Citations

Abstract Post-translational modifications (PTM) of tau are implicated in Alzheimer disease (AD) progression and are established biomarkers in cerebrospinal fluid and plasma; however, the labor-intensive nature of conventional proteomics limits their investigation in histology-specific contexts. We describe the findings of an artificial intelligence-guided laser capture microdissection (LCM) pipeline for harvesting neurofibrillary tangles (NFTs) by maturation level into pretangles (pre-NFTs), mature tangles (iNFTs), and ghost tangles (eNFTs) using 38 cases obtained from 2 independent biobanks. We evaluated the performance characteristics of proprietary machine learning algorithms for the subclassification of these NFT categories in anti-pTau217-stained whole slide images of entorhinal cortex, hippocampus, frontal, and parietal cortex sections. Overall precision/recall/F1 scores were highest for Classifier A (0.6/0.46/0.5). The best performing algorithm was used to guide LCM capture and inform NFT enrichment. Targeted proteomics on tau signature peptides (pTau181, pTau217, and TauMTBR) was performed on approximately 1250 NFT collections. The results demonstrated that their abundance increased from pretangles to mature tangles (∼2-11-fold increase), and that this was followed by a sharp reduction in ghost tangles (∼3-116-fold decrease), with pTau217 showing the most drastic change. Pathologist-trained NFT classifiers represent an objective albeit imperfect means to enrich specific morphologic forms permitting coupled LCM-MS (mass spectrometry) to investigate AD-associated PTM.

Abstract INTRODUCTION We investigated associations of plasma proteins with blood‐based amyloid/tau/neurodegeneration/inflammation (A/T/N/I) biomarkers for Alzheimer's disease (AD). METHODS Plasma proteomics and clinical data from the Indiana AD Research Center ( N = 498) were used. Association analysis of plasma proteins with blood A/T/N/I biomarkers as well as diagnosis was performed, followed by replication in an independent cohort ( N = 323), network analysis, pathway enrichment, and machine learning classification to identify proteins and pathways related to AD risk. RESULTS We identified 35 proteins associated with AD, 20 of which were replicated in the independent cohort. We identified 150, 448, and 219 proteins associated with T/N/I biomarkers, respectively, revealing biomarker‐specific pathways. Network analysis identified two modules associated with T/N/I biomarkers, preserved in cerebrospinal fluid (CSF), and their enriched pathways. The classification model of proteins effectively differentiated AD (area under the curve [AUC] = 0.930). CONCLUSION Our findings suggest dysregulated plasma proteins and pathways in AD, enhancing our understanding of molecular mechanisms and diagnostic strategies for AD. Highlights Plasma proteins were identified as being associated with Alzheimer's disease (AD) and plasma biomarkers. The identified proteins were replicated in both plasma and cerebrospinal fluid (CSF) proteomics. The identified proteins were associated with AD biomarker‐specific pathways. The identified proteins improved the performance of the AD classification. Protein network analysis identified network modules and their enriched pathways.

Objective: Describe changes in symptoms of velopharyngeal insufficiency (VPI)—hypernasality, audible nasal emission, and VPI-related quality of life—following LeFort I osteotomy in individuals with cleft palate +/- cleft lip. Design: Single-center, retrospective cohort study. Participants: Twenty-one patients with a history of cleft palate repaired in infancy were included in this study. Ten patients had no prior history of VPI surgery and eleven had a pharyngeal flap in place at the time of LeFort I osteotomy. The mean age at time of surgery was 17.2 years. Main Outcome Measure: Pre- and postoperative hypernasality severity, frequency of audible nasal emission, and total score on the VPI Effects on Life Outcomes youth questionnaire (VELO-Y) before and after LeFort osteotomy I. Fischer exact test was used to assess differences between groups for categorical variables and a t test was used for continuous variables. Results: Patients with no prior history of VPI management had a significant increase in hypernasality severity compared with those with a pharyngeal flap in place at the time of surgery ( P =0.004). Patients without a prior history of VPI management also had a significant increase in frequency of audible nasal emission, while patients with a pharyngeal flap had decreased audible nasal emission ( P =0.004). There was not a significant difference between groups for change in the total score on the VELO-Y ( P =0.16). Conclusions: Findings from this study may improve preoperative counseling provided to patients and caregivers on the risk of acquiring VPI after LeFort I osteotomy based on prior VPI surgical history.

Abstract Objective Autoimmune encephalitis is a cause of brain inflammation characterized by auto‐antibodies, which target cell surface neuronal proteins and lead to neuronal dysfunction. The most common form is associated with auto‐antibodies to leucine‐rich glioma‐inactivated 1 (LGI1) protein, the presentation of which includes frequent focal seizures. The exact cause of these auto‐antibodies remains unknown, but established predispositions include overrepresented human leukocyte antigen ( HLA ) alleles. Yet, these HLA alleles are themselves common in the healthy ancestry‐matched population. One potential etiological hypothesis is that an environmental trigger, such as the gut microbiome, interacts with a genetically predisposed individual. Methods To investigate this, we studied 42 patients with LGI1‐antibody encephalitis (LGI1‐Ab‐E) and 27 familial/environmentally matched controls, and performed metagenomic shotgun sequencing, to describe the compositional and functional differences in the gut microbiome. Results We observed that LGI1‐Ab‐E gut microbiomes exhibited a significant reduction in the ratio of Firmicutes (or Bacillota) and Bacteroidetes phyla, which is associated with the dosage of HLA susceptibility allele count in patients with LGI1‐Ab‐E. Furthermore, we identified differences in functional gene profiles in the gut microbiome that led to a reduction of neuroinflammatory protective short‐chain fatty acids (SCFAs) in LGI1‐Ab‐E patients. Significance Taken together, our results suggest that a compositional shift in the gut microbiome of LGI1‐Ab‐E associates with a neuroinflammatory state, possibly through the reduction of SCFA production. Our study highlights the potential of the gut microbiome to explain some of the complex condition and unravel etiological questions. Validation studies with greater sample sizes are recommended.

