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Amyloid PET predicts longitudinal functional and cognitive trajectories in a heterogeneous cohort
No full textIntroduction: Amyloid positron emission tomography (PET) is increasingly available for diagnosis of Alzheimer`s disease (AD); however, its practical implications in heterogenous cohorts are debated.
Methods: Amyloid PET from 890 National Alzheimer`s Coordinating Center participants with up to 10 years post-PET follow up was analyzed. Cox proportional hazards and linear mixed models were used to investigate amyloid burden prediction of etiology and prospective functional status and cognitive decline.
Results: Amyloid positivity was associated with progression from unimpaired to mild cognitive impairment and dementia. Amyloid burden in the unimpaired group was associated with lower initial memory levels and faster decline in memory, language, and global cognition. In the Impaired group, amyloid was associated with lower initial levels and faster decline for memory, language, executive function, and global cognition.
Discussion: Amyloid burden is an important prognostic marker in a clinically heterogeneous cohort. Future work is needed to establish the proportion of decline driven by AD versus non-AD processes in the context of mixed pathology.
Highlights: Our findings highlight the importance of amyloid positron emission tomography (PET) in heterogenous cohorts, including diverse demographics, clinical syndromes, and underlying etiologies. The results also provide evidence that higher amyloid levels were linked to functional progression from unimpaired cognition to mild cognitive impairment (MCI) and from MCI to dementia. In cognitively unimpaired individuals, higher amyloid burden was associated with poorer memory at baseline and subsequent declines in memory, language, and global cognition. Among individuals with cognitive impairment, amyloid burden was associated with worse initial memory, language, executive function, and global cognition, and faster declines over time
Pediatric relapsed/refractory ALK-positive anaplastic large cell lymphoma treatment and outcomes in the targeted-drug era
No full textTreatment options for patients with relapsed or refractory (R/R) anaplastic large cell lymphoma (ALCL) have increased in the era of targeted therapies such as brentuximab vedotin (BV) and anaplastic lymphoma kinase (ALK) inhibitors. However, there is no standard treatment and published data evaluating their use are limited. The goal of this retrospective study was to describe current real-world treatment and outcomes of pediatric, adolescent, and young adult patients with R/R ALK-positive ALCL. We conducted a retrospective, multi-institutional study identifying 81 patients with R/R ALK-positive ALCL aged ≤21 years at initial diagnosis treated between 2011 and 2022 across 18 institutions. Median time from diagnosis to relapse was 8.9 months (range, 2.6-131.9). Initial reinduction regimens included ALK-inhibitor monotherapy (n = 37, 46%), BV monotherapy (n = 19, 23%), chemotherapy without targeted therapy (n = 12, 15%), chemotherapy with targeted therapy (n = 9, 11%), or vinblastine monotherapy (n = 4, 5%), with 83% of patients achieving a complete response to initial reinduction regimen. Fifty-eight patients received a hematopoietic stem cell transplant (HSCT), 11 autologous and 48 allogeneic, with 1 receiving both. Duration of treatment for patients receiving BV or the ALK-inhibitor crizotinib (CZ) varied widely (BV, 1-11 years; CZ, 2-10 years). Five-year event-free survival was 63% (95% confidence interval [CI], 53-75) and 5-year overall survival was 91% (95% CI, 84-98). This is, to our knowledge, the largest collection of patients with R/R ALK-positive ALCL treated in the era of targeted therapy. Patients achieved excellent responses to ALK-inhibitor or BV monotherapy, but questions remain about duration of therapy and role of HSCT
Tabletop RPG Recommendations for All Ages
No full textThis guide features a diverse selection of tabletop role-playing games (RPGs), from kid-friendly storytelling adventures to deep sci-fi epics and horror mysteries created by Monroe County Librarians. Whether you’re a librarian, educator, or curious gamer, this list offers something for every genre, age group, and play style
MammOnc-DB, an integrative breast cancer data analysis platform for target discovery
No full textBreast cancer (BCa), a leading malignancy among women, is characterized by morphological and molecular heterogeneity. While early-stage, hormone receptor, and HER2-positive BCa are treatable, triple-negative BCa and metastatic BCa remains largely untreatable. Advances in sequencing and proteomic technologies have improved our understanding of the molecular alterations that occur during BCa initiation and progression and enabled identification of subclass-specific biomarkers and therapeutic targets. Despite the availability of abundant omics data in public repositories, user-friendly tools for multi-omics data analysis and integration are scarce. To address this, we developed a comprehensive BCa data analysis platform called MammOnc-DB ( http://resource.path.uab.edu/MammOnc-Home.html ), comprising data from more than 20,000 BCa samples. MammOnc-DB facilitates hypothesis generation and testing, biomarker discovery, and therapeutic targets identification. The platform also includes pre- and post-treatment data, which can help users identify treatment resistance markers and support combination therapy strategies, offering researchers and clinicians a comprehensive tool for BCa data analysis and visualization
Subject-Specific Mapping of Excess Manganese Accumulation in the Brain of Welders Using Magnetic Resonance Imaging Relaxometry
