Citations

AbstractPurposeThe time structures of proton spot delivery in proton pencil beam scanning (PBS) radiation therapy are essential in many clinical applications. This study aims to characterize the time structures of proton PBS delivered by both synchrotron and synchrocyclotron accelerators using a non‐invasive technique based on scattered particle tracking.MethodsA pixelated semiconductor detector, AdvaPIX‐Timepix3, with a temporal resolution of 1.56 ns, was employed to measure time of arrival of secondary particles generated by a proton beam. The detector was placed laterally to the high‐flux area of the beam in order to allow for single particle detection and not interfere with the treatment. The detector recorded counts of radiation events, their deposited energy and the timestamp associated with the single events. Individual recorded events and their temporal characteristics were used to analyze beam time structures, including energy layer switch time, magnet switch time, spot switch time, and the scanning speeds in the x and y directions. All the measurements were repeated 30 times on three dates, reducing statistical uncertainty.ResultsThe uncertainty of the measured energy layer switch times, magnet switch time, and the spot switch time were all within 1% of average values. The scanning speeds uncertainties were within 1.5% and are more precise than previously reported results. The measurements also revealed continuous sub‐milliseconds proton spills at a low dose rate for the synchrotron accelerator and radiofrequency pulses at 7 µs and 1 ms repetition time for the synchrocyclotron accelerator.ConclusionThe AdvaPIX‐Timepix3 detector can be used to directly measure and monitor time structures on microseconds scale of the PBS proton beam delivery. This method yielded results with high precision and is completely independent of the machine log files.

Despite major advances in non-small-cell lung cancer (NSCLC) treatment, the five-year survival rates for patients with non-oncogene-driven tumors remain low, necessitating combinatory approaches to improve outcomes. Our prior high-throughput RNAi screening identified Aurora kinase A (AURKA) as a potential key player in cisplatin resistance. In this study, we investigated AURKA’s role in platinum and radiation sensitivity in multiple NSCLC cell lines and xenograft mouse models, as well as its effect on immune checkpoints, including PD-L1, B7x, B7-H3, and HHLA2. Of 94 NSCLC patient tumor specimens, 91.5% tested positive for AURKA expression, with 34% showing moderate-to-high levels. AURKA expression was upregulated following cisplatin treatment in NSCLC cell lines PC9 and A549. Both AURKA inhibition by alisertib and inducible AURKA knockdown potentiated the cytotoxic effects of cisplatin and radiation, leading to tumor regression in doxycycline-inducible xenograft mice. Co-treated cells exhibited increased DNA double-strand breaks, apoptosis, and senescence. Additionally, AURKA inhibition alone by alisertib increased PD-L1 and B7-H3 expression. In conclusion, our study demonstrates that AURKA inhibition enhances the efficacy of platinum-based chemotherapy in NSCLC cells and modulates the expression of multiple immune checkpoints. Therefore, combinatory regimens with AURKA inhibitors should be strategically designed and further studied within the evolving landscape of chemo-immunotherapy.

Abstract Transcriptome profiling using RNA sequencing (RNA-seq) of bulk formalin-fixed paraffin-embedded (FFPE) tissue blocks is a standard method in biomedical research. However, when used on tissues with diverse cell type compositions, it yields averaged gene expression profiles, complicating biomarker identification due to variations in cell proportions. To address the need for optimized strategies for defining individual cell type compositions from bulk FFPE samples, we constructed single-cell RNA-seq reference data for breast tissue and tested cell type deconvolution methods. Initial simulation experiments showed similar performances across multiple commonly used deconvolution methods. However, the introduction of FFPE artifacts significantly impacted their performances, with a root mean squared error (RMSE) ranging between 0.04 and 0.17. Scaden, a deep learning-based method, consistently outperformed the others, demonstrating robustness against FFPE artifacts. Testing these methods on our 62-sample RNA-seq benign breast disease cohort in which cell type composition was estimated using digital pathology approaches, we found that pre-filtering of the reference data enhanced the accuracy of most methods, realizing up to a 32% reduction in RMSE. To support further research efforts in this domain, we introduce SCdeconR, an R package designed for streamlined cell type deconvolution assessments and downstream analyses.

Abstract Objective To use an artificial intelligence (AI)‐powered large language model (LLM) to improve readability of patient handouts. Study Design Review of online material modified by AI. Setting Academic center. Methods Five handout materials obtained from the American Rhinologic Society (ARS) and the American Academy of Facial Plastic and Reconstructive Surgery websites were assessed using validated readability metrics. The handouts were inputted into OpenAI's ChatGPT‐4 after prompting: “Rewrite the following at a 6th‐grade reading level.” The understandability and actionability of both native and LLM‐revised versions were evaluated using the Patient Education Materials Assessment Tool (PEMAT). Results were compared using Wilcoxon rank‐sum tests. Results The mean readability scores of the standard (ARS, American Academy of Facial Plastic and Reconstructive Surgery) materials corresponded to “difficult,” with reading categories ranging between high school and university grade levels. Conversely, the LLM‐revised handouts had an average seventh‐grade reading level. LLM‐revised handouts had better readability in nearly all metrics tested: Flesch‐Kincaid Reading Ease (70.8 vs 43.9; P < .05), Gunning Fog Score (10.2 vs 14.42; P < .05), Simple Measure of Gobbledygook (9.9 vs 13.1; P < .05), Coleman‐Liau (8.8 vs 12.6; P < .05), and Automated Readability Index (8.2 vs 10.7; P = .06). PEMAT scores were significantly higher in the LLM‐revised handouts for understandability (91 vs 74%; P < .05) with similar actionability (42 vs 34%; P = .15) when compared to the standard materials. Conclusion Patient‐facing handouts can be augmented by ChatGPT with simple prompting to tailor information with improved readability. This study demonstrates the utility of LLMs to aid in rewriting patient handouts and may serve as a tool to help optimize education materials. Level of Evidence Level VI.

