Search

High-grade (grade 3) neuroendocrine neoplasms (G3 NENs) have poor survival outcomes. From a clinical standpoint, G3 NENs are usually grouped regardless of primary site and treated similarly. Little is known regarding the underlying genomics of these rare tumors, especially when compared across different primary sites. We performed whole transcriptome (n = 46), whole exome (n = 40), and gene copy number (n = 43) sequencing on G3 NEN formalin-fixed, paraffin-embedded samples from diverse organs (in total, 17 were lung, 16 were gastroenteropancreatic, and 13 other). G3 NENs despite arising from diverse primary sites did not have gene expression profiles that were easily segregated by organ of origin. Across all G3 NENs, TP53, APC, RB1, and CDKN2A were significantly mutated. The CDK4/6 cell cycling pathway was mutated in 95% of cases, with upregulation of oncogenes within this pathway. G3 NENs had high tumor mutation burden (mean 7.09 mutations/MB), with 20% having >10 mutations/MB. Two somatic copy number alterations were significantly associated with worse prognosis across tissue types: focal deletion 22q13.31 (HR, 7.82; P = 0.034) and arm amplification 19q (HR, 4.82; P = 0.032). This study is among the most diverse genomic study of high-grade neuroendocrine neoplasms. We uncovered genomic features previously unrecognized for this rapidly fatal and rare cancer type that could have potential prognostic and therapeutic implications.

Analytics can help identify strategies to improve the equity and capacity of health services for populations. However, many government agencies experience challenges with heavy workloads, limited time for continued analytic education, and employee turnover among contracted staff. Therefore, streamlining analytical workflows has the potential to (1) improve labor cost-efficiencies and (2) identify strategies to improve health among enrollees. We describe an analytic framework design that automates several empirical methods and provides recommendations for increasing healthcare access for Alabama Medicaid Agency (AMA) enrollees. The described framework, which includes descriptive and prescriptive elements, has been successfully used to inform various day-to-day analyses conducted by AMA’s Analytics Department and comprehensively analyze AMA-enrolled youths’ accessibility to licensed dentists. Specifically, in the dental context, the framework assisted in identifying (1) dental procedures that were ideal candidates for increased reimbursement payments and (2) geographical locations that AMA should target for interventions to improve physical access to care for AMA’s youth enrollees. The insights offered by the framework for dental care impact more than 0.5 million underserved youth and roughly $90 million of annual revenue for licensed dentists through reimbursements. Funding: D. Lewis, J. Parton, M. Hudnall, R. Tramp, X. T. Yang, and S. Samsel received salary support from the Alabama Medicaid Agency during the execution of this study. B. Cambron, T. Tyner, N. Biligowda, and D. Rush were employed at the Alabama Medicaid Agency during the execution of this study. The other authors do not declare the receipt of funding associated with entities affiliated with this study.

Purpose:Taletrectinib (DS-6051b/AB-106) is an oral, tyrosine kinase inhibitor of ROS1 and NTRK with potent preclinical activity against ROS1 G2032R solvent-front mutation among others. We report the first-in-human U.S. phase I results of taletrectinib.Patients and Methods:Patients ≥18 years old with neuroendocrine tumors, with tumor-induced pain, or tumors harboring ROS1/NTRK rearrangements were eligible. Accelerated titration followed by modified continuous reassessment method and escalation with overdose control was used (50–1,200 mg once daily or 400 mg twice daily). Primary objectives were safety/tolerability, and MTD determination. Secondary objectives were food-effect pharmacokinetics and antitumor activity.Results:A total of 46 patients were enrolled. Steady-state peak concentration (Cmax) and exposure (AUC0-8) increased dose dependently from 50-mg to 800-mg once-daily doses. The ratio of the geometric mean of AUC0-24 between low-fat-diet-fed/fasted state was 123% (90% confidence interval, 104%–149%). Dose-limiting toxicities (grade 3 transaminases increase) occurred in two patients (1,200-mg once-daily dose). MTD was 800 mg once daily. Most common treatment-related adverse events were nausea (47.8%), diarrhea (43.5%), and vomiting (32.6%). Pain score reductions were observed in the 800-mg once-daily dose cohort. Confirmed objective response rate was 33.3% among the six patients with RECIST-evaluable crizotinib-refractory ROS1+ NSCLC. One patient with TPM3-NTRK1 differentiated thyroid cancer achieving a confirmed partial response of 27 months at data cutoff. We identified a cabozantinib-sensitive ROS1 L2086F as an acquired taletrectinib-resistance mutation.Conclusions:Taletrectinib has manageable toxicities at the MTD of 800 mg daily. Preliminary efficacy was observed in patients with crizotinib-refractory ROS1+ NSCLC.

