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Introduction: Ineffective esophageal motility (IEM) is the most common motility disorder identified on esophageal high-resolution manometry (HRM), but patients with this finding may be asymptomatic. Therefore, we aimed to identify specific HRM findings predictive of symptoms in IEM., Methods: Adult patients (≥18 y) who underwent HRM between March 2016 and July 2019 were retrospectively evaluated and reclassified according to Chicago Classification 4.0 (CC4.0). Demographic information, HRM parameters, and gastroesophageal reflux disease Health-Related Quality of Life Questionnaire responses were captured among those with normal manometry or IEM. We evaluated the association between heartburn, regurgitation, and dysphagia, with respect to HRM findings including ineffective swallows., Results: Of 379 patients, 243 (64.1%) had a normal manometry, 136 (35.9%) were on IEM spectrum, and 73 (19.3%) had conclusive IEM by CC4.0. Mean dysphagia scores were significantly higher in those with conclusive IEM compared with those with normal HRM (2.00 vs. 1.36, P =0.002), as was the percentage of individuals reporting dysphagia affecting daily activities (21.9% vs. 11.4%, P =0.02). Heartburn and regurgitation symptoms did not differ between groups. In a multivariable model of IEM patients, the percentage of ineffective swallows independently predicted a higher dysphagia burden (β regression coefficient: 0.032, P =0.04)., Conclusions: Applying the CC4.0 definition for conclusive IEM identifies a group of patients with worse dysphagia symptoms. Within this group, the percentage of ineffective swallows was an independent predictor of dysphagia severity. These findings may help practitioners and patients contextualize the heterogeneous diagnosis of IEM., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Spatiotemporal regulation of the cellular transcriptome is crucial for proper protein expression and cellular function. However, the intricate subcellular dynamics of RNA remain obscured due to the limitations of existing transcriptomics methods. Here, we report TEMPOmap-a method that uncovers subcellular RNA profiles across time and space at the single-cell level. TEMPOmap integrates pulse-chase metabolic labeling with highly multiplexed three-dimensional in situ sequencing to simultaneously profile the age and location of individual RNA molecules. Using TEMPOmap, we constructed the subcellular RNA kinetic landscape in various human cells from transcription and translocation to degradation. Clustering analysis of RNA kinetic parameters across single cells revealed 'kinetic gene clusters' whose expression patterns were shaped by multistep kinetic sculpting. Importantly, these kinetic gene clusters are functionally segregated, suggesting that subcellular RNA kinetics are differentially regulated in a cell-state- and cell-type-dependent manner. Spatiotemporally resolved transcriptomics provides a gateway to uncovering new spatiotemporal gene regulation principles., (© 2023. The Author(s).)

CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. CIViC contains peer-reviewed, published literature curated and expertly-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViC's functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination of structured curated data. To support the full breadth of variant interpretation from basic to translational, including integration of somatic and germline variant knowledge and inference of drug response, we have enabled curation of three new Evidence Types (Predisposing, Oncogenic and Functional). The growing CIViC knowledgebase has over 300 contributors and distributes clinically-relevant cancer variant data currently representing >3200 variants in >470 genes from >3100 publications., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Pneumothorax is a potentially life-threatening condition that can be rapidly and accurately assessed via the lung sliding artefact generated using lung ultrasound (LUS). Access to LUS is challenged by user dependence and shortage of training. Image classification using deep learning methods can automate interpretation in LUS and has not been thoroughly studied for lung sliding. Using a labelled LUS dataset from 2 academic hospitals, clinical B-mode (also known as brightness or two-dimensional mode) videos featuring both presence and absence of lung sliding were transformed into motion (M) mode images. These images were subsequently used to train a deep neural network binary classifier that was evaluated using a holdout set comprising 15% of the total data. Grad-CAM explanations were examined. Our binary classifier using the EfficientNetB0 architecture was trained using 2535 LUS clips from 614 patients. When evaluated on a test set of data uninvolved in training (540 clips from 124 patients), the model performed with a sensitivity of 93.5%, specificity of 87.3% and an area under the receiver operating characteristic curve (AUC) of 0.973. Grad-CAM explanations confirmed the model's focus on relevant regions on M-mode images. Our solution accurately distinguishes between the presence and absence of lung sliding artefacts on LUS., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Pancreatic cancer is a disease with an incredibly poor survival rate. As only about 20% of patients are eligible for surgical resection, neoadjuvant treatments that can relieve symptoms and shrink tumors for surgical resection become critical. Many forms of treatments rely on increased vulnerability of cancerous cells, but tumors or regions within the tumors that may be hypoxic could be drug resistant. Particularly for neoadjuvant therapies such as the tyrosine kinase inhibitors utilized to shrink tumors, it is critical to monitor changes in vascular function and hypoxia to predict treatment efficacy. Current clinical imaging modalities used to obtain structural and functional information regarding hypoxia or oxygen saturation (StO 2 ) do not provide sufficient depth penetration or require the use of exogenous contrast agents. Recently, ultrasound-guided photoacoustic imaging (US-PAI) has garnered significant popularity, as it can noninvasively provide multiparametric information on tumor vasculature and function without the need for contrast agents. Here, we built upon existing literature on US-PAI and demonstrate the importance of changes in StO 2 values to predict treatment response, particularly tumor growth rate, when the outcomes are suboptimal. Specifically, we image xenograft mouse models of pancreatic adenocarcinoma treated with suboptimal doses of a tyrosine kinase inhibitor cabozantinib. We utilize the US-PAI data to develop a multivariate regression model that demonstrates that a therapy-induced reduction in tumor growth rate can be predicted with 100% positive predictive power and a moderate (58.33%) negative predictive power when a combination of pretreatment tumor volume and changes in StO 2 values pretreatment and immediately posttreatment was employed. Overall, our study indicates that US-PAI has the potential to provide label-free surrogate imaging biomarkers that can predict tumor growth rate in suboptimal therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Claus, Sweeney, Sankepalle, Li, Wong, Xavierselvan and Mallidi.)

