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Apigenin, a common plant flavonoid, has been shown to possess anti-tumor properties; however, the underlying molecular mechanisms are still not completely understood. In the present study, we investigated the effects of apigenin on human hepatoma Huh7 cell proliferation, cell cycle distribution, apoptosis, and colony formation in vitro, as well as on the tumorigenicity of Huh7 cells in vivo. To get more insight into the mechanism of apigenin action, we performed genome-wide expression profiling of apigenin-treated Huh7 cells using cDNA microarrays (Agilent Whole Human Genome Oligo Microarray) that contain 41,000 genes. Ten of the most differentially expressed genes (5-fold changes) were selected for further evaluation by quantitative RT-PCR (qPCR) and Western blot analyses. Notably, apigenin (5-20[mu]g/ml) remarkably inhibited Huh7 cell proliferation and colony formation as compared to the vehicle control, which was in a dose-dependent manner. Accompanying with the decreased growth, apigenin-treated cells showed a cell cycle arrest at G2/M phase and an increased rate of apoptosis. Moreover, the xenografts derived from Huh7 cells were significantly (p<0.05) retarded by the delivery of apigenin (50[mu]g/mouse/day) relative to the control counterparts. Gene expression profile analysis revealed that 1336 genes were up-regulated and 428 genes were down-regulated by apigenin. The down-regulation of interleukin-4 receptor and ubiquitin specific protease 18 and the up-regulation of SLC27A3 and chemokine (C-C motif) receptor 2 were further confirmed by the qPCR and Western blot results. In conclusion, apigenin exhibits inhibitory effects on hepatoma cell growth, which is likely mediated through alteration of gene expression profiles. [ABSTRACT FROM AUTHOR]

MORC family CW-type zinc finger 2 (MORC2) is a newly identified chromatin remodeling protein, and has been proposed as a prognostic biomarker associated with survival in some types of human cancer, but the role of MORC2 in cervical cancer remains unknown. Here, we investigated the role of MORC2 expression in predicting the survival outcomes of locally advanced cervical cancer patients treated with cisplatin-based concurrent chemoradiotherapy (CCRT). In this retrospectively study, we detected MORC2 immunohistochemical expression on 55 biopsies from patients who underwent CCRT. The association between the MORC2 expression and various clinicopathological characteristics were analyzed, as were association between MORC2 expression and locoregional failure and progression-free survival (PFS) of cervical cancer patients. MORC2 expression was positively associated with pelvic node metastasis and locoregional failure. Higher MORC2 expression was a significant indicator of worse PFS. Our results suggest that MORC2 expression may be a prognostic indicator in patients with locally advanced cervical cancer undergoing CCRT., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Stratification strategies for chemotherapy plus PD-1 inhibitors in advanced non-small-cell lung cancer (NSCLC) are critically demanded. We performed high-throughput panel-based deep next-generation sequencing and low-pass whole genome sequencing on prospectively collected circulating tumor DNA (ctDNA) specimens from 460 patients in the phase 3 CHOICE-01 study at different time points. We identified predictive markers for chemotherapy plus PD-1 inhibitor, including ctDNA status and genomic features such as blood-based tumor mutational burden, intratumor heterogeneity, and chromosomal instability. Furthermore, we established an integrated ctDNA-based stratification strategy, blood-based genomic immune subtypes (bGIS) scheme, to distinguish patients who benefit from the addition of PD-1 inhibitor to first-line chemotherapy. Moreover, we demonstrated potential applications for the dynamic monitoring of ctDNA. Overall, we proposed a potential therapeutic algorithm based on the ctDNA-based stratification strategy, shedding light on the individualized management of immune-chemotherapies for patients with advanced NSCLC., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To investigate the genetic subtypes and drug resistance monitoring of newly reported human immunodeficiency virus (HIV) infection/AIDS virus in Anhui Province from 2020 to 2023. Methods: An observational design study was used to collect blood samples from patients diagnosed with HIV/AIDS in the AIDS Prevention and Control Department of Anhui Provincial Center for Disease Control and Prevention from January 2020 to December 2023.The HIV-1 pol gene was amplified by reverse transcription-nested PCR, and the genetic subtypes were identified by phylogenetic tree analysis using MEGA 7.0 software. The mutation sites of drug resistance were analyzed by the online software tool of Stanford University's HIV Drug resistance database. The influencing factors of drug resistance before treatment were analyzed by multivariate logistic analysis. Results: A total of 335 plasma samples were collected, and 332 HIV-1 pol gene sequences were obtained successfully. The main gene subtypes were CRF01-AE, accounting for 35.55% (118/332), followed by CRF07-BC, B and B+C types [29.22% (97/332), 11.74% (39/332), 9.93% (33/332)]. The total drug resistance rate before treatment was 30.12%(32/100), and the drug resistance rate of protease inhibitor (PIs) in HIV-1 was 6.33% (21/332). The drug resistance rate of nucleoside reverse transcriptase inhibitors (NRTI) before treatment was 6.33% (21/332). The drug resistance rate of non-nucleoside reverse transcriptase inhibitors (NNRTI) before treatment was 17.47% (58/332).The comparison of drug resistance rate of different drug types showed statistical significance ( χ 2 =30.435, P <0.05).Among the 100 cases of drug resistance, the main mutation point of HIV-1 protease inhibitor was Q58E (21.00%), and the main mutation point of nucleoside reverse transcriptase inhibitor was M184V/I (6.00%). Non-nucleoside reverse transcriptase inhibitor resistance mutation points mainly K103N (22.00%).There were statistically significant differences in the starting time of antiviral therapy, the number of CD4 + T cells at baseline and the drug resistance rate of gene subtypes (the chi-square values are respectively 24.152, 32.516, 11.652, P <0.05).Multivariate logistic analysis showed that the baseline CD4 + T cell count was <200/μl, subtype B, subtype B+C, CRF01-AE subtype, CRF55-01B subtype and 01-BC subtype was the influential factor of drug resistance before treatment (the chi-square values are respectively 4.577, 8.202, 4.416, 5.206, 7.603 and 4.804, P <0.05). Conclusion: The newly reported HIV/AIDS population in Anhui Province from 2020 to 2023 has a variety of viral gene subtypes, and NNRTIs are the main types of drug resistance gene mutations before treatment. Attention should be paid to the number of baseline CD4 + T cells, the duration of antiviral treatment, and the distribution of gene subtypes to reduce the drug resistance of HIV/AIDS patients before treatment.