Supplemental tables and figures

Lung neuroendocrine tumors (NETs)-typical carcinoids and atypical carcinoids-have unique molecular alterations that are distinct from neuroendocrine carcinomas of the lung and non-small cell lung cancers. Here, we review the role of molecular profiling in the prognosis and treatment of lung NETs.There have been no recently identified molecular prognostic factors for lung NETs and none that have been routinely used to guide management of patients with lung NETs. Previous findings suggest that patients with loss of chromosome 11q may have a worse prognosis along with upregulation of anti-apoptotic pathways (e.g., loss of CD44 and OTP protein expression). Lung NETs rarely harbor driver mutations commonly found in non-small cell lung cancer (NSCLC) or TP53/RB1 mutations found universally in small cell lung cancer. Lung NETs also have low tumor mutation burden and low PD-L1 expression. Everolimus, an mTOR inhibitor and the only FDA approved therapy for unresectable lung NETs, is an effective treatment but the presence of a molecular alteration in the PI3K/AKT/mTOR pathway is not known to predict treatment response. The predominant mutations in lung NETs occur in genes regulating chromatin remodeling and histone modification, with potential targeted therapies emerging in clinical trials. Lung NETs have recurring alterations in genes that regulate the epigenome. Future targeted therapy interfering with epigenetic pathways may hold promise.

The map recovery and fusion is a key issue in the application of large scale and long-term augmented reality (AR) scenarios. However, they are still not addressed well in an efficient and precise way, especially for complex industrial environments. In this article, we propose a map recovery and fusion strategy based on vision-inertial simultaneous localization and mapping. We first develop a heuristic strategy that can fast search and match map points among multiple maps, and can be used for efficient map fusion. For map recovery, we leverage the inertial sensors for short time motion estimation, and transform the previous lost map to the current map. Based on this strategy, a novel framework for collaborative AR is implemented and can parallelly run in multiple mobile devices in real time. Extensive experiments have been carried out on a public data set, and the results show that the proposed method can recovery and fuse multiple maps with high completeness and precision.

This paper presents a novel 7 DOF (i.e., orientation, translation, and scale) visual simultaneous localization and mapping (vSLAM) system for mobile robots in outdoor environments. In the front end of this vSLAM system, a fast initialization method is designed for different vSLAM backbones, which upgrades the accuracy of trajectory and reconstruction of vSLAM with an absolute scale computed from depth maps generated by building blocks. In the back end of this vSLAM, we propose a nonlinear optimization mechanism throughout which multimodal data are combined for more robust optimization. The modality of building blocks in optimization can improve the tracking accuracy and the scale estimation. By integrating the pose estimated from visual information and the position received through GPS, the optimization further alleviates the drift. The experimental results prove that the proposed method is extremely suitable for outer AR application for outdoor environments, because our method has superior initialization performance, runs in real time, and achieves real scale, higher accuracy, and robustness.

