AI-based differential diagnosis of dementia etiologies on multimodal data.

Differential diagnosis of dementia remains a challenge in neurology due to symptom overlap across etiologies, yet it is crucial for formulating early, personalized management strategies. Here, we present an artificial intelligence (AI) model that harnesses a broad array of data, including demographics, individual and family medical history, medication use, neuropsychological assessments, functional evaluations and multimodal neuroimaging, to identify the etiologies contributing to dementia in individuals. The study, drawing on 51,269 participants across 9 independent, geographically diverse datasets, facilitated the identification of 10 distinct dementia etiologies. It aligns diagnoses with similar management strategies, ensuring robust predictions even with incomplete data. Our model achieved a microaveraged area under the receiver operating characteristic curve (AUROC) of 0.94 in classifying individuals with normal cognition, mild cognitive impairment and dementia. Also, the microaveraged AUROC was 0.96 in differentiating the dementia etiologies. Our model demonstrated proficiency in addressing mixed dementia cases, with a mean AUROC of 0.78 for two co-occurring pathologies. In a randomly selected subset of 100 cases, the AUROC of neurologist assessments augmented by our AI model exceeded neurologist-only evaluations by 26.25%. Furthermore, our model predictions aligned with biomarker evidence and its associations with different proteinopathies were substantiated through postmortem findings. Our framework has the potential to be integrated as a screening tool for dementia in clinical settings and drug trials. Further prospective studies are needed to confirm its ability to improve patient care.

AI-based differential diagnosis of dementia etiologies on multimodal data.

Differential diagnosis of dementia remains a challenge in neurology due to symptom overlap across etiologies, yet it is crucial for formulating early, personalized management strategies. Here, we present an AI model that harnesses a broad array of data, including demographics, individual and family medical history, medication use, neuropsychological assessments, functional evaluations, and multimodal neuroimaging, to identify the etiologies contributing to dementia in individuals. The study, drawing on 51,269 participants across 9 independent, geographically diverse datasets, facilitated the identification of 10 distinct dementia etiologies. It aligns diagnoses with similar management strategies, ensuring robust predictions even with incomplete data. Our model achieved a micro-averaged area under the receiver operating characteristic curve (AUROC) of 0.94 in classifying individuals with normal cognition, mild cognitive impairment and dementia. Also, the micro-averaged AUROC was 0.96 in differentiating the dementia etiologies. Our model demonstrated proficiency in addressing mixed dementia cases, with a mean AUROC of 0.78 for two co-occurring pathologies. In a randomly selected subset of 100 cases, the AUROC of neurologist assessments augmented by our AI model exceeded neurologist-only evaluations by 26.25%. Furthermore, our model predictions aligned with biomarker evidence and its associations with different proteinopathies were substantiated through postmortem findings. Our framework has the potential to be integrated as a screening tool for dementia in various clinical settings and drug trials, with promising implications for person-level management.

Chromatin accessibility dynamics of neurogenic niche cells reveal defects in neural stem cell adhesion and migration during aging.

The regenerative potential of brain stem cell niches deteriorates during aging. Yet the mechanisms underlying this decline are largely unknown. Here we characterize genome-wide chromatin accessibility of neurogenic niche cells in vivo during aging. Interestingly, chromatin accessibility at adhesion and migration genes decreases with age in quiescent neural stem cells (NSCs) but increases with age in activated (proliferative) NSCs. Quiescent and activated NSCs exhibit opposing adhesion behaviors during aging: quiescent NSCs become less adhesive, whereas activated NSCs become more adhesive. Old activated NSCs also show decreased migration in vitro and diminished mobilization out of the niche for neurogenesis in vivo. Using tension sensors, we find that aging increases force-producing adhesions in activated NSCs. Inhibiting the cytoskeletal-regulating kinase ROCK reduces these adhesions, restores migration in old activated NSCs in vitro, and boosts neurogenesis in vivo. These results have implications for restoring the migratory potential of NSCs and for improving neurogenesis in the aged brain.

Strength of CAR signaling determines T cell versus ILC differentiation from pluripotent stem cells.

Generation of chimeric antigen receptor (CAR) T cells from pluripotent stem cells (PSCs) will enable advances in cancer immunotherapy. Understanding how CARs affect T cell differentiation from PSCs is important for this effort. The recently described artificial thymic organoid (ATO) system supports in vitro differentiation of PSCs to T cells. Unexpectedly, PSCs transduced with a CD19-targeted CAR resulted in diversion of T cell differentiation to the innate lymphoid cell 2 (ILC2) lineage in ATOs. T cells and ILC2s are closely related lymphoid lineages with shared developmental and transcriptional programs. Mechanistically, we show that antigen-independent CAR signaling during lymphoid development enriched for ILC2-primed precursors at the expense of T cell precursors. We applied this understanding to modulate CAR signaling strength through expression level, structure, and presentation of cognate antigen to demonstrate that the T cell-versus-ILC lineage decision can be rationally controlled in either direction, providing a framework for achieving CAR-T cell development from PSCs.

Brain Metastases from Endometrial Cancer: Clinical Characteristics, Outcomes, and Review of the Literature.