No full textChronic overexposure to manganese (Mn) can occur in occupational settings, such as welding, leading to increased Mn levels in the brain. Excess brain Mn accumulation may result in neurotoxicity, which is characterized by Parkinsonian-like symptoms including motor and cognitive dysfunctions. In this work, we demonstrate a novel methodology for personalized diagnosis and spatial characterization of abnormal Magnetic Resonance Imaging R1 (R1 = 1/T1) relaxation rates arising from excessive Mn accumulation in welders' brains. Utilizing voxel-wise population-derived norms based on a frequency age-matched non-exposed group (n = 25), we demonstrate the ability to conduct subject-specific assessments and mapping of Mn exposure using MRI relaxometry. Our results show elevated R1 in multiple brain regions in individual welders, but also extreme between-subject variability in Mn accumulation, debasing the concept that high exposures correlate with uniformly high Mn deposition in the brain. Consequently, the presented personalized methodology serves as a counterpart to group-based comparison, which allows for understanding the level of individual exposure and the toxicokinetics of Mn accumulation. This work lays a foundation for improved occupational health assessments and preventive measures against neurotoxic metal exposure
A CRISPR mis-insertion in the Zic3 5'UTR inhibits in vivo translation and is predicted to result in formation of an mRNA stem-loop hairpin
No full textZic3 loss of function is associated with a range of congenital defects, including heterotaxy and isolated heart defects in humans, as well as neural tube defects, situs anomalies, and tail kinks in model organisms. Here, we describe a novel Zic3ins5V mouse line generated due to a mis-insertion during the CRISPR genome editing process, which altered the Zic3 5'UTR structure. Mice with this insertion developed similar phenotypes to Zic3LacZ null mice, including heterotaxy, isolated heart defects, neural tube defects and tail kinks. Surprisingly, gene expression analysis revealed that the novel Zic3ins5V line displays higher levels of Zic3 mRNA, but western blot analysis confirmed that levels of ZIC3 were greatly reduced in vivo. RNAfold, an RNA secondary structure prediction tool, showed that this mis-insertion may cause the formation of a large stem-loop hairpin incorporating some of the 5'UTR and first exon of Zic3, and the insertion of similar hairpins in a cell-based assay caused the loss of ZIC3 expression. Thus, this mouse line displays a loss of ZIC3 protein consistent with the inhibitory effects of 5'UTR stem-loop hairpin structures
Co-Occurrence of Sotos Syndrome and Mayer-Rokitansky-Küster-Hauser (MRKH) Syndrome in 2 Patients
No full textSotos syndrome is an autosomal dominant condition caused by a pathogenic variant of NSD1 and characterized by a distinctive facial appearance, learning disability, and overgrowth. Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a congenital disorder characterized by agenesis or aplasia of the uterus and upper part of the vagina in females with a normal female karyotype. The coexistence of the 2 syndromes has been reported only twice to date. We describe 2 girls with Sotos syndrome who presented with primary amenorrhea. The patient in case 1 had central precocious puberty diagnosed at age 6.5 years, which was appropriately managed for 2 years. The patient in case 2 had congenital hypothyroidism due to thyroid aplasia, treated with levothyroxine. Investigations in both girls revealed normal gonadotropin and estradiol levels. Pelvic ultrasound and magnetic resonance imaging showed absence of the uterus and the presence of normal ovaries. Based on these findings, both patients were diagnosed with müllerian agenesis/MRKH. The presence of Sotos and MRKH syndromes in these 2 patients, along with the 2 previously documented cases, might be coincidental. However, with 4 reported cases, the possibility exists for a rare link between Sotos syndrome and MRKH. Additionally, the psychosocial effect of infertility should not be underestimated
Integration and evaluation of implementation strategies to improve guideline-concordant bladder cancer surveillance: a prospective observational study
No full textBackground: Despite guideline recommendations, our prior work revealed more than half of low-risk bladder cancer patients within the Department of Veterans Affairs (VA) undergo too many surveillance procedures and about a third of high-risk patients do not undergo enough procedures. Thus, we developed and integrated implementation strategies to improve risk-aligned bladder cancer surveillance for the VA.
Methods: Prior work used Implementation Mapping to develop nine implementation strategies: change record systems, educational meetings, champions, tailoring, preparing patients to be active participants, external facilitation, remind clinicians, audit & feedback, and a blueprint. We integrated these strategies as improvement approaches across four VA urology clinics. Primary implementation outcomes were qualitatively measured via coding of semi-structured interviews with clinicians and co-occurrence of codes. Implementation outcomes included: appropriateness, acceptability, and feasibility. Exploratory quantitative outcomes included clinicians' recommendations for guideline-concordant bladder cancer surveillance intervals and sustainability.
Results: Eleven urologists were interviewed. Co-occurrence analysis of codes across strategies indicated that urologists most commonly reported on the acceptability and appropriateness of changing the record system, preparing patients to be active participants ("surveillance grid"), reminders (i.e., cheat sheet), and educational sessions. We confirmed feasibility of all implementation strategies. Urologists indicated that changing the record system had a high impact, reduced documentation time, and guided resident physicians. Preparing patients to be active participants using the "surveillance grid" was seen as an effective but time-consuming tool. Educational sessions were seen as critical to support implementation. In quantitative analyses, clinicians recommended guideline-concordant surveillance about 65% of the time at baseline for low-risk patients, and this improved to 70% during evaluation. Across all risk levels, the largest improvement was observed at site 2 while site 3 did not improve. All sites sustained use of the changed record system, while sustainability of other strategies was variable.
Conclusions: Based on summative interpretation of results, the most appropriate, acceptable, and feasible strategies include changing record systems via a template and educational meetings focused on guideline-concordant surveillance. Future work should assess the impact of the improvement approaches on clinical care processes, particularly on reducing overuse of surveillance procedures among low-risk patients