Objective This prospective, open-label, multicenter study evaluated the feasibility of spinal cord stimulation (SCS) therapy programming for chronic low back pain that uses multiple electrical pulsed signals (Differential Target Multiplexed). Methods Twenty-five SCS candidates with low back pain equal to or greater than lower limb pain were enrolled at 7 sites in the United States. The subjects evaluated standard and Differential Target Multiplexed programs, each for 4 ± 1 days. A commercially available SCS trial system was used for standard SCS therapy programming. During the trialing of the multiplexed programs, implanted temporary leads were connected to an investigational external trial stimulator system. Results Twenty subjects concluded the study. The mean baseline numeric pain rating scale (NPRS) score for low back pain was 7.4, with a mean age of 62.4 years and mean pain duration of 18.0 years. Significant relief in back pain was observed for both treatments, with significantly better response with multiplexed programming. At the end of the trial period, subjects reported a reduction in their mean NPRS score from baseline to 4.2 after standard programming and to 2.4 after Differential Target Multiplexed programming. The difference between standard and multiplexed programming was significant. The responder rate for low back pain relief was 50% for standard programming and 80% for Differential Target Multiplexed programming. Eighty-five percent of subjects who evaluated both programming approaches preferred Differential Target Multiplexed SCS. Conclusion In this difficult-to-treat patient population, subjects reported significant reduction in chronic back pain when using multiplexed programming. A randomized clinical trial is needed to confirm the results from this feasibility study.

Networked finite state machine takes into account communication losses in industrial communication interfaces due to the limited bandwidth. The reachability analysis of networked finite state machine is a fundamental and important research topic in blocking detection, safety analysis, communication system design and so on. This paper is concerned with the impact of arbitrary communication losses on the reachability of networked finite state machine from a switched perspective. First, to model the dynamics under arbitrary communication losses in communication interfaces (from the controller to the actuator), by resorting to the semi-tensor product (STP) of matrices, a switched algebraic model of networked finite state machine with arbitrary communication losses is proposed, and the reachability analysis can be investigated by using the constructed model under arbitrary switching signal. Subsequently, based on the algebraic expression and its transition matrix, necessary and sufficient conditions for the reachability are derived for networked finite state machine. Finally, some typical numerical examples are exploited to demonstrate the effectiveness of the proposed approach. Note that current results provide valuable clues to design reliable and convergent Internet-of-Things networks.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is considered a preinvasive lesion that may progress to carcinoid tumour [1]. Histologically, it is marked by a proliferation of neuroendocrine cells that is confined to the basement membrane (neuroendocrine cell hyperplasia; NECH), and/or has invaded past the basement membrane (carcinoid tumourlet) [2]. Tumourlets equal to or larger than 5 mm are classified as carcinoid tumours. Per the World Health Organization 2021 criteria, DIPNECH can be pathological (based solely on characteristic histological features) or clinical (diagnosed per characteristic symptoms and imaging findings, e.g. respiratory symptoms, bilateral pulmonary nodules, mosaic attenuation on computed tomography (CT)) [2]. In contrast to some lung diseases or neoplasms that can cause secondary, reactive NECH/tumourlets to form, DIPNECH is marked by such hyperplasia without an identifiable cause., DIPNECH is a rare disease that is often misdiagnosed. In this study, it primarily affected elderly white women who were non-smokers. Lung nodules could slowly progress over years to carcinoid tumours. Average growth rate per nodule was 0.8 mm per year. https://bit.ly/3q1HD1k

Low earth orbit CubeSat swarms improve the spatial and temporal resolution of remote sensing, rural communication, and space exploration due to their innovative and economical satellite design. Unlike conventional large satellites, which demand high transmission power for data exchange, the CubeSat swarm communication system provides interoperability, a high data rate between networked nodes, and global coverage with real-time measurement. However, CubeSat swarms’ main challenges include inefficient usage of spectrum resources and delay of data exchange, and the issues become more severe with the increased number of on-orbit CubeSats. Spectrum sensing in cognitive radio is often proposed as a critical solution to efficient spectrum utilization and low delay of data exchange. Typically, the secondary user takes over the link while the primary user does not occupy the channel. This paper proposes blind source separation (BSS) and Least Mean Square (LMS) for primary user detection with MIMO antennas equipped in all CubeSats. Each antenna receives a mixture of radio signals, including primary and interfering signals. Practical implementation issues are studied through simulations, with main performance metrics including algorithm performance and MIMO antenna deployment. These are essential for the communication resource allocation, power budget calculation, and hardware design of the CubeSat platform on configuring LEO non-terrestrial networks.

