Citations

ABSTRACT Phage therapy has not been established in the clinical routine, in part due to uncertainties concerning efficacy and immunogenicity. Here, three rabbits were immunized against staphylococcal phage K to assess viral potency in the presence of immunized serum. Three rabbits received weekly intramuscular injections of ~10 10±1 pfu/mL phage K. Phage K-specific IgG formation was measured by an enzyme-linked immunosorbent assay (ELISA); phage inactivation was assessed by calculating K-rates. Using transmission electron microscopy (TEM) and immunogold labeling, antibody binding to phage K was visualized. This was numerically assessed by objective imaging analysis comparing the relative distances of each gold particle to the nearest phage head and tail structure. Immunization led to a strong IgG response, plateauing 7 days after the last phage injection. There was no significant correlation between K-rate and antibody titer over time. TEM showed IgG binding to the head structure of phage K. Image analysis showed a significant reduction in relative distances between antibodies and phage head structures when comparing samples from day 0 and day 28 ( P < 0.0001). These results suggest that while individual serum analysis for antibodies against therapeutic phage bears consideration prior to and with prolonged therapy, during phage application, the formation of specific antibodies against phage may only partially explain decreased phage potency in the presence of immunized serum. Instead, other factors may contribute to an individual’s “humoral receptiveness” to phage therapy. Future investigations should be directed toward the identification of the humoral factors that have the most significant predictive value on phage potency in vivo .

Importance Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD). Objective To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment. Design, Setting, and Participants From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed. Interventions In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks. Main Outcomes and Measures Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3–like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL. Results Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] β = −242.43 [48.04] pg/mL; P &amp;lt; .001); reduced plasma GFAP level at year 1 (mean [SD] β = −0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] β = −0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] β = −0.06 [0.02] ng/mL; P &amp;lt; .001); and increased CSF sTREM2 level at year 2 (mean [SD] β = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] β = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] β = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo. Conclusions and Relevance This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification. Trial Registration ClinicalTrials.gov Identifier: NCT04623242

Abstract Purpose Our objectives were to compare overall survival (OS) and pulmonary relapse between patients with metastatic Ewing sarcoma (EWS) at diagnosis who achieve rapid complete response (RCR) and those with residual pulmonary nodules after induction chemotherapy (non‐RCR). Patients and methods This retrospective cohort study included children under 20 years with metastatic EWS treated from 2007 to 2020 at 19 institutions in the Pediatric Surgical Oncology Research Collaborative. Chi‐square tests were conducted for differences among groups. Kaplan–Meier curves were generated for OS and pulmonary relapse. Results Among 148 patients with metastatic EWS at diagnosis, 61 (41.2%) achieved RCR. Five‐year OS was 71.2% for patients who achieved RCR, and 50.2% for those without RCR ( p = .04), and in multivariable regression among patients with isolated pulmonary metastases, RCR (hazards ratio [HR] 0.42; 95% confidence interval [CI]: 0.17–0.99) and whole lung irradiation (WLI) (HR 0.35; 95% CI: 0.16–0.77) were associated with improved survival. Pulmonary relapse occurred in 57 (37%) patients, including 18 (29%) in the RCR and 36 (41%) in the non‐RCR groups ( p = .14). Five‐year pulmonary relapse rates did not significantly differ based on RCR (33.0%) versus non‐RCR (47.0%, p = .13), or WLI (38.8%) versus no WLI (46.0%, p = .32). Discussion Patients with EWS who had isolated pulmonary metastases at diagnosis had improved OS if they achieved RCR and received WLI, despite having no significant differences in rates of pulmonary relapse.