All-trans retinoic acid (ATRA) is an essential therapy in the treatment of acute promyelocytic leukemia (APL), but nearly 20% of patients with APL are resistant to ATRA. As there are no biomarkers for ATRA resistance that yet exist, we investigated whether cell mechanics could be associated with this pathological phenotype. Using mechano-node-pore sensing, a single-cell mechanical phenotyping platform, and patient-derived APL cell lines, we discovered that ATRA-resistant APL cells are less mechanically pliable. By investigating how different subcellular components of APL cells contribute to whole-cell mechanical phenotype, we determined that nuclear mechanics strongly influence an APL cell's mechanical response. Moreover, decondensing chromatin with trichostatin A is especially effective in softening ATRA-resistant APL cells. RNA-seq allowed us to compare the transcriptomic differences between ATRA-resistant and ATRA-responsive APL cells and highlighted gene expression changes that could be associated with mechanical changes. Overall, we have demonstrated the potential of "physical" biomarkers in identifying APL resistance., Competing Interests: L.L.S. is an inventor for mechano node-pore sensing (US2017/056423, WO2018071731A1)., (© 2022 The Author(s).)

Node-Pore Sensing, NPS, is an extremely versatile and powerful technique for the analysis of cells and the detection of extracellular vesicles (EVs). NPS involves measuring the modulated current pulse caused by a cell transiting a microfluidic channel that has been segmented by a series of inserted nodes. As the current pulse reflects the number of nodes and segments of the channel, NPS can achieve exquisite sensitivity. Thus, when used as a Coulter counter, NPS can measure the sub-micron size increase of antibody-coated colloids to which EVs are specifically bound. By simply inserting between two nodes a "contraction" channel through which cells can squeeze, one can mechanically phenotype cells. We discuss the details of performing these two NPS applications., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Goal: The goal of this study was to evaluate the inpatient mortality risk among geriatric patients with inflammatory bowel disease (IBD)., Background: The challenges of caring for elderly patients with IBD will increase with the aging of the US population. Given the complications of hospitalization, we set to examine if elderly patients age older than 65 were at higher risk of mortality., Materials and Methods: All patients with ulcerative colitis (UC) or Crohn's disease (CD) in the National Inpatient Sample (NIS) from 2016 and 2017 as the primary diagnosis or secondary diagnosis with an IBD-related cause of admission were included. Outcomes for patients aged above 65 were compared with below 65 using multivariable survey-adjusted regression. CD and UC were analyzed separately., Results: In 2016-2017, there were an estimated 162,800 admissions for CD and related complications compared with 96,450 for UC. In total, 30% of UC and 20% of CD admissions were geriatric. Geriatric status was associated with higher odds of mortality for CD [odds ratio (OR)=3.47, 95% confidence interval (CI): 2.72-4.44] and UC (OR=2.75, 95% CI: 2.16-3.49) after adjustment for comorbidities, admission type, hospital type, inpatient surgery, and IBD subtype. The cause of death was ∼80% infectious in both CD and UC in all groups. An average of 0.19 days (95% CI: 0.05-0.34) and $2467 (95% CI: 545-4388) increase was seen for geriatric CD patients. No significant change was seen for UC., Conclusions: Age over 65 was independently associated with higher odds of death in both UC and CD patients, even after appropriate adjustment. Further research is needed to optimize care for this growing patient population., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: To evaluate the utility of a digital psychological self-assessment