BACKGROUND Many patients with chronic medical conditions search the internet to obtain medical advice and health information to improve their health condition and quality of life. Diabetes is a common chronic disease that disproportionately affects different race and ethnicity groups in the United States. In the existing literature on the popularity of internet health information seeking among persons with a chronic medical condition, there are limited data on US adults living with diabetes. OBJECTIVE This study aims to examine the factors associated with internet health information seeking among US adults living with diabetes and whether there is a disparity in internet health information seeking stratified by race and ethnicity. METHODS We conducted a cross-sectional study using the Health Information National Trends Survey data from 2017 to 2020. We selected our study sample based on respondents’ reports on whether they were told they had diabetes, and our primary outcome was internet health information–seeking behavior. We used 2 multivariable logistic regression models to examine the effects of sociodemographic factors and other covariates on the internet health information–seeking behavior of adults with diabetes. Jackknife replicate weights were used to provide bias-corrected variance estimates. RESULTS Our study sample included 2903 adults who self-reported that they had diabetes. In total, 60.08% (1744/2903) were non-Hispanic White individuals, 46.88% (1336/2850) were men, and 64% (1812/2831) had some college or graduate education. The prevalence of internet health information seeking in this population was 64.49% (1872/2903), and the main factors associated with internet health information seeking included education level (some college vs less than high school: odds ratio [OR] 1.42, 95% CI 1.44-1.88; and college graduate or higher vs less than high school: OR 2.50, 95% CI 1.79-3.50), age (age group ≥65 years vs age group 18-44 years: OR 0.46, 95% CI 0.34-0.63), and household income level (P CONCLUSIONS The findings from this study suggest that internet health information seeking is common among US adults living with diabetes. Internet health information could influence the relationship between health care providers and adults living with diabetes and improve their self-management and quality of life.

Background Many patients with chronic medical conditions search the internet to obtain medical advice and health information to improve their health condition and quality of life. Diabetes is a common chronic disease that disproportionately affects different race and ethnicity groups in the United States. In the existing literature on the popularity of internet health information seeking among persons with a chronic medical condition, there are limited data on US adults living with diabetes. Objective This study aims to examine the factors associated with internet health information seeking among US adults living with diabetes and whether there is a disparity in internet health information seeking stratified by race and ethnicity. Methods We conducted a cross-sectional study using the Health Information National Trends Survey data from 2017 to 2020. We selected our study sample based on respondents’ reports on whether they were told they had diabetes, and our primary outcome was internet health information–seeking behavior. We used 2 multivariable logistic regression models to examine the effects of sociodemographic factors and other covariates on the internet health information–seeking behavior of adults with diabetes. Jackknife replicate weights were used to provide bias-corrected variance estimates. Results Our study sample included 2903 adults who self-reported that they had diabetes. In total, 60.08% (1744/2903) were non-Hispanic White individuals, 46.88% (1336/2850) were men, and 64% (1812/2831) had some college or graduate education. The prevalence of internet health information seeking in this population was 64.49% (1872/2903), and the main factors associated with internet health information seeking included education level (some college vs less than high school: odds ratio [OR] 1.42, 95% CI 1.44-1.88; and college graduate or higher vs less than high school: OR 2.50, 95% CI 1.79-3.50), age (age group ≥65 years vs age group 18-44 years: OR 0.46, 95% CI 0.34-0.63), and household income level (P Conclusions The findings from this study suggest that internet health information seeking is common among US adults living with diabetes. Internet health information could influence the relationship between health care providers and adults living with diabetes and improve their self-management and quality of life.

There are limited data on health service use and cost in low-income children with type 1 diabetes. This study examined the pattern of use and cost of health care services among low-income children diagnosed with type 1 diabetes in the state of Alabama Medicaid program. The authors performed descriptive analysis and examined factors that influence cost and health service utilization. Results showed that 5638 children with type 1 diabetes were enrolled in the Medicaid program over 7 years. Direct medical costs for patients with type 1 diabetes increased at a rate substantially higher than total Medicaid spending. White children with type 1 diabetes were found to have significantly higher Medicaid spending and service utilization than Black children with type 1 diabetes, while Hispanic children had the lowest costs. Further, older children with type 1 diabetes were found to have significantly higher Medicaid spending and service utilization than younger children with type 1 diabetes.