Objectives: The absence of predictive markers for kidney stone recurrence poses a challenge for the clinical management of stone disease. The unpredictability of stone events is also a significant limitation for clinical trials, where many patients must be enrolled to obtain sufficient stone events for analysis. In this study, we sought to use machine learning methods to identify a novel algorithm to predict stone recurrence. Subjects/Patients and Methods: Patients enrolled in the Registry for Stones of the Kidney and Ureter (ReSKU), a registry of nephrolithiasis patients collected between 2015-2020, with at least one prospectively collected 24-hour urine test (Litholink 24-hour urine test; Labcorp) were included in the training set. A validation set was obtained from chart review of stone patients not enrolled in ReSKU with 24-hour urine data. Stone events were defined as either an office visit where a patient reports symptomatic passage of stones or a surgical procedure for stone removal. Seven prediction classification methods were evaluated. Predictive analyses and receiver operator characteristics (ROC) curve generation were performed in R. Results: A training set of 423 kidney stone patients with stone event data and 24-hour urine samples were trained using the prediction classification methods. The highest performing prediction model was a Logistic Regression with ElasticNet machine learning model (area under curve [AUC] = 0.65). Restricting analysis to high confidence predictions significantly improved model accuracy (AUC = 0.82). The prediction model was validated on a validation set of 172 stone patients with stone event data and 24-hour urine samples. Prediction accuracy in the validation set demonstrated moderate discriminative ability (AUC = 0.64). Repeat modeling was performed with four of the highest scoring features, and ROC analyses demonstrated minimal loss in accuracy (AUC = 0.63). Conclusion: Machine-learning models based on 24-hour urine data can predict stone recurrences with a moderate degree of accuracy.

Genome structural variations within species are rare. How selective constraints preserve gene order and chromosome structure is a central question in evolutionary biology that remains unsolved. Our sequencing of several genomes of the appendicularian tunicate Oikopleura dioica around the globe reveals extreme genome scrambling caused by thousands of chromosomal rearrangements, although showing no obvious morphological differences between these animals. The breakpoint accumulation rate is an order of magnitude higher than in ascidian tunicates, nematodes, Drosophila, or mammals. Chromosome arms and sex-specific regions appear to be the primary unit of macrosynteny conservation. At the microsyntenic level, scrambling did not preserve operon structures, suggesting an absence of selective pressure to maintain them. The uncoupling of the genome scrambling with morphological conservation in O. dioica suggests the presence of previously unnoticed cryptic species and provides a new biological system that challenges our previous vision of speciation in which similar animals always share similar genome structures., (© 2024 Plessy et al.; Published by Cold Spring Harbor Laboratory Press.)

Accurate spectroscopic data of carbon dioxide are widely used in many important applications, such as carbon monitoring missions. Here, we present comb-locked cavity ring-down saturation spectroscopy of the second most abundant isotopologue of CO 2 , 13 C 16 O 2 . We determined the positions of 88 lines in three vibrational bands in the 1.6 μm region, 30011e/30012e/30013e-00001e, with an accuracy of a few kHz. Based on the analysis of combination differences, we obtained for the first time the ground-state rotational energies with kHz accuracy. We also provide a set of hybrid line positions for 150 13 C 16 O 2 transitions. The rotational energies ( J < 50) in the 30013e vibrational state can be fitted by a set of rotational and centrifugal constants with deviations within a few kHz, indicating that the 30013e state is free of perturbations. These precise isotopic line positions will be utilized to improve the Hamiltonian model and quantitative remote sensing of carbon dioxide. Moreover, they will help to track changes in the carbon source and sink through isotopic analysis.

Background: Patient engagement attrition in mobile health (mHealth) remote patient monitoring (RPM) programs decreases program benefits. Systemic disparities lead to inequities in RPM adoption and use. There is an urgent need to understand patients' experiences with RPM in the real world, especially for patients who have stopped using the programs, as addressing issues faced by patients can increase the value of mHealth for patients and subsequently decrease attrition., Objective: This study sought to understand patient engagement and experiences in an RPM mHealth intervention in lung transplant recipients., Methods: Between May 4, 2020, and November 1, 2022, a total of 601 lung transplant recipients were enrolled in an mHealth RPM intervention to monitor lung function. The predictors of patient engagement were evaluated using multivariable logistic and linear regression. Semistructured interviews were conducted with 6 of 39 patients who had engaged in the first month but stopped using the program, and common themes were identified., Results: Patients who underwent transplant more than 1 year before enrollment in the program had 84% lower odds of engaging (odds ratio [OR] 0.16, 95% CI 0.07-0.35), 82% lower odds of submitting pulmonary function measurements (OR 0.18, 95% CI 0.09-0.33), and 78% lower odds of completing symptom checklists (OR 0.22, 95% CI 0.10-0.43). Patients whose primary language was not English had 78% lower odds of engaging compared to English speakers (OR 0.22, 95% CI 0.07-0.67). Interviews revealed 4 prominent themes: challenges with devices, communication breakdowns, a desire for more personal interactions and specific feedback with the care team about their results, understanding the purpose of the chat, and understanding how their data are used., Conclusions: Care delivery and patient experiences with RPM in lung transplant mHealth can be improved and made more equitable by tailoring outreach and enhancements toward non-English speakers and patients with a longer time between transplant and enrollment. Attention to designing programs to provide personalization through supplementary provider contact, education, and information transparency may decrease attrition rates., (©Andrew W Liu, William Brown, III, Ndubuisi E Madu, Ali R Maiorano, Olivia Bigazzi, Eli Medina, Christopher Sorric, Steven R Hays, Anobel Y Odisho. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 20.03.2024.)

Background: In many large health centers, patients face long appointment wait times and difficulties accessing care. Last-minute cancellations and patient no-shows leave unfilled slots in a clinician's schedule, exacerbating delays in care from poor access. The mismatch between the supply of outpatient appointments and patient demand has led health systems to adopt many tools and strategies to minimize appointment no-show rates and fill open slots left by patient cancellations., Objective: We evaluated an electronic health record (EHR)-based self-scheduling tool, Fast Pass, at a large academic medical center to understand the impacts of the tool on the ability to fill cancelled appointment slots, patient access to earlier appointments, and clinical revenue from visits that may otherwise have gone unscheduled., Methods: In this retrospective cohort study, we extracted Fast Pass appointment offers and scheduling data, including patient demographics, from the EHR between June 18, 2022, and March 9, 2023. We analyzed the outcomes of Fast Pass offers (accepted, declined, expired, and unavailable) and the outcomes of scheduled appointments resulting from accepted Fast Pass offers (completed, canceled, and no-show). We stratified outcomes based on appointment specialty. For each specialty, the patient service revenue from appointments filled by Fast Pass was calculated using the visit slots filled, the payer mix of the appointments, and the contribution margin by payer., Results: From June 18 to March 9, 2023, there were a total of 60,660 Fast Pass offers sent to patients for 21,978 available appointments. Of these offers, 6603 (11%) were accepted across all departments, and 5399 (8.9%) visits were completed. Patients were seen a median (IQR) of 14 (4-33) days sooner for their appointments. In a multivariate logistic regression model with primary outcome Fast Pass offer acceptance, patients who were aged 65 years or older (vs 20-40 years; P=.005 odds ratio [OR] 0.86, 95% CI 0.78-0.96), other ethnicity (vs White; P<.001, OR 0.84, 95% CI 0.77-0.91), primarily Chinese speakers (P<.001; OR 0.62, 95% CI 0.49-0.79), and other language speakers (vs English speakers; P=.001; OR 0.71, 95% CI 0.57-0.87) were less likely to accept an offer. Fast Pass added 2576 patient service hours to the clinical schedule, with a median (IQR) of 251 (216-322) hours per month. The estimated value of physician fees from these visits scheduled through 9 months of Fast Pass scheduling in professional fees at our institution was US $3 million., Conclusions: Self-scheduling tools that provide patients with an opportunity to schedule into cancelled or unfilled appointment slots have the potential to improve patient access and efficiently capture additional revenue from filling unfilled slots. The demographics of the patients accepting these offers suggest that such digital tools may exacerbate inequities in access., (©Smitha Ganeshan, Andrew W Liu, Anne Kroeger, Prerna Anand, Richard Seefeldt, Alexis Regner, Diana Vaughn, Anobel Y Odisho, Michelle Mourad. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 19.03.2024.)

