Citations

AbstractBackgroundAlzheimer’s disease (AD) is a pervasive neurodegeneration disease with high heritability. Whole exome sequencing study identified two rare African American (AA)‐specific variants in AKAP9, a kinase anchor protein 9, (rs144662445 and rs149979685), that increased the odds of AD more than 2.75‐fold. However, the functional impact of the AKAP9 rs144662445 (I2558M) mutation in the central nervous system and the underlying mechanism in AD remain unclear.MethodAKAP9 I2558M mutation was introduced by CRISPR‐mediated knock‐in and validated by Sanger sequence in SH‐SY5Y cells stably expressing P301L Tau (SH‐SY5Y P301L cells), which was further differentiated into neuronal cells. Tau phosphorylated level between AKAP9 WT and I2558M cells was evaluated by immunocytochemistry and ELISA assay. Moreover, we analyzed the tau interactome in AKAP9 I2558M cells by affinity purification‐mass spectrometry. In silico analysis was performed to compare the differences between AKAP9 WT and mutation in tau‐interacting proteins. The protein synthesis and oxidative activity in SH‐SY5Y P301L neurons with and without I2558M were measured by using the Click‐iT protein synthesis kit and CellRox dye, respectively.ResultNo difference in the neuronal cell morphology was observed between differentiated WT and mutant SH‐SY5Y P301L cells. The AD‐associated AKAP9 I2558M mutation resulted in a significant increase in phosphorylated tau protein at residues S396 and S404 site in a differentiated SH‐SY5Y P301L cell line. The presence of this mutation altered the composition of tau‐interacting proteins, by increasing interaction of proteins associated with translation, RNA localization and oxidative activity. Importantly, functional studies showed a significant reduction in protein synthesis activity and excessive oxidative stress in AKAP9 mutant compared to wild type cells.ConclusionOur results demonstrated specific effects of rs14462445 on mis‐processing of tau and suggest a potential role of AKAP9 in AD pathogenesis.

Abstract Ketogenic diets appear promising for obesity, diabetes, cancer, and other illnesses. Because older patients are more likely to contend with such illnesses and because of a paucity of dietary outcomes among these patients, we examined ketogenic diets in older patients. This multisite study focused on patients (≥65 years of age) on a ketogenic diet. Medical records were identified with the keywords “keto,” “ketogenic,” and “Atkins.” Records were reviewed in detail with extraction of direct quotations to substantiate observations. We report on 200 consecutive patients with a median age of 70 years. Reasons for diet included weight loss, diabetes, and cancer; the majority remained on the diet for >1 month. In 134 (67%: 95% confidence interval: 60, 73%), the ketogenic diet appeared beneficial: 93 of 117 (79%) who sought weight loss lost weight (“She has lost 15 pounds and plans to lose another 8”); 36 of 67 (54%) who sought glucose control appeared to achieve the latter (“He has gone on a ketogenic diet and has been able to bring his sugars down significantly”); and 5 of 8 (63%) who sought improved cancer outcomes appeared to derive them (“He attributes part of the control of his cancer and increased QOL to adopting the keto for cancer diet”). Adverse events occurred in 30 patients (15%): dyslipidemia (n = 14), constipation (n = 9), sub-therapeutic international normalized ratio (n = 3), pancreatitis (n = 2), diarrhea (n = 1), and fatigue (n = 1). Trials that test ketogenic diets for a variety of illnesses should enroll older adults.

Introduction Simulation and gamification are two popular educational tools utilized to enhance student learning and engagement. This study aimed to evaluate the effectiveness of integrating a hybrid cancer clinic simulation into the curricula for third-year pharmacy (P3) students. Methods This prospective, single-arm pilot study incorporated a mixed-method learning activity involving patient simulation and escape room elements. Two cancer clinic simulations were developed by faculty members. For each clinic, students were randomly divided into 6 groups and tasked with completing a series of Pharmacist Patient Care Process (PPCP) activities involving patient actors. The PPCP activities were interwoven with engaging puzzles and games to simulate an escape room. Student learning and retention was measured by pre- and post-simulation quizzes and course level exams. A perceptions survey was administered after each simulation activity. Results Thirty-six students participated in both cancer clinic simulations, with 100% completing all aspects of the study. Mean student quiz scores improved from 61.4% to 81.7% (p < 0.0001) and 52.6% to 81.8% (p < 0.0001) following the first and second simulations, respectively. Exam performance improved for 16 out of 19 exam questions, with a significant increase in 4 questions (p < 0.05). Students overwhelmingly agreed that the cancer clinic simulations 1) reinforced knowledge, 2) facilitated PPCP, 3) improved their ability to make chemotherapeutic recommendations, 4) enhanced problem-solving skills, and 5) encouraged collaboration. Conclusion This innovative hybrid simulation enhanced oncology-related knowledge and supported an interactive environment that improved student confidence and teamwork. Students enjoyed the simulations and recommended continuation for all future cohorts.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Small Cell Lung Cancer (SCLC) provide recommended management for patients with SCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. This selection for the journal focuses on metastatic (known as extensive-stage) SCLC, which is more common than limited-stage SCLC. Systemic therapy alone can palliate symptoms and prolong survival in most patients with extensive-stage disease. Smoking cessation counseling and intervention should be strongly promoted in patients with SCLC and other high-grade neuroendocrine carcinomas. The “Summary of the Guidelines Updates” section in the SCLC algorithm outlines the most recent revisions for the 2022 update, which are described in greater detail in this revised Discussion text.

