized expertise in retinal and systemic vasculitis, retinal imaging, or consensus methodology. Study data were analyzed from March to September 2025. Participation in a structured Delphi process evaluating proposed definitions and terminology related to retinal vasculitis and associated vascular inflammatory entities. Consensus definitions for retinal vasculitis and related entities, with agreement using predefined consensus thresholds. A total of 27 international experts participated in the Delphi process. After 5 executive committee members involved in developing preliminary definitions were excluded from voting to minimize bias, a total of 22 independent experts completed both Delphi rounds. All candidate statements exceeded the predefined consensus threshold in the first round (agreement range, 83.3%-95.5%), although some demonstrated variability in the strength of agreement. After refinement of definitions, consensus strengthened in the second round, with agreement levels ranging from 95.2% to 100%. The panel established consensus definitions for 8 terms: retinal vasculitis, vascular leakage, infectious retinal vasculitis, noninfectious retinal vasculitis, retinal perivasculitis, retinal vasculopathy, primary retinal vasculitis, and far-peripheral vascular leakage. These definitions were developed to distinguish vascular leakage from true vasculitis, clarify inflammatory and noninflammatory vascular disorders, and promote consistent terminology across clinical practice and research. This international Delphi consensus established standardized nomenclature for retinal vasculitis and related vascular inflammatory entities. Adoption of these definitions may improve diagnostic accuracy, facilitate interpretation of imaging findings, enhance consistency across clinical studies, and support future research efforts, including the development of artificial intelligence-based classification systems for retinal vascular disease.
BACKGROUND: Organophosphate ester flame retardants and plasticizers (OPEs) have myriad uses in industry and consumer products. Increasing human exposure to OPEs has raised concerns about their potential effects on child neurodevelopment during the pregnancy. Objective: We investigated whether OPE urinary concentrations during pregnancy were associated with child's autism-related outcomes. METHODS: We included 4159 mother-child pairs from 15 cohorts in the NIH Environmental influences on Child Health Outcomes (ECHO) Consortium, with children born from 2006-2020 (median age [interquartile range]: 6 [4,10] years). Nine OPE biomarkers were measured in urine samples collected mid- to late pregnancy. Dilution-adjusted biomarkers were modeled continuously, categorically (high [>median], moderate [≤median], nondetect), or as detect/nondetect depending on their detection frequency. We assessed child autism-related traits via a) parent report on the Social Responsiveness Scale (SRS) and b) clinical autism diagnosis. We examined associations of OPEs with child outcomes, including modification by child sex, using generalized estimating equations to account for clustering by ECHO cohort. RESULTS: Compared with nondetectable concentrations, high exposure to bis-(butoxyethyl) phosphate (BBOEP) was associated with higher autistic trait scores (adj-β 0.97, 95% confidence interval [CI]: 0.42, 1.52) and greater odds of autism diagnosis (adjusted odds ratio [adj-OR]: 1.27, 95% CI: 1.07, 1.50). Bis-(1-chloro-2-propyl) phosphate (BCPP) showed associations with autistic trait scores (BCPP adj-β for high exposure vs nondetect: 0.34, 95% CI: -0.46, 1.13; BCPP adj-β for moderate exposure vs nondetect: 0.72, 95% CI: 0.24, 1.20). High exposure to bis-(2-chloroethyl) phosphate (BCETP) was associated with lower odds of autism diagnosis (adj-OR: 0.76, 95% CI: 0.60, 0.95). Other OPEs showed no associations in adjusted models. Associations between BBOEP and higher autistic trait scores were stronger in males than females. DISCUSSION: Prenatal exposure to OPEs, specifically BCPP and BBOEP, may be associated with a higher risk of autism diagnosis and related traits in childhood.
Treatment response in high grade gliomas (HGG) is influenced by O6-methylguanine-DNA methyltransferase promoter methylation (MGMTpm). Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) is a non-invasive approach for potential molecular tumor characterization, although previous studies have reported inconsistent results for MGMTpm. This study investigates fluid-suppressed (FS) CEST metrics and automated tumor segmentation in the preoperative prediction of MGMTpm in HGG. 3 T MRI including CEST imaging was performed in 44 patients with HGG (mean age 59 years, 16 female, 24 MGMTpm, 39 glioblastoma and five astrocytoma, grade 4). Contrast-enhancing tumor (ET), necrosis, and peritumoral edema were segmented manually and with two machine learning (ML) based models (DeepBraTumIA and Raidionics). Maximum, minimum and percentile-based metrics were extracted from FS amide proton transfer-weighted signal at 3.5 ppm (APTw) and FS CEST signal at 2.0 ppm (CEST@2ppm), normalized with contralateral normal-appearing white matter. The APTw/CEST@2ppm ratio was calculated. Statistical analysis was performed between MGMTpm and non-MGMTpm tumors using group comparisons, Spearman correlation, and receiver operating characteristics with area under curve (AUC), corrected for multiple comparisons. Significant differences were found in non-MGMTpm relative to MGMTpm tumors: higher 90th percentile and max APTw in necrosis across all segmentation methods; higher 90th percentile APTw, max APTw and max CEST@2ppm in ET with the ML-based models; higher max CEST@2ppm and max ratio in necrosis with Raidionics. The findings with APTw and CEST@2ppm remained consistent in glioblastoma patients and were further supported by significant inverse correlations between the CEST metrics and percentage of MGMTpm. The best-performing parameters for predicting MGMTpm status were the max APTw in ET and necrosis (AUC 0.76-0.82) and max CEST@2ppm in ET and necrosis (AUC 0.67-0.85), achieving higher sensitivity (69-100%) compared to specificity (59-82%). MGMTpm status in HGG may be predicted with fluid-suppressed CEST MRI. Using publicly available ML-based segmentation tools highlights a potential reproducible workflow in the clinical setting. Future multicenter studies with optimized acquisition protocols and independent, multimodal validation are warranted.
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