Introduction: Metropolitan governance's efficacy is regularly gauged by its capability for public health preparedness, a critical component, particularly in the post-pandemic climate, as global cities reassess their mitigation abilities. This process has broader implications, curbing mortality rates and amplifying sustainability. Current methodologies for preparedness assessment lean primarily on either Subjective Evaluation-Based Assessment (SBA), predicated on experts' input on various capacity indicators, or they opt for Data-Based quantitative Assessments (DBA), chiefly utilizing public statistic data., Methods: The manuscript discusses an urgent need for integrating both SBA and DBA to adequately measure Metropolitan Public Health Pandemics Preparedness (MPHPP), thus proposing a novel entropy-TOPSIS-IF model for comprehensive evaluation of MPHPP. Within this proposed model, experts' subjective communication is transformed into quantitative data via the aggregation of fuzzy decisions, while objective data is collected from public statistics sites. Shannon's entropy and TOPSIS methods are enacted on these data sets to ascertain the optimal performer after normalization and data isotropy., Results and Discussion: The core contribution of the entropy-TOPSIS-IF model lies in its assessment flexibility, making it universally applicable across various contexts, regardless of the availability of expert decisions or quantitative data. To illustrate the efficacy of the entropy-TOPSIS-IF model, a numerical application is presented, examining three Chinese metropolises through chosen criteria according to the evaluations of three experts. A sensitivity analysis is provided to further affirm the stability and robustness of the suggested MPHPP evaluation model., Competing Interests: The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Liu, Li, Li, Luo and Chen.)

Competing Interests: Supported by the National Institutes of Health T32 grant number 5T32AI007044 (WTY). The authors do not declare financial conflicts of interest. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding source had no role in the creation of this article.

Background: Providing timely peri-procedural education, reminders, and check-ins can improve patient adherence and clinical outcomes. We sought to retrospectively evaluate the impact of a peri-procedural digital health tool on emergency department (ED) visits and readmissions., Methods: A digital health tool for peri-procedural care engaged patients at scheduled intervals, resulting in an overall engagement score. Multivariate models determined predictors of tool engagement and post-procedural 30- and 90-day rehospitalizations and ED visits., Results: 11,737 unique completed procedures were analyzed from 10,438 patients. Patients of Black and Latinx race/ethnicity (vs White), those with Medicare and Medicaid insurance (vs commercial), and those with non-activated patient portals (vs activated) were less likely to engage. After adjustment for confounders, higher engagement with the tool was associated with lower rates of 30-day hospitalizations (OR 0.64), 90-day hospitalizations (OR 0.65), and 90-day ED visits (OR 0.77)., Conclusions: Highly engaged patients had fewer 30-day and 90-day ED visit and readmissions, even after adjustment for key confounders. Engagement, and thus the resulting benefits, were not equitably distributed., Competing Interests: Declaration of competing interest All authors declare that they have no conflict of interest regarding the material presented in this manuscript. All authors declare that they approve submission of the final article., (Copyright © 2023. Published by Elsevier Inc.)

Background: Inflammatory bowel disease (IBD) is a chronic condition that requires close monitoring. Digital health virtual care platforms can enable self-monitoring and allow providers to remotely surveil patients and efficiently identify those with active disease., Objectives: The primary aim was to design and implement an IBD remote monitoring program, identify predictors of patient engagement, and determine who found the chat to be a valuable tool., Methods: We developed the IBD Virtual Care Chat, an electronic health record (EHR)-integrated chat to monitor electronic patient reported outcomes (ePROs), medication changes, and disease activity, and subsequently report concerning findings to providers via the EHR. All patients in the IBD practice over age 18 with a clinical encounter in the preceding 12 months were eligible to be enrolled. The primary aim was to identify predictors of patient engagement and determine who found the chat to be a valuable tool., Results: Between May 2021 and March 2022, 2,934 patients were enrolled. A total of 1,160 engaged at least once and 687 (23.4%) continually engaged, submitting at least three ePROs. Disease severity (based on Harvey-Bradshaw Index or Simple Clinical Colitis Activity Index) did not impact ePRO submissions. Patients were significantly more likely to be continually engaged if they self-reported the presence of extraintestinal manifestations (7%, 95% confidence interval: 0.01-0.14; p  = 0.04). Patient satisfaction remained moderately high with a median score of 8 (interquartile range: 5-10) on a scale of 1 (poor) to 10 (good)., Conclusion: Our program demonstrates the potential for EHR-integrated digital health as part of routine IBD care to achieve sustained engagement with high patient satisfaction., Competing Interests: A.Y.O. was a consultant for VSee, LLC and obtained research support from Pfizer, Microsoft Research, Hatchleaf.ai; U.M. was a consultant for Abbvie, Janssen, BMS, Takeda, Pfizer, Lilly, Gilead, Arena, Prometheus Biosciences, Protagonist, Boehringer Ingelheim. The other authors report no conflict of interest., (Thieme. All rights reserved.)

Background: We developed an automated, chat-based, digital health intervention using Bluetooth-enabled home spirometers to monitor for complications of lung transplantation in a real-world application., Methods: A chat-based application prompted patients to perform home spirometry, enter their forced expiratory volume in 1 second (FEV 1 ), answer symptom queries, and provided patient education. The program alerted patients and providers to substantial FEV 1 decreases and concerning symptoms. Data was integrated into the electronic health record (EHR) system and dashboards were developed for program monitoring., Result: Between May 2020 and December 2021, 544 patients were invited to enroll, of whom 427 were invited remotely and 117 were enrolled in-person. 371 (68%) participated by submitting ≥1 FEV 1 values. Overall engagement was high, with an average of 197 unique patients submitting FEV 1 data per month. In-person enrollees submitted an average of 4.6 FEV 1 values per month and responded to 55% of scheduled chats. Home and laboratory FEV 1 values correlated closely (rho = 0.93). There was an average of 133 ± 59 FEV 1 decline alerts and 59 ± 23 symptom alerts per month. 72% of patients accessed education modules, and the program had a high net promoter score (53) amongst users., Conclusions: We demonstrate that a novel, automated, chat-based, and EHR-integrated home spirometry intervention is well accepted, generates reliable assessments of graft function, and can deliver automated feedback and education resulting in moderately-high adherence rates. We found that in-person onboarding yields better engagement and adherence. Future work will aim to demonstrate the impact of remote care monitoring on early detection of lung transplant complications., Competing Interests: Disclosure statement This study was support by UCSF Digital Patient Experience Program., (Copyright © 2023. Published by Elsevier Inc.)