Blood transfusion is a common therapeutic intervention in hospitalized patients. There are numerous indications for transfusion, including anemia and coagulopathy with deficiency of single or multiple coagulation components such as platelets or coagulation factors. Nevertheless, the practice of transfusion in critically ill patients has been controversial mainly due to a lack of evidence and the need to consider the appropriate clinical context for transfusion. Further, transfusion carries many risk factors that must be balanced with benefits. Therefore, transfusion practice in ICU patients has constantly evolved, and we endeavor to present a contemporary review of transfusion practices in this population guided by clinical trials and expert guidelines.

Abstract Background It was reported that patients with Non-Alcoholic Fatty Liver Disease (NAFLD) were at increased risk of contracting severe infections requiring hospitalization which could end up with sepsis. However, data regarding the impact of comorbid NAFLD on the in-hospital outcomes of sepsis admission is scarce. Methods This nationwide retrospective observational study included 21,057,911 adult patients who were admitted into hospitals in the United States between 2000 and 2019 with a primary discharge diagnosis of sepsis. These patients were categorized according to the presence or absence of comorbid NAFLD. The twenty-year trend of nationwide NAFLD prevalence among sepsis inpatients was elucidated. Multivariate logistic regression analysis was used to analyze NAFLD's impact on in-hospital outcomes of sepsis. Results In the twenty-year study period, the prevalence of NALFD among sepsis inpatients trended up from 1.2% in 2000 to 4.2 % in 2019. While sepsis mortality had trended down, comorbid NAFLD in sepsis patients was consistently associated with a higher adjusted in-hospital all-cause mortality rate (adjusted odds ratio (OR), 1.45; 95% confidence interval (CI), 1.42-1.48), higher odds of developing septic shock, and multi-organ dysfunctions (including cardiovascular-, renal-, and hepatic dysfunction). They were more likely to be discharged to another acute hospital. The length of stay of sepsis patients with NAFLD who died in the hospital was significantly shorter than those without NAFLD. Conclusions Comorbid NAFLD is associated with higher in-hospital all-cause mortality and worse clinical outcomes in sepsis inpatients. Addressing this rising epidemic will be of paramount importance to improve sepsis in-hospital outcomes.

OBJECTIVE Determine if a longitudinal point-of-care ultrasonography (POCUS) elective for medical students is effective in improving POCUS knowledge. METHODS We share the format of our longitudinal POCUS elective for medical students. To evaluate the efficacy of our longitudinal elective, we compare the difference between pre-elective and post-elective scores on a POCUS test using a paired t-test with threshold of statistical significance of p ≤ .05. We also share the results of a post-elective survey evaluating the effectiveness and quality of the longitudinal POCUS elective. RESULTS Pretest mean score was 56.3% (σ = 13.6), while posttest mean score was 73.3% (σ = 9.4), with an average score improvement of 17.0% (95% CI 9.9-24.0%, p < .0001). All students strongly or moderately agreed that they would recommend the elective to future medical students, that they were more confident with their POCUS skills after completing the elective, that the time commitment of the elective was appropriate, and that they felt they had the time to fit the elective into their schedule as a medical school student. Most students (56.7%) strongly or moderately agreed that the knowledge gained from the POCUS elective had helped them in their clinical rotations. CONCLUSIONS Our longitudinal POCUS curriculum subjectively and objectively improves medical students’ POCUS knowledge while remaining accessible to students. We share our unique longitudinal POCUS elective curriculum, the format of which and its benefits are transferable to other medical schools. Through this, we hope to provide others with ideas on how they may implement a longitudinal POCUS elective.

Abstract This study explored the role of the ubiquitin-proteasome system (UPS) in dominantly inherited Alzheimer’s disease (DIAD) by examining changes in cerebrospinal fluid (CSF) levels of UPS proteins along with disease progression, AD imaging biomarkers (PiB PET, tau PET), neurodegeneration imaging measures (MRI, FDG PET), and Clinical Dementia Rating® (CDR®). Using the SOMAscan assay, we detected subtle increases in specific ubiquitin enzymes associated with proteostasis in mutation carriers (MCs) up to two decades before the estimated symptom onset. This was followed by more pronounced elevations of UPS-activating enzymes, including E2 and E3 proteins, and ubiquitin-related modifiers. Our findings also demonstrated consistent correlations between UPS proteins and CSF biomarkers such as Aβ42/40 ratio, total tau, various phosphorylated tau species to total tau ratios (ptau181/T181, ptauT205/T205, ptauS202/S202, ptauT217/T217), and MTBR-tau243, alongside Neurofilament light chain (NfL) and the CDR®. Notably, a positive association was observed with imaging markers (PiB PET, tau PET) and a negative correlation with markers of neurodegeneration (FDG PET, MRI), highlighting a significant link between UPS dysregulation and neurodegenerative processes. The correlations suggest that the increase in multiple UPS proteins with rising tau levels and tau-tangle associated markers, indicating a potential role for the UPS in relation to misfolded tau/neurofibrillary tangles (NFTs) and symptom onset. These findings indicate that elevated CSF UPS proteins in DIAD MCs could serve as early indicators of disease progression and suggest a link between UPS dysregulation and amyloid plaque, tau tangles formation, implicating the UPS as a potential therapeutic target in AD pathogenesis.