tool, MyHEARTSMAP (scores on 10 sections: home, education and activities, alcohol and drugs, relationships and bullying, thoughts and anxiety, safety, sexual health, mood, abuse, and professional resources), in youth presenting to the pediatric emergency department (ED) with a mental health concern., Study Design: We conducted a prospective cohort study in 2 tertiary care pediatric EDs from December 2017 to October 2019. Youth 10-17 years old triaged for a mental health concern were screened and enrolled to complete MyHEARTSMAP on a mobile device. A clinician blinded to the MyHEARTSMAP assessment conducted their own assessment which was used as the reference standard. Utility was quantified as the sensitivity and specificity of MyHEARTSMAP in detecting psychiatric, social, youth health, and functional concerns., Results: Among 379 eligible youth, 351 were approached and 233 (66.4%) families were enrolled. Sensitivity for youth MyHEARTSMAP self-assessments ranged from 87.4% in the youth health domain to 99.5% in the psychiatric domain for identifying any concern, and 33.3% in the social domain to 74.6% in the psychiatric domain for severe concerns. Specificity ranged from 66.7% in the psychiatric domain to 98.2% in the youth health domain for no or only mild concerns., Conclusions: Youth and guardian MyHEARTSMAP assessments are sensitive for detecting psychosocial concerns requiring follow-up beyond pediatric ED evaluation. Specificity for no or only mild concerns was high in the nonpsychiatric domains., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Advancements in microfluidic technologies have led to the development of many new tools for both the characterization and sorting of single cells without the need for exogenous labels. Label-free microfluidics reduce the preparation time, reagents needed, and cost of conventional methods based on fluorescent or magnetic labels. Furthermore, these devices enable analysis of cell properties such as mechanical phenotype and dielectric parameters that cannot be characterized with traditional labels. Some of the most promising technologies for current and future development toward label-free, single-cell analysis and sorting include electronic sensors such as Coulter counters and electrical impedance cytometry; deformation analysis using optical traps and deformation cytometry; hydrodynamic sorting such as deterministic lateral displacement, inertial focusing, and microvortex trapping; and acoustic sorting using traveling or standing surface acoustic waves. These label-free microfluidic methods have been used to screen, sort, and analyze cells for a wide range of biomedical and clinical applications, including cell cycle monitoring, rapid complete blood counts, cancer diagnosis, metastatic progression monitoring, HIV and parasite detection, circulating tumor cell isolation, and point-of-care diagnostics. Because of the versatility of label-free methods for characterization and sorting, the low-cost nature of microfluidics, and the rapid prototyping capabilities of modern microfabrication, we expect this class of technology to continue to be an area of high research interest going forward. New developments in this field will contribute to the ongoing paradigm shift in cell analysis and sorting technologies toward label-free microfluidic devices, enabling new capabilities in biomedical research tools as well as clinical diagnostics. This article is categorized under: Diagnostic Tools > Biosensing Diagnostic Tools > Diagnostic Nanodevices., (© 2018 Wiley Periodicals, Inc.)

Objective: We provide a brief review of the tumor microenvironment, the impact of six interventional radiology treatments on the tumor microenvironment, and potential methods to improve treatment efficacy., Conclusion: Interventional oncology plays a unique role in cancer therapy, contributing to both antitumorigenic and protumorigenic effects.