Objective: Anti-angiogenic therapy has proven effective in non-small-cell lung cancer (NSCLC) patients. The purpose of this study was to evaluate the efficacy of programmed cell death protein 1 (PD-1) inhibitors combined with anti-angiogenic therapy in patients with driver gene mutation negative NSCLC and brain metastases (BMs)., Methods: A retrospective analysis was performed on NSCLC BMs in patients without driver gene mutations who received PD-1 inhibitors. Two groups, receiving either PD-1 inhibitor monotherapy or PD-1 inhibitor plus anti-angiogenesis therapy, were identified. The primary endpoints were overall survival (OS) and intracranial progression-free survival (iPFS). The secondary endpoints were safety, intracranial objective response rate (iORR) and intracranial disease control rate (iDCR)., Results: 113 NSCLC patients were included, 51 (45.1%) in the PD-1 inhibitor monotherapy group and 62 (54.9%) in the PD-1 inhibitor plus anti-angiogenesis therapy group. The median follow-up time was 26.2 months. OS was higher in the combination therapy cohort than in the monotherapy cohort (OS: 21.4 vs . 11.8 months; p = 0.004), with no significant difference in iPFS ( p = 0.088). Moreover, the PD-1 inhibitor + anti-angiogenic therapeutic regimen exhibited the preferred iDCR ( p = 0.005) but not the iORR ( p = 0.121). There was no significant difference in the incidence of grade 3-4 adverse events between the two groups. In multivariate Cox regression analysis, PD-1 inhibitor therapy combined with anti-angiogenic treatment ( p = 0.003) was an independent prognostic indicator of OS., Conclusions: Combining PD-1 inhibitor therapy with anti-angiogenic treatment significantly improves the OS of driver gene mutation negative NSCLC patients with BMs., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s). Published by Discovery Medicine.)

The skin is a barrier organ populated by many types of skin-resident immune cells and sensory neurons. It has become increasingly appreciated that neuroimmune interactions are an important component of inflammatory diseases such as atopic dermatitis and allergic contact dermatitis. Neuropeptides secreted from nerve terminals play an important role in mediating cutaneous immune cell function, and soluble mediators derived from immune cells interact with neurons to induce itch. In this review article, we will explore emerging research describing neuronal effector functions on skin immune cells in mouse models of atopic and contact dermatitis. We will also discuss the contributions of both specific neuronal subsets and secreted immune factors to itch induction and the associated inflammatory processes. Finally, we will explore how treatment strategies have emerged around these findings and discuss the relationship between scratching and dermatitis., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Accurate and sensitive detection of multicomponent trace gases below the parts-per-million (ppm) level is needed in a variety of medical, industrial, and environmental applications. Raman spectroscopy can identify multiple molecules in the sample simultaneously and has excellent potential for fast diagnosis of various samples, but applications are often limited by its sensitivity. In this contribution, we report the development of a cavity-enhanced Raman spectroscopy instrument using a narrow-line width 532 nm laser locked with a high-finesse cavity through a Pound-Drever-Hall locking servo, which allows continuous measurement in a broad spectral range. An intracavity laser power of up to 1 kW was achieved with an incident laser power of about 240 mW, resulting in a significant enhancement of the Raman signal in the range of 200-5000 cm -1 and a sub-ppm sensitivity for various molecules. The technique is applied in the detection of different samples, including ambient air, natural gas, and reference gas of sulfur hexafluoride, demonstrating its capability for the quantitative measurement of various trace components.

Information about molecular collisions is encoded in the shapes of collision-perturbed molecular resonances. This connection between molecular interactions and line shapes is most clearly seen in simple systems, such as the molecular hydrogen perturbed by a noble gas atom. We study the H 2 -Ar system by means of highly accurate absorption spectroscopy and ab initio calculations. On the one hand, we use the cavity-ring-down-spectroscopy technique to record the shapes of the S(1) 3-0 line of molecular hydrogen perturbed by argon. On the other hand, we simulate the shapes of this line using ab initio quantum-scattering calculations performed on our accurate H 2 -Ar potential energy surface (PES). In order to validate the PES and the methodology of quantum-scattering calculations separately from the model of velocity-changing collisions, we measured the spectra in experimental conditions in which the influence of the latter is relatively minor. In these conditions, our theoretical collision-perturbed line shapes reproduce the raw experimental spectra at the percent level. However, the collisional shift, δ 0 , differs from the experimental value by 20%. Compared to other line-shape parameters, collisional shift displays much higher sensitivity to various technical aspects of the computational methodology. We identify the contributors to this large error and find the inaccuracies of the PES to be the dominant factor. With regard to the quantum scattering methodology, we demonstrate that treating the centrifugal distortion in a simple, approximate manner is sufficient to obtain the percent-level accuracy of collisional spectra.

Purpose: The CHOICE-01 study investigated the efficacy and safety of toripalimab in combination with chemotherapy as a first-line treatment for advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: Patients (N = 465) with treatment-naive, advanced NSCLC without EGFR/ALK mutations were randomly assigned 2:1 to receive toripalimab 240 mg (n = 309) or placebo (n = 156) once every 3 weeks in combination with chemotherapy for 4-6 cycles, followed by the maintenance of toripalimab or placebo once every 3 weeks plus standard care. Stratification factors included programmed death ligand-1 expression status, histology, and smoking status. The primary end point was progression-free survival (PFS) by investigator per RECIST v1.1. Secondary end points included overall survival and safety., Results: At the final PFS analysis, PFS was significantly longer in the toripalimab arm than in the placebo arm (median PFS, 8.4 v 5.6 months, hazard ratio = 0.49; 95% CI, 0.39 to 0.61; two-sided P < .0001). At the interim OS analysis, the toripalimab arm had a significantly longer OS than the placebo arm (median OS not reached v 17.1 months, hazard ratio = 0.69; 95% CI, 0.53 to 0.92; two-sided P = .0099). The incidence of grade ≥ 3 adverse events was similar between the two arms. Treatment effects were similar regardless of programmed death ligand-1 status. Genomic analysis using whole-exome sequencing from 394 available tumor samples revealed that patients with high tumor mutational burden were associated with significantly better PFS in the toripalimab arm (median PFS 13.1 v 5.5 months, interaction P = .026). Notably, patients with mutations in the focal adhesion-PI3K-Akt signaling pathway achieved significantly better PFS and OS in the toripalimab arm (interaction P values ≤ .001)., Conclusion: Toripalimab plus chemotherapy significantly improves PFS and OS in patients with treatment-naive advanced NSCLC while having a manageable safety profile. Subgroup analysis showed the OS benefit was mainly driven by the nonsquamous subpopulation.