Shared decision making (SDM) has been advocated to improve patient care, patient decision acceptance, patient-provider communication, patient motivation, adherence, and patient reported outcomes. Documentation of SDM is endorsed in several society guidelines and is a condition of reimbursement for selected cardiovascular and cardiac arrhythmia procedures. However, many clinicians argue that SDM already occurs with clinical encounter discussions or the process of obtaining informed consent and note the additional imposed workload of using and documenting decision aids without validated tools or evidence that they improve clinical outcomes. In reality, SDM is a process and can be done without decision tools, although the process may be variable. Also, SDM advocates counter that the low-risk process of SDM need not be held to the high bar of demonstrating clinical benefit and that increasing the quality of decision making should be sufficient. Our review leverages a multidisciplinary group of experts in cardiology, cardiac electrophysiology, epidemiology, and SDM, as well as a patient advocate. Our goal is to examine and assess SDM methodology, tools, and available evidence on outcomes in patients with heart rhythm disorders to help determine the value of SDM, assess its possible impact on electrophysiological procedures and cardiac arrhythmia management, better inform regulatory requirements, and identify gaps in knowledge and future needs.

AbstractPurposeDue to the employment of quadratic programming using soft constraints to implement dose volume constraints and the “trial‐and‐error” procedure needed to achieve a clinically acceptable plan, conventional dose volume constraints (upper limit) are not adequately effective in controlling small and isolated hot spots in the dose/linear energy transfer (LET) distribution. Such hot spots can lead to adverse events. In order to mitigate the risk of brain necrosis, one of the most clinically significant adverse events in patients receiving intensity‐modulated proton therapy (IMPT) for base of skull (BOS) cancer, we propose per‐voxel constraints to minimize hot spots in LET‐guided robust optimization.Methods and materialsTen BOS cancer patients treated with IMPT were carefully selected by meeting one of the following conditions: (1) diagnosis of brain necrosis during follow‐up; and (2) considered high risk for brain necrosis by not meeting dose constraints to the brain. An optimizing structure (BrainOPT) and an evaluating structure (BrainROI) that both contained the aforementioned hot dose regions in the brain were generated for optimization and evaluation, respectively. Two plans were generated for every patient: one using conventional dose‐only robust optimization, the other using LET‐guided robust optimization. The impact of LET was integrated into the optimization via a term of extra biological dose (xBD). A novel optimization tool of per‐voxel constraints to control small and isolated hot spots in either the dose, LET, or combined (dose/LET) distribution was developed and used to minimize dose/LET hot spots of the selected structures. Indices from dose‐volume histogram (DVH) and xBD dose‐volume histogram (xBDVH) were used in the plan evaluation. A newly developed tool of the dose‐LET‐volume histogram (DLVH) was also adopted to illustrate the underlying mechanism. Wilcoxon signed‐rank test was used for statistical comparison of the DVH and xBDVH indices between the conventional dose‐only and the LET‐guided robustly optimized plans.ResultsPer‐voxel constraints effectively and efficiently minimized dose hot spots in both dose‐only and LET‐guided robust optimization and LET hot spots in LET‐guided robust optimization. Compared to the conventional dose‐only robust optimization, the LET‐guided robust optimization could generate plans with statistically lower xBD hot spots in BrainROI (VxBD,50 Gy[RBE], p = 0.009; VxBD,60 Gy[RBE], p = 0.025; xBD1cc, p = 0.017; xBD2cc, p = 0.022) with comparable dose coverage, dose hot spots in the target, and dose hot spots in BrainROI. DLVH analysis indicated that LET‐guided robust optimization could either reduce LET at the same dose level or redistribute high LET from high dose regions to low dose regions.ConclusionPer‐voxel constraint is a powerful tool to minimize dose/LET hot spots in IMPT. The LET‐guided robustly optimized plans outperformed the conventional dose‐only robustly optimized plans in terms of xBD hot spots control.

On behalf of the International Society for Magnetic Resonance in Medicine (ISMRM) Quantitative MR Study Group, this article provides an overview of considerations for the development, validation, qualification, and dissemination of quantitative MR (qMR) methods. This process is framed in terms of two central technical performance properties, i.e., bias and precision. Although qMR is confounded by undesired effects, methods with low bias and high precision can be iteratively developed and validated. For illustration, two distinct qMR methods are discussed throughout the manuscript: quantification of liver proton‐density fat fraction, and cardiacT1. These examples demonstrate the expansion of qMR methods from research centers toward widespread clinical dissemination. The overall goal of this article is to provide trainees, researchers, and clinicians with essential guidelines for the development and validation of qMR methods, as well as an understanding of necessary steps and potential pitfalls for the dissemination of quantitative MR in research and in the clinic.