Purpose: Survival rates for individuals diagnosed with retinoblastoma (RB) exceed 95% in the United States; however, little is known about the long-term psychosocial outcomes of these survivors., Patients and Methods: Adult RB survivors, diagnosed from 1932 to 1994 and treated in New York, completed a comprehensive questionnaire adapted from the Childhood Cancer Survivor Study (CCSS), by mail or telephone. Psychosocial outcomes included psychological distress, anxiety, depression, somatization, fear of cancer recurrence, satisfaction with facial appearance, post-traumatic growth, and post-traumatic stress symptoms; noncancer CCSS siblings served as a comparison group., Results: A total of 470 RB survivors (53.6% with bilateral RB; 52.1% female) and 2,820 CCSS siblings were 43.3 (standard deviation [SD], 11) years and 33.2 (SD, 8.4) years old at the time of study, respectively. After adjusting for sociodemographic factors, RB survivors did not have significantly higher rates of depression, somatization, distress, or anxiety compared with CCSS siblings. Although RB survivors were more likely to report post-traumatic stress symptoms of avoidance and/or hyperarousal (both P < .01), only five (1.1%) of 470 met criteria for post-traumatic stress disorder. Among survivors, having a chronic medical condition did not increase the likelihood of psychological problems. Bilateral RB survivors were more likely than unilateral RB survivors to experience fears of cancer recurrence (P < .01) and worry about their children being diagnosed with RB (P < .01). However, bilateral RB survivors were no more likely to report depression, anxiety, or somatic complaints than unilateral survivors., Conclusion: Most RB survivors do not have poorer psychosocial functioning compared with a noncancer sample. In addition, bilateral and unilateral RB survivors seem similar with respect to their psychological symptoms., (© 2015 by American Society of Clinical Oncology.)

OBJECTIVES. To review the results of patching for amblyopia management in Hong Kong. DESIGN. Retrospective case series. SETTING. Regional hospital, Hong Kong. PATIENTS. Records of all patients attending Paediatric Ophthalmology Clinic at United Christian Hospital, Hong Kong from 1 January 2009 to 31 March 2009 were retrospectively reviewed. Records of all children who underwent patching for amblyopia in the study period were evaluated. RESULTS. The mean age of 50 children (50 eyes) was 4 (standard deviation, 1; range, 2-7) years and mean pretreatment visual acuity was 0.35 (0.15; 0.02-0.63) [~20/60]. The values for mean, standard deviation, and range of treatment duration were 27, 16, 4-67 months respectively, and corresponding values for prescribed patching per day were 4, 1, 2-8 hours. The mean, standard deviation, and range of visual acuity at final post-treatment assessment were 0.66, 0.16, 0.1-1.0 (~20/30), respectively. The overall success rate (ie final visual acuity >0.7 or 20/30) was 62%. Children with moderate amblyopia (20/40-20/80) and severe amblyopia (20/100-20/400) had success rates of 74% and 55%, respectively. The mean visual acuity improvements for moderate and severely amblyopic children were 2.3 lines and 5.8 lines, respectively. The mean, standard deviation, and range of patching prescriptions for moderate and severely amblyopic children were 5, 1, 2-7 hours and 5, 1, 3-6 hours, respectively. Recurrence ensued in 7% of the children with moderate amblyopia and 46% of those with severe amblyopia. Reported compliance was good (>75% of the time) in 68% of the children. CONCLUSION. Occlusion therapy is the mainstay of treatment in Hong Kong. The overall success rate was comparable to that achieved in the Amblyopia Treatment Study. Recurrence was more common in patients with severe amblyopia, for whom maintenance therapy may reduce the risk of recurrence. The duration of treatment was much longer in our locality than in western countries. Reported compliance was suspicious possibly due to traditional cultural contexts. It is important to emphasise compliance to all parents.

Germline mutations in mismatch repair genes predispose patients to Lynch Syndrome and the majority of these mutations have been detected in two key genes, MLH1 and MSH2. In particular, about a third of the missense variants identified in MLH1 are of unknown clinical significance. Using the PeakPicker software program, we have conducted a proof-of-principle study to investigate whether missense variants in MLH1 lead to allelic imbalances. Lymphocyte RNA extracted from patients harboring known MLH1 variants was used to quantify the ratio of variant to wild-type transcript, while patient lymphocyte DNA was used to establish baseline allelic expression levels. Our analysis indicated that the missense variants c.350C>T, c.793C>T, and c.1852&#95;1853AA>GC, as well as the truncating variant c.1528C>T were all associated with significantly unbalanced allelic expression. However, the variants c.55A>T and c.2246T>C did not demonstrate an allelic imbalance. These results illustrate a novel and efficient method to investigate the pathogenicity of unclassified genetic variants discovered in mismatch repair genes, as well as genes implicated in other inherited diseases. In addition, the PeakPicker methodology has the potential to be applied in the diagnostic setting, which, in conjunction with results from other assays, will help increase both the accuracy and efficiency of genetic testing of colorectal cancer, as well as other inherited diseases.