Objective: The utilization of video telemedicine has dramatically increased due to the COVID-19 pandemic. However, significant social and technological barriers have led to disparities in access. We aimed to identify factors associated with patient inability to successfully initiate a video visit across a high-volume urologic practice., Materials and Methods: Video visit completion rates and patient characteristics were extracted from the electronic medical record and linked with census-level socioeconomic data. Associations between video visit failure were identified using multivariate regression modeling and random forest ensemble classification modeling., Results: Six thousand eighty six patients and their first video visits were analyzed. On multivariate logistic regression analysis, Hispanic or Latino patients (OR 0.52, 95%CI 0.31-0.89), patients insured by Medicare (OR 0.46, 95%CI 0.26-0.79) or Medicaid (OR 0.50, 95%CI 0.29-0.87), patients of low socioeconomic status (OR 0.98, 95%CI 0.98-0.99), patients with an un-activated MyChart patient portal (OR 0.43, 95%CI 0.29-0.62), and patients unconfirmed at appointment reminder (OR 0.68, 95%CI 0.48-0.96) were significantly associated with video visit failure. Patients with primary diagnosis category of men's health (OR 47.96, 95%CI 10.24-856.35), and lower urinary tract syndromes (OR 2.69, 95%CI 1.66-4.51) were significantly associated with video visit success. Random forest analyses identified insurance status and socioeconomic status as the top predictors of video visit failure., Conclusion: An analysis of a urology video telemedicine cohort reveals clinical and demographic disparities in video visit completion and priorities for future interventions to ensure equity of access. Our study further suggests that specific urologic indications may play a role in success or failure of video visits., (Published by Elsevier Inc.)

Narrow optical resonances of atoms or molecules have immense significance in various precision measurements, such as testing fundamental physics and the generation of primary frequency standards. In these studies, accurate transition centers derived from fitting the measured spectra are demanded, which critically rely on the knowledge of spectral line profiles. Here, we propose a new mechanism of Fano-like resonance induced by distant discrete levels and experimentally verify it with Doppler-free spectroscopy of vibration-rotational transitions of CO&#95;{2}. The observed spectrum has an asymmetric profile and its amplitude increases quadratically with the probe laser power. Our results facilitate a broad range of topics based on narrow transitions.

Background: Symptom checkers have been widely used during the COVID-19 pandemic to alleviate strain on health systems and offer patients a 24-7 self-service triage option. Although studies suggest that users may positively perceive web-based symptom checkers, no studies have quantified user feedback after use of an electronic health record-integrated COVID-19 symptom checker with self-scheduling functionality., Objective: In this paper, we aimed to understand user experience, user satisfaction, and user-reported alternatives to the use of a COVID-19 symptom checker with self-triage and self-scheduling functionality., Methods: We launched a patient-portal-based self-triage and self-scheduling tool in March 2020 for patients with COVID-19 symptoms, exposures, or questions. We made an optional, anonymous Qualtrics survey available to patients immediately after they completed the symptom checker., Results: Between December 16, 2021, and March 28, 2022, there were 395 unique responses to the survey. Overall, the respondents reported high satisfaction across all demographics, with a median rating of 8 out of 10 and 288/395 (47.6%) of the respondents giving a rating of 9 or 10 out of 10. User satisfaction scores were not associated with any demographic factors. The most common user-reported alternatives had the web-based tool not been available were calling the COVID-19 telephone hotline and sending a patient-portal message to their physician for advice. The ability to schedule a test online was the most important symptom checker feature for the respondents. The most common categories of user feedback were regarding other COVID-19 services (eg, telephone hotline), policies, or procedures, and requesting additional features or functionality., Conclusions: This analysis suggests that COVID-19 symptom checkers with self-triage and self-scheduling functionality may have high overall user satisfaction, regardless of user demographics. By allowing users to self-triage and self-schedule tests and visits, tools such as this may prevent unnecessary calls and messages to clinicians. Individual feedback suggested that the user experience for this type of tool is highly dependent on the organization's operational workflows for COVID-19 testing and care. This study provides insight for the implementation and improvement of COVID-19 symptom checkers to ensure high user satisfaction., (©Andrew W Liu, Anobel Y Odisho, William Brown III, Ralph Gonzales, Aaron B Neinstein, Timothy J Judson. Originally published in JMIR Human Factors (https://humanfactors.jmir.org), 13.09.2022.)

Introduction: Tebentafusp is a novel bispecific immune mobilizing T cell receptor (TCR)-based agent developed for the treatment of metastatic uveal melanoma, a highly fatal disease with no currently approved treatment options. Recent evidence suggests this drug may become the standard of care for first-line treatment of metastatic uveal melanoma., Areas Covered: This review focuses on the development and investigation of tebentafusp for metastatic uveal melanoma. First, we discuss preclinical studies followed by clinical evaluation, culminating in a phase III trial showing improved overall survival with tebentafusp compared to standard of care. Finally, we expand upon key toxicities of tebentafusp and highlight biomarkers that may correlate with drug efficacy., Expert Opinion: Tebentafusp provides a promising advancement to date for the management of metastatic uveal melanoma. Future studies should aim at identifying biomarkers that can predict treatment response or toxicity, combination therapy, application of tebentafusp in the adjuvant setting to reduce the risk of recurrence, and development of bispecifics with activity in other HLA subtypes. With its novel mechanism of action, degree of efficacy and safety profile, tebentafusp is expected to change the standard of care for treating metastatic and, potentially localized, uveal melanoma.

Background : Automation has increasingly become more commonplace in the research laboratory workspace. The introduction of articulated robotic arms allows the researcher more flexibility in the tasks a single piece of automated machinery can perform. We set out to incorporate automation in processing of genomic DNA organic extractions to increase throughput and limit researchers to the exposure of organic solvents. Methods : In order to automate the genome sequencing pipeline in our laboratory, we programmed a dual-arm anthropomorphic robot, the Robotic Biology Institute's Maholo LabDroid, to perform organic solvent-based genomic DNA extraction from cell lysates. To the best of our knowledge, this is the first time that automation of phenol-chloroform extraction has been reported. Results: We achieved routine extraction of high molecular weight genomic DNA (>100 kb) from diverse biological samples including algae cultured in sea water, bacteria, whole insects, and human cell lines. The results of pulse-field electrophoresis size analysis and the N50 sequencing metrics of reads obtained from Nanopore MinION runs verified the presence of intact DNA suitable for direct sequencing. Conclusions : We present the workflow that can be used to program similar robots and discuss the problems and solutions we encountered in developing the workflow. The protocol can be adapted to analogous methods such as RNA extraction, and there is ongoing work to incorporate further post-extraction steps such as library construction. This work shows the potential for automated robotic workflows to free molecular biological researchers from manual interventions in routine experimental work. A time-lapse movie of the entire automated run is included in this report., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Liu AW et al.)

The (30012) ← (00001) band of 12 C 16 O 2 in the 1.6 μm region is used for satellite observation of carbon dioxide in the Earth's atmosphere. Here, we report a Doppler-free spectroscopy study of this band with comb-locked wavelength-modulated cavity-enhanced absorption spectroscopy. Frequencies of 18 transitions with the rotational quantum numbers up to 42 were determined with sub-kHz accuracy, corresponding to a fractional uncertainty at the 10 -12 level. With this precision, we revealed an anomalous decrease of the line shift and an increase of the line broadening for the Lamb dips of CO 2 in the low-pressure regime compared to values obtained from Doppler-limited spectra at higher pressures.