Abstract Introduction Insomnia is a common sleep disorder in pediatric patients with neurodevelopmental disabilities. There are no FDA approved medications for insomnia in the pediatric population, and treatment can be challenging. We present a case of successful treatment of sleep maintenance insomnia in a 15-year-old male with doxepin with supportive actigraphy data. Report of case(s) A 15-year-old male with a past history pertinent for a genetic neurodevelopmental disorder, autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) was evaluated in Pediatric Sleep Medicine Clinic for long standing difficulties with sleep maintenance. He experienced frequent, prolonged nocturnal awakenings and early morning awakenings. Previous polysomnogram was negative for sleep disordered breathing. He previously trialed clonidine, guanfacine, trazodone, melatonin, and mirtazapine without significant benefit. Baseline actigraphy demonstrated frequent and prolonged nocturnal awakenings and early morning awakenings. He was initiated on doxepin 3 mg at bedtime, and it was subsequently increased to 6 mg at bedtime. Parental report and repeat actigraphy 4 months later (on doxepin 6 mg) demonstrated improvement in nocturnal awakenings and early morning awakenings. Conclusion Up to now, there are no FDA approved medications for the treatment of insomnia in the pediatric population. A prior study of patients with ASD and ADHD demonstrated the use of doxepin provided clinical improvement in sleep onset and maintenance insomnia based on subjective evidence with parental report. In this case, doxepin improved subjective report of insomnia and correlated with objective findings on actigraphy. Support (if any) NA

Abstract Introduction A prospective, longitudinal, multicenter study was designed to test the hypothesis that sleep-disordered breathing (SDB) is ubiquitous among newborns with myelomeningocele (MMC). We evaluated variability in polysomnography (PSG) scoring and interpretation. Methods Nine US pediatric centers participated. Neonates with MMC born at &gt;30 weeks gestation underwent bedside PSG at ≥35 weeks postmenstrual age, before hospital discharge. PSGs were scored by registered technologists (RPSGTs) at each site using AASM Scoring Manual infant criteria and interpreted by a board-certified sleep medicine physician (BCSMP). A single, central RPSGT blinded to clinical outcomes then re-scored all PSGs. One of two pediatric BCSMPs reviewed each study; the two BCSMPs jointly determined diagnoses for consensus central reports. Differences in scoring and overall PSG interpretation were evaluated with kappa and intraclass correlation coefficients (ICC). Results For 110 neonates with MMC, the median apnea-hypopnea index (AHI) was 26.5 [11.3-43.3] as reported by sites, and 23.0 [IQR 13.0-44.8] as reported centrally (к 0.81). The central apnea index (CAI) was also scored similarly by sites (3.3 [0.9-7.0]) and centrally (2.6 [0.6-7.3]; к 0.88), as were hypopneas (15.2 [7.5;26.9]) and 14.1 [6.4;27.9]; к 0.82). However, the obstructive apnea index (OAI) was reported to be much higher by sites (10.0 [1.9-29.1]) than centrally (1.5 [0.5 – 4.1]; к 0.29). Moreover, overall PSG interpretation differed between sites and central reviewers. Obstructive sleep apnea (OSA) was reported as a diagnosis by sites for 57.6% of neonates, vs. 10.9% by central review (ICC 0.06); central sleep apnea was reported by sites for 26.6% of neonates, vs. 14.5% by central review (ICC 0.50). When hypopneas were the most prevalent respiratory events, central review favored a less specific diagnosis of sleep-disordered breathing. Conclusion Considerable variability in scoring of obstructive apneas, and in polysomnography-based diagnoses, may exist for neonates. Sites may have designated hypopneas as obstructive, driving the diagnosis of OSA, while central review noted equivocal features of neonatal hypopneas, leading to a less specific diagnosis of sleep-disordered breathing. Further work to develop infant respiratory scoring rules, and diagnostic criteria, and to evaluate their clinical use may be warranted. Support (if any) This study is supported by NIH (R01 HL147261).

The NCCN Guidelines for Prostate Cancer include recommendations for staging and risk assessment after a prostate cancer diagnosis and for the care of patients with localized, regional, recurrent, and metastatic disease. These NCCN Guidelines Insights summarize the panel's discussions for the 2024 update to the guidelines with regard to initial risk stratification, initial management of very-low-risk disease, and the treatment of nonmetastatic recurrence.