BACKGROUND: Brain metastases from endometrial cancer are rare and poorly described. We aimed to estimate the proportion of brain metastases at our institution that arose from endometrial cancer, and to detail clinicopathologic features and survival outcomes. METHODS: We retrospectively identified and reviewed the charts of 30 patients with brain metastases from endometrial cancer seen at Stanford Hospital from 2008 to 2018. RESULTS: Among all patients with brain metastases, the proportion arising from endometrial cancer was 0.84%. The median age at diagnosis was 62 years (range, 39-79 years), and the median overall survival from brain metastasis diagnosis was 6.8 months (range, 1.0-58.2 months). Most patients harbored endometrioid histology (53.3%), and some had concurrent metastases to lung (50.0%), bone (36.7%), and liver (20.0%). The median time from endometrial cancer diagnosis to brain metastasis development was 20.8 months (range, 1.4 months to 11.2 years), and the median number of brain metastases was 2 (range, 1-20). Patients with non-endometrioid histologies had more brain metastases than those with endometrioid histology (6.21 vs. 2.44, P = 0.029). There was no difference in overall survival by histology. CONCLUSIONS: We describe the largest cohort to date of patients with brain metastases originating from endometrial cancer. These patients represent a small fraction of all patients with brain metastases and have poor prognoses. These data enable providers caring for patients with brain metastases from endometrial cancer to appropriately counsel their patients.

Effect of Aerobic Exercise on Dialysis-Related Symptoms in Individuals Undergoing Maintenance Hemodialysis: A Systematic Review and Meta-Analysis of Clinical Trials.

BACKGROUND: Hemodialysis is associated with a high symptom burden that impairs health-related quality of life and functional status. Effective symptom management is a priority for individuals receiving hemodialysis. Aerobic exercise may be an effective, nonpharmacologic treatment for specific hemodialysis-related symptoms. This systematic review investigated the effect of aerobic exercise on hemodialysis-related symptoms in adults with kidney failure undergoing maintenance hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We searched MEDLINE, PubMed, Cochrane CENTRAL, CINAHL, PsycINFO, SPORTDiscus, EMBASE, PEDro, and Scopus databases from 1960 or inception until April 15, 2020 for randomized controlled trials investigating the effect of aerobic exercise on hemodialysis-related symptoms, identified as prespecified primary or secondary outcomes, as compared with controls in adults on maintenance hemodialysis. We identified restless legs syndrome as the primary outcome. RESULTS: Of 3048 studies identified, 15 randomized controlled trials met the eligibility criteria. These studies investigated the effect of aerobic exercise on restless legs syndrome (two studies), sleep disturbance (four studies), anxiety (four studies), depression (nine studies), muscle cramping (one study), and fatigue (one study). Exercise interventions were intradialytic in ten studies and outside of hemodialysis in five studies. Heterogenous interventions and outcomes and moderate to high risk of bias precluded meta-analysis for most symptoms. Aerobic exercise demonstrated improvement in symptoms of restless legs syndrome, muscle cramping, and fatigue, as compared with nonexercise controls. Meta-analysis of depressive symptoms in studies using the Beck Depression Inventory demonstrated a greater reduction in Beck Depression Inventory score with exercise as compared with control (mean difference -7.57; 95% confidence interval, -8.25 to -6.89). CONCLUSIONS: Our review suggests that in adults on maintenance hemodialysis, aerobic exercise improves several hemodialysis-related symptoms, including restless legs syndrome, symptoms of depression, muscle cramping, and fatigue. However, the use of validated outcome measures with demonstrated reliability and responsiveness in more diverse hemodialysis populations is required to fully characterize the effect of this intervention. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: PROSPERO #CRD42017056658.

Quality of Life of Postoperative Photon versus Proton Radiation Therapy for Oropharynx Cancer.

PURPOSE: Quality of life (QOL) for patients with oropharyngeal squamous cell cancer is negatively affected by conventional radiation (RT) owing to radiation exposure to normal tissues. Proton therapy, via pencil beam scanning (PBS), can better spare many of these tissues, and may thereby improve QOL. PATIENTS AND METHODS: Patient-reported outcomes were prospectively collected from patients treated from April 2013 to April 2015. Patients were treated with PBS or intensity-modulated radiation therapy (IMRT) via volumetric arc therapy after transoral robotic surgery. Validated QOL questionnaires were collected before RT, and 3, 6, and 12 months post RT. RESULTS: Sixty-four patients were treated with adjuvant RT after transoral robotic surgery, 33 (52%) with volumetric arc therapy, and 31 (48%) with PBS. Both groups were similar in terms of age, site, stage, and dose delivered. Patients receiving PBS had significantly less dose to many normal structures than those receiving IMRT. These dosimetric advantages with PBS were reflected in higher scores in head and neck specific, as well as general, QOL measures. Most notable was significantly less xerostomia with PBS, on multiple patient-reported outcomes at multiple timepoints (6 and 12 months). CONCLUSION: Pencil beam scanning, when compared to IMRT, confers a significant dosimetric advantage to many normal organs at risk, with a corresponding benefit in multiple patient-reported QOL parameters in patients receiving adjuvant RT for oropharyngeal squamous cell cancer.

Trim58 degrades Dynein and regulates terminal erythropoiesis.

TRIM58 is an E3 ubiquitin ligase superfamily member implicated by genome-wide association studies to regulate human erythrocyte traits. Here, we show that Trim58 expression is induced during late erythropoiesis and that its depletion by small hairpin RNAs (shRNAs) inhibits the maturation of late-stage nucleated erythroblasts to anucleate reticulocytes. Imaging flow cytometry studies demonstrate that Trim58 regulates polarization and/or extrusion of erythroblast nuclei. In vitro, Trim58 directly binds and ubiquitinates the intermediate chain of the microtubule motor dynein. In cells, Trim58 stimulates proteasome-dependent degradation of the dynein holoprotein complex. During erythropoiesis, Trim58 expression, dynein loss, and enucleation occur concomitantly, and all are inhibited by Trim58 shRNAs. Dynein regulates nuclear positioning and microtubule organization, both of which undergo dramatic changes during erythroblast enucleation. Thus, we propose that Trim58 promotes this process by eliminating dynein. Our findings identify an erythroid-specific regulator of enucleation and elucidate a previously unrecognized mechanism for controlling dynein activity.