Objective: Rearranged during transfection genes are present in 1-2% of patients who have non-small cell lung cancer and 10-30% of patients with papillary thyroid cancer. The objective of this article is to review the current rearranged during transfection inhibitors indicated for patients with rearranged during transfection-mutated cancers and their future directions. Data sources: The pivotal phase I/II studies for selpercatinib and pralsetinib were evaluated. Current studies on rearranged during transfection inhibitors were searched on ClinicalTrials.gov using the key word "RET." Data summary: Selpercatinib and pralsetinib were the first two U.S. Food and Drug Administration-approved rearranged during transfection-selective inhibitors for advanced or metastatic rearranged during transfection fusion-positive non-small cell lung cancer, rearranged during transfection-mutant medullary thyroid cancer, and rearranged during transfection fusion-positive thyroid cancer. Both agents showed promising efficacy with objective response rate ranging from 60% to 73% in all aforementioned rearranged during transfection-mutated cancers. Additionally, benefits were seen even in patients with intracranial metastasis at baseline. Both showed favorable safety profiles. Some common class adverse events included elevated liver function tests and hypertension. Hematologic side effects such as anemia and neutropenia were more common with pralsetinib. Selpercatinib had interactions with acid suppressive therapy and specific instructions when used concomitantly., Conclusions: While the rearranged during transfection inhibitors are generally well-tolerated, each agent possesses slightly different efficacy, side-effect profile, and drug-drug interactions.

Interactions between a molecule and two or more laser fields are of great interest in various studies, but weak and highly overlapping transitions hinder precision measurements. We present the method of comb-locked cavity-assisted double resonance spectroscopy based on narrow-linewidth continuous-wave lasers, which allows for state-selective pumping and probing of molecules. By locking two near-infrared diode lasers to one cavity with a finesse at the order of 10 5 , we measured all three types of double resonances. Carbon monoxide molecules with selected speeds along the laser beam were excited to vibrationally excited states, and absorption spectra with sub-MHz linewidths were observed. Positions of double resonance transitions were determined with an accuracy of 3.7 kHz, which was verified by comparing to Lamb-dip measurements. The present work paves the way to the pump-probe study of highly excited molecules with unprecedented precision.

Background: The larvacean Oikopleura dioica is an abundant tunicate plankton with the smallest (65-70 Mbp) non-parasitic, non-extremophile animal genome identified to date. Currently, there are two genomes available for the Bergen (OdB3) and Osaka (OSKA2016) O. dioica laboratory strains. Both assemblies have full genome coverage and high sequence accuracy. However, a chromosome-scale assembly has not yet been achieved., Results: Here, we present a chromosome-scale genome assembly (OKI2018&#95;I69) of the Okinawan O. dioica produced using long-read Nanopore and short-read Illumina sequencing data from a single male, combined with Hi-C chromosomal conformation capture data for scaffolding. The OKI2018&#95;I69 assembly has a total length of 64.3 Mbp distributed among 19 scaffolds. 99% of the assembly is contained within five megabase-scale scaffolds. We found telomeres on both ends of the two largest scaffolds, which represent assemblies of two fully contiguous autosomal chromosomes. Each of the other three large scaffolds have telomeres at one end only and we propose that they correspond to sex chromosomes split into a pseudo-autosomal region and X-specific or Y-specific regions. Indeed, these five scaffolds mostly correspond to equivalent linkage groups in OdB3, suggesting overall agreement in chromosomal organization between the two populations. At a more detailed level, the OKI2018&#95;I69 assembly possesses similar genomic features in gene content and repetitive elements reported for OdB3. The Hi-C map suggests few reciprocal interactions between chromosome arms. At the sequence level, multiple genomic features such as GC content and repetitive elements are distributed differently along the short and long arms of the same chromosome., Conclusions: We show that a hybrid approach of integrating multiple sequencing technologies with chromosome conformation information results in an accurate de novo chromosome-scale assembly of O. dioica's highly polymorphic genome. This genome assembly opens up the possibility of cross-genome comparison between O. dioica populations, as well as of studies of chromosomal evolution in this lineage.

Background: Leptomeningeal metastasis (LM) is associated with poor prognosis in non-small cell lung cancer (NSCLC). The aim of this study was to investigate the efficacy and safety of osimertinib combined with bevacizumab for LM from epidermal growth factor receptor mutation (EGFRm) NSCLC., Methods: We conducted a phase II single-arm prospective clinical trial of EGFRm NSCLC with LM treated with osimertinib combined with bevacizumab. LM response assessment was based on the modified RANO LM radiological criteria; CNS and extra-CNS response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The primary end points included LM progression-free survival (PFS) and objective response rate (ORR); the secondary end points included safety and LM overall survival (OS)., Results: A total of 14 patients were included in the study, with a median age of 61 years, and they were predominantly female (64%). EGFR mutations were reported in exons 19 del (n = 7) and 21 L858R (n = 7). When LM was diagnosed, 12 (85.7%) patients had clinical symptoms, 71.4% (10/14) of patients were diagnosed with LM by cytology, and five (35.7%) patients had a performance status (PS) score > 2. The median LM PFS was 9.3 months (95% CI: 8.2-10.4), and the LM ORR was 50%. The safety findings in the present study were consistent with the known profile of osimertinib with bevacizumab; the median LM OS was 12.6 months, and the one-year survival rate was 35.7%., Conclusions: Osimertinib combined with bevacizumab is an appropriate treatment option for patients with LM from EGFRm NSCLC., Key Points: SIGNIFICANT FINDINGS OF THE STUDY: To date, there is no prospective clinical study on the treatment of osimertinib combined with bevacizumab in EGFRm NSCLC with LM., What This Study Adds: The median LM PFS was 9.3 months (95% CI: 8.2-10.4), and the LM ORR was 50%, the median LM OS was 12.6 months, and the one-year survival rate was 35.7%. Osimertinib combined with bevacizumab is an appropriate treatment option for patients with LM from EGFRm NSCLC., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Selective pumping and probing of highly excited states of molecules are essential in various studies but are also challenging because of high density of states, weak transition moments, and lack of precise spectroscopy data. We develop a comb-locked cavity-assisted double-resonance spectroscopy (COCA-DR) method for precision measurements using low-power continuous-wave lasers. A high-finesse cavity locked with an optical frequency comb is used to enhance both the pumping power and the probing sensitivity. As a demonstration, Doppler-free stepwise two-photon absorption spectra of CO 2 were recorded by using two milliwatt diode lasers (1.60 and 1.67 μm), and the rotation energies in a highly excited state (CO-stretching quanta = 8) were determined with an unprecedented accuracy of a few kilohertz.

