Benchmarking Outcomes after Ablative Radiotherapy for Molecularly Characterized Intrahepatic Cholangiocarcinoma.

We have previously shown that ablative radiotherapy (A-RT) with a biologically effective dose (BED10) ≥ 80.5 Gy for patients with unresectable intrahepatic cholangiocarcinoma (ICC) is associated with longer survival. Despite recent large-scale sequencing efforts in ICC, outcomes following RT based on genetic alterations have not been described. We reviewed records of 156 consecutive patients treated with A-RT for unresectable ICC from 2008 to 2020. For 114 patients (73%), next-generation sequencing provided molecular profiles. The overall survival (OS), local control (LC), and distant metastasis-free survival (DMFS) were estimated using the Kaplan-Meier method. Univariate and multivariable Cox analyses were used to determine the associations with the outcomes. The median tumor size was 7.3 (range: 2.2-18.2) cm. The portal vein thrombus (PVT) was present in 10%. The RT median BED10 was 98 Gy (range: 81-144 Gy). The median (95% confidence interval) follow-up was 58 (42-104) months from diagnosis and 39 (33-74) months from RT. The median OS was 32 (29-35) months after diagnosis and 20 (16-24) months after RT. The one-year OS, LC, and intrahepatic DMFS were 73% (65-80%), 81% (73-87%), and 34% (26-42%). The most common mutations were in IDH1 (25%), TP53 (22%), ARID1A (19%), and FGFR2 (13%). Upon multivariable analysis, the factors associated with death included worse performance status, larger tumor, metastatic disease, higher CA 19-9, PVT, satellitosis, and IDH1 and PIK3CA mutations. TP53 mutation was associated with local failure. Further investigation into the prognostic value of individual mutations and combinations thereof is warranted.

Primary care experience among older adults in the United States: a retrospective cross-sectional study.

BACKGROUND: While the importance of primary care becomes more imminent for older adults to manage multi-morbidities, the perception of primary care among this group is not well examined. AIM: To evaluate the primary care experience among older adults in the United States (US). METHODS: We conducted a retrospective cross-sectional study examining four domains of primary care: first contact, longitudinality, comprehensiveness, and coordination. Using survey responses from Medical Expenditure Panel Survey (MEPS), we used propensity score matching method to compare the percentage of geriatric (≥65 years old) and non-geriatric (< 65 years old) who answered favorably to questions that supported each domain from 2014 to 2016. Using multivariate regression, we also assessed the impact of each domain on various demographic and perceived need for care features of older adults. RESULTS: A total of 12,982 surveys were analyzed for geriatric, compared to 62,694 surveys for non-geriatric. Overall, older adults answered more favorably than younger adults for all four domains. However, uninsured older adults, Black older adults and older adults with limitation in activities, cognitive impairments, and multiple comorbidities were more likely to have difficulties in accessing their usual source of care (USC). Additionally, Black, Hispanic, and Asian older adults and cognitively impaired adults perceived less contribution in their own treatment management. CONCLUSION: Older adults in the US generally experience good quality of primary care, compared to younger adults. However, establishing and maintaining access (first contact) and being involved in disease management (coordination) were perceived as poor by several cohorts of older adults.

Cortical Neuron Migration and Dendrite Morphology are Regulated by Carboxypeptidase E.

Higher brain function relies on proper development of the cerebral cortex, including correct positioning of neurons and dendrite morphology. Disruptions in these processes may result in various neurocognitive disorders. Mutations in the CPE gene, which encodes carboxypeptidase E (CPE), have been linked to depression and intellectual disability. However, it remains unclear whether CPE is involved in early brain development and in turn contributes to the pathophysiology of neurocognitive disorders. Here, we investigate the effects of CPE knockdown on early brain development and explore the functional significance of the interaction between CPE and its binding partner p150Glued. We demonstrate that CPE is required for cortical neuron migration and dendrite arborization. Furthermore, we show that expression of CPE-C10 redistributes p150Glued from the centrosome and that disruption of CPE interaction with p150Glued leads to abnormal neuronal migration and dendrite morphology, suggesting that a complex between CPE and p150Glued is necessary for proper neurodevelopment.