The NCCN Clinical Practice Guidelines (NCCN Guidelines) for Wilms Tumor (WT; nephroblastoma) cover strategies for the screening, diagnosis, and treatment of WT, which is the most frequent primary kidney tumor in children. WT can generally be separated into 2 histology types: favorable histology WT and anaplastic WT. Five-year survival is high for children with favorable histology WT who receive appropriate treatment; however, survival rates are much lower for patients who present with higher stage diffuse anaplastic WT. Treatment of WT can range from surgery alone to surgery plus intensive chemotherapy and radiation depending on whether the tumor is unilateral or bilateral, histology, and local stage. The goal of therapy is to maximize cure while minimizing long-term toxicities. The content featured in this issue covers the NCCN panel’s recommendations for overall management of both favorable histology WT and anaplastic WT.

While hormonal changes have been recognised to influence seizure control and have been studied in association with menstrual cycles and pregnancy, there is a paucity of data on the menopause transition in epilepsy. Given the known effects of sex steroid hormones on neuronal excitability, their endogenous fluctuations during perimenopause, as well as menopause hormone treatments, may alter seizure control. Epilepsy may also be associated with premature ovarian insufficiency and early menopause. This is especially important for epilepsy-related comorbidities, for which menopause can constitute a second hit, such as osteoporosis. Additional considerations for females with epilepsy across the menopause continuum include changes in antiseizure medication clearance and potential interactions with menopausal hormone therapy or other concomitant medications. This comprehensive review summarises the currently available literature on epilepsy and menopause, highlights gaps in knowledge, and underscores the need for research efforts, particularly longitudinal studies investigating the menopause transition.

Abstract Background Clostridioides difficile infection (CDI) treatment guidelines suggest varied approaches for patients with first (frCDI) or multiply recurrent CDI (mrCDI). Low microbial diversity, elevated primary bile acids (BA), and low secondary BA concentrations favor germination of C. difficile spores into toxin-producing bacteria and are believed to increase rCDI risk. Greater understanding of the gastrointestinal (GI) microbiome in rCDI may inform management of the disease. We describe a post hoc comparison of GI microbiome and bile acid profiles between patients with frCDI and mrCDI in a Phase 3 open-label trial, ECOSPOR IV, of fecal microbiota spores, live-brpk (VOWST®; VOS, formerly SER-109), an orally-administered live microbiome therapeutic. Methods Patients received VOS following symptom resolution after standard-of-care antibiotics. Pretreatment baseline (within 3 days following antibiotic completion) and Week 1 post-dosing stool samples were collected for whole metagenomic sequencing and metabolomics. Diversity was calculated from MetaPhlAn2 species profiles. Concentrations of primary and secondary BAs were measured via targeted LC-MS/MS. Results rCDI rates through Week 8 were similarly low in both frCDI and mrCDI patients (6.5% versus 9.7%, respectively). Baseline microbial diversity was similarly low between frCDI and mrCDI subgroups (P > .05). Diversity and secondary BA concentrations increased in both subgroups, whereas primary BA concentrations declined following VOS dosing, leading to few differences between subgroups at Week 1. Conclusions These data suggest commonalities in microbiome disruption in patients with frCDI and mrCDI that contribute to recurrence and suggest that antibiotics followed by a live microbiome therapy may be an optimal treatment strategy for rCDI, regardless of number of prior CDI recurrences.

Abstract Tisagenlecleucel (tisa-cel) is a CD19-directed chimeric antigen receptor T-cell therapy for relapsed/refractory precursor B-cell acute lymphoblastic leukemia (R/R B-ALL). We report infectious complications for 100 days (D100) following tisa-cel therapy in 471 pediatric and young adults (median age 13.8 years) with R/R B-ALL reported from September 2017 to June 2022. By D100, 137 (29%) patients had an infectious event, with an infection density of 0.542 per 100 person-days at risk. D100 cumulative incidences of bacterial, viral, and fungal infections were 14.1%, 11.6%, and 1.3%, corresponding to infection density scores of 0.296, 0.213, and 0.033 per 100 person-days at risk, respectively. In a multivariable analysis, receipt of ≥3 lines of therapy before tisa-cel (hazard ratio [HR], 1.86; 95% confidence interval [CI], 1.13-3.08; P = .015), any-grade cytokine release syndrome (HR, 1.78; 95% CI, 1.17-2.71; P = .007), and lack of neutrophil recovery (HR, 2.63; 95% CI, 1.47-4.69; P = .001) were associated with an increased risk for any infection. Similar associations were observed for bacterial infections, with the addition of younger age as an adverse risk (<6 vs 6-15 years; HR, 2.38; 95% CI, 1.23-4.61; P = .01). Risk factors for viral infections included increasing age (1-year increase; HR, 1.05; 95% CI, 1.01-1.09; P = .016), prior history of any infection (HR, 2.76, 95% CI, 1.40-5.46; P = .004), and prior hematopoietic cell transplant (HR, 2.10; 95% CI, 1.18-3.71; P = .011). D100 infection-related mortality (IRM) rate was low at 0.2% (95% CI, 0.0-0.8). In this multicenter real-world study, we observed a high incidence of infectious complications but a low IRM following tisa-cel for R/R B-ALL.