Background: Patients newly diagnosed with lung adenocarcinoma with bone metastases (LABM) have poor survival rates after treatment with conventional therapies. To improve outcomes, we retrospectively investigated whether the application of a more comprehensive genetic test of tumor biopsies samples from LABM patients could provide the basis for treatment with more effective tyrosine kinase inhibitors (TKIs) regimens., Methods: Fine needle biopsies were taken from the primary tumor (PT) and a secondary bone metastasis (BM) of 17 LABM patients before treatment. Simple genetic profiles for selecting therapies were initially obtained using an ARMS-PCR test for EGFR and ALK fusion mutations. More detailed genetic profiles of somatic exon SNVs and CNVs in 457 cancer-related genes were retrospectively derived using capture single molecule amplification and resequencing technology (capSMART)., Results: ARMS-PCR identified 14 EGFR positive, 3 EGFR negative and 1 ALK fusion positive patient. A therapy regimen incorporating TKIs Gefitinib and Crizotinib was offered to the EGFR and ALK fusion positive patients, respectively. With the exception of two patients, molecular profiling of matching PT and BM biopsies identified a highly shared somatic variant fingerprint, although the BMs exhibited additional genomic instability. In six of 13 EGFR positive patients and in all three EGFR negative patients, examination of the genetic profiles identified additional clinically significant mutations that are known or experimental drug targets for treatment of lung cancer., Conclusion: Our findings firstly suggest that treatment regimens based on comprehensive genetic assessment of newly diagnosed LABM patients should target both the PT and secondary BMs, including rogue clones with potential to form new BMs. Second, the additional information gained should allow clinicians to design and implement more personalized treatment regimens and potentially improve outcomes for LABM patients.

Spectroscopy of molecules in the mid-infrared (MIR) region has important applications in various fields, such as astronomical observation, environmental detection, and fundamental physics. However, compared to that in the near-infrared, precision spectroscopy in the MIR is often limited by the light source and has not shown full potential in sensitivity. Here we report a cavity ring-down spectroscopy system using a tunable narrow-linewidth optical parametric oscillator, which fulfills the requirement of high sensitivity and high precision in the MIR region. The Lamb-dip spectrum of the N 2 O molecule at 2.7 μm was measured as a demonstration of spectroscopy in the MIR with kilohertz accuracy.

The discovery of Kamin blocking led to the idea that associative learning occurs only when there is a mismatch between actual and predicted outcomes, or prediction error. The neural substrates involved in regulating this prediction error during behavioral learning are still not fully elucidated. We investigated in rats the role of the ventral tegmental area and the nucleus accumbens in Kamin blocking. Our blocking paradigm involved three phases: appetitive classical conditioning of a lever cue, conditioning of a compound of the lever cue plus an auditory cue, and testing response to the auditory cue in extinction. We found that disruption of inhibition in the ventral tegmental area by bicuculline, or designer receptor mediated inactivation of the nucleus accumbens, during compound cue conditioning, attenuated Kamin blocking. These results suggest that inhibition in the ventral tegmental area and inhibitory output from the nucleus accumbens are necessary for blocking and make behaviorally significant contributions to the computation of reward prediction error. In addition, we found that inactivating the neurons in the nucleus accumbens during classical conditioning of the lever cue also attenuated blocking, without affecting classical conditioning of the lever. This indicates that learning in the nucleus accumbens is necessary for blocking and reward estimation. Our results reveal a causal role for nucleus accumbens modulated inhibitory inputs to the ventral tegmental area in the blocking effect and suggest that they contribute to computation of reward prediction error during associative learning., (© 2020 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Oikopleura dioica is a ubiquitous marine tunicate of biological interest due to features that include dioecious reproduction, short life cycle, and vertebrate-like dorsal notochord while possessing a relatively compact genome. The use of tunicates as model organisms, particularly with these characteristics, offers the advantage of facilitating studies in evolutionary development and furthering understanding of enduring attributes found in the more complex vertebrates. At present, we are undertaking an initiative to sequence the genomes of Oikopleura individuals in populations found among the seas surrounding the Ryukyu Islands in southern Japan. To facilitate and validate genome assemblies, karyotyping was employed to count individual animals' chromosomes in situ using centromere-specific antibodies directed against H3S28P, a prophase-metaphase cell cycle-specific marker of histone H3. New imaging data of embryos and oocytes stained with two different antibodies were obtained; interpretation of these data lead us to conclude that the Okinawan Oikopleura dioica has three pairs of chromosomes, akin to previous results from genomic assemblies in Atlantic populations. The imaging data have been deposited to the open-access EBI BioImage Archive for reuse while additionally providing representative images of two commercially available anti-H3S28P antibodies' staining properties for use in epifluorescent and confocal based fluorescent microscopy., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Liu AW et al.)

Oikopleura dioica is a ubiquitous marine zooplankton of biological interest owing to features that include dioecious reproduction, a short life cycle, conserved chordate body plan, and a compact genome. It is an important tunicate model for evolutionary and developmental research, as well as investigations into marine ecosystems. The genome of north Atlantic O. dioica comprises three chromosomes. However, comparisons with the genomes of O. dioica sampled from mainland and southern Japan revealed extensive sequence differences. Moreover, historical studies have reported widely varying chromosome counts. We recently initiated a project to study the genomes of O. dioica  individuals collected from the coastline of the Ryukyu (Okinawa) Islands in southern Japan. Given the potentially large extent of genomic diversity, we employed karyological techniques to count individual animals' chromosomes in situ using centromere-specific antibodies directed against H3S28P, a prophase-metaphase cell cycle-specific marker of histone H3. Epifluorescence and confocal images were obtained of embryos and oocytes stained with two commercial anti-H3S28P antibodies (Abcam ab10543 and Thermo Fisher 07-145). The data lead us to conclude that diploid cells from Okinawan O. dioica  contain three pairs of chromosomes, in line with the north Atlantic populations. The finding facilitates the telomere-to-telomere assembly of Okinawan O. dioica genome sequences and gives insight into the genomic diversity of O. dioica from different geographical locations. The data deposited in the EBI BioImage Archive provide representative images of the antibodies' staining properties for use in epifluorescent and confocal based fluorescent microscopy., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Liu AW et al.)

Objective: To determine whether 60 Gy is superior to standard 50 Gy for definitive concurrent chemoradiation(CCRT) in esophageal squamous cell carcinoma (ESCC) using modern radiation technology in a phase Ⅲ prospective randomized trial. Methods: From April 2013 to May 2017, 331 patients from 22 hospitals who were pathologically confirmed with stage ⅢA-ⅣA ESCC were randomized to 60 Gy or 50 Gy with random number table. Total of 305 patients were analyzed, including 152 in 60 Gy group and 153 in 50 Gy group. The median age was 63 years, 242(79.3%) males and 63(20.7%) females. The median length of primary tumor was 5.6 cm. The clinical characteristics between two groups were comparable. All patients were delivered 2 Gy per fraction, 5 fractions per week. Concurrent weekly chemotherapy with docetaxel (25 mg/m(2)) and cisplatin (25 mg/m(2)) and 2 cycles consolidation chemotherapy with docetaxel (70 mg/m(2)) and cisplatin (25 mg/m(2), d1-3) were administrated. The primary endpoint was local/regional progression-free survival (LRPFS). The data were compared with Pearson chi-square test or Fisher's exact test. Results: At a median follow-up of 27.3 months, the disease progression rate was 37.5% (57/152), 43.8% (67/153) in the high and standard-dose group, respectively (χ(2)=1.251, P= 0.263). The 1, 2, 3-year LRPFS rate was 75.4%, 56.8%, 52.1% and 74.2%, 58.4%, 50.1%, respectively ( HR : 0.95, 95 %CI : 0.69-1.31, P= 0.761). The 1, 2, 3-year overall survival rate was 84.1%, 64.8%, 54.1% and 85.4%, 62.9%, 54.0%, respectively ( HR : 0.98, 95 %CI : 0.71-1.38, P= 0.927). The 1, 2, 3-year progression-free survival rate was 70.8%, 54.2%, 48.5% and 65.5%, 51.9%, 45.1%, respectively ( HR : 0.93, 95 %CI : 0.68-1.26, P= 0.621). The incidence rates in toxicities between the two groups were similar except for higher rate of severe pneumonitis in high dose group (χ(2)=11.596, P= 0.021). Conclusions: The efficacy in disease control is similar between 60 Gy and 50 Gy using modern radiation technology concurrent with chemotherapy for ESCC. The 50 Gy should be recommended as the regular radiation dose with CCRT for ESCC.

Oikopleura dioica is a planktonic chordate with exceptional filter-feeding ability, rapid generation time, conserved early development, and a compact genome. For these reasons, it is considered a useful model organism for marine ecological studies, evolutionary developmental biology, and genomics. As research often requires a steady supply of animal resources, it is useful to establish a reliable, low-maintenance culture system. Here we describe a step-by-step method for establishing an O. dioica culture. We describe how to select potential sampling sites, collection methods, target animal identification, and the set-up of the culturing system. We provide troubleshooting advice based on our own experiences. We also highlight critical factors that help sustain a robust culture system. Although the culture protocol provided here is optimized for O. dioica, we hope our sampling technique and culture setup will inspire new ideas for maintaining other fragile pelagic invertebrates.

Background: Early screening and diagnosis of radiation-induced heart disease (RIHD) is difficult in patients with chest radiation exposure. sST-2 is involved in myocardial stress or injury. We evaluated the relationship between heart dose parameters and sST-2 changes in chest malignant tumor patients who received chest radiation., Methods: We prospectively collected thoracic malignancy cancer patients who had received chest radiotherapy. Heart dosimetry parameters were extracted from the treatment planning system. sST-2 was measured at baseline, the middle stage, and after radiotherapy (recorded as pre-ST-2, mid-ST-2, and post-ST-2). sST-2 change rate was calculated. Scatter plots showed the relationship between cardiac dose parameters and ST-2 change rate. Multiple regression was used to analyze the relationship between cardiac dose parameters and ST-2 change rate., Results: Totally, 60 patients were enrolled. The mean V 5 , V 10 , V 20 , V 30 , V 40 , and MHD was 60.93 ± 27.79%, 51.43 ± 25.44%, 39.17 ± 21.75%, 28.07 ± 17.15%,18.66 ± 12.18%, and 18.60 ± 8.63 Gy, respectively. The median M-LAD was 11.31 (IQR 3.33-18.76) Gy. The mean pre-ST-2, mid-ST-2, and post-ST-2 was 5.1 ± 3.8, 6.4 ± 3.9, and 7.6 ± 4.4, respectively. sST-2 was elevated with thoracic irradiation (P < .001). Multivariate linear regression analyses showed that V 5 , V 10 , V 20 , and MHD were independently and positively associated with ST-2 change rate (β = .04, .04, .04, and .10, respectively, all P < .05)., Conclusion: Serum sST-2 levels were elevated over time during radiotherapy. V 5 , V 10 , V 20 and MHD were independently and positively associated with the elevated ST-2 change rate., (© 2019 The Authors. Journal of Clinical Laboratory Analysis Published by Wiley Periodicals, Inc.)

Aims: Microvascular endothelial cell dysfunction is a leading cause of radiation-induced heart disease (RIHD). BRCA1 plays an important role in DNA damage repair. The study aims to explore the effect of BRCA1 in endothelial cells involved in RIHD., Materials and Methods: BRCA1 and p21 expression were detected in human umbilical vein endothelial cells (HUVECs) and in mouse heart tissue after irradiation exposure. The effects of BRCA1 on cell proliferation, cell cycle and radiosensitivity were determined in HUVECs with overexpression and knockdown of BRCA1. A mouse model of RIHD was established. Heart damage was detected in C57BL/6J mice and endothelial cell specific knockout BRCA1 mice (EC-BRCA1 - / - )., Key Findings: BRCA1 and p21 expression was significantly increased both in vitro and vivo response to irradiation. BRCA1 overexpression in endothelial cells enhanced cell growth and G1/S phase arrest, and the opposite results were observed in BRCA1 knockdown endothelial cells. BRCA1 downregulated endothelial cell cycle-related genes cyclin A, cyclin D1, cyclin E and p-Rb through increasing p21 expression, and HUVECs with BRCA1 gene knockdown were more sensitive to radiation. In vivo, a decrease in cardiac microvascular density, as well as cardiomyocyte hypoxia and apoptosis were observed in a time-dependent manner. EC-BRCA1 - / - mice were more prone to severe RIHD than EC-BRCA1 +/ - mice after 16Gy radiation exposure due to endothelial dysfunction caused by loss of BRCA1, and p21 was declined in EC-BRCA1 - / - mice heart., Significance: These findings indicate that BRCA1 plays a protective role in RIHD by regulating endothelial cell cycle arrest mediated by p21 signal., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Precision spectroscopy of fundamental bands of molecules in the mid-infrared (MIR) region is of great interest in applications of trace detection and testing fundamental physics, where high-power and narrow-linewidth MIR lasers are needed. By using a frequency-stabilized near-infrared laser as a seed of the signal light of a continuous-wave optical parametric oscillator, we established a broadly tunable MIR light source that has an output power of several hundred milliwatts and a linewidth of a few tens of kilohertz. The MIR laser frequency drift was reduced to below 1 kHz by using an optical frequency comb to stabilize the frequency of the 1064 nm pumping laser. The performance of the light source was investigated and tested by measuring the saturated absorption spectroscopy of a few molecular transitions at 3.3 µm.

Quantitative determination of atmospheric CO 2 concentration by remote sensing relies on accurate line parameters. Lamb dips of the lines up to J'' = 72 in the 30013-00001 band at 1605 nm were measured using a comb-locked cavity ring-down spectrometer, and the positions were determined with an accuracy of a few kHz. A simple effective Hamiltonian model can fit the rotational energies in the 30013 state ideally within the experimental accuracy, indicating that the vibrational state is well-isolated and can be regarded as free from perturbations. From a comparison between other bands using a similar analysis, we conclude that the transitions in the 30013-00001 band could be more suitable as reference lines for sensing applications with the potentially improved line parameter accuracy.

Cutaneous TRPV1 + neurons directly sense noxious stimuli, inflammatory cytokines, and pathogen-associated molecules and are required for innate immunity against some skin pathogens. Important unanswered questions are whether TRPV1 + neuron activation in isolation is sufficient to initiate innate immune responses and what is the biological function for TRPV1 + neuron-initiated immune responses. We used TRPV1-Ai32 optogenetic mice and cutaneous light stimulation to activate cutaneous neurons in the absence of tissue damage or pathogen-associated products. We found that TRPV1 + neuron activation was sufficient to elicit a local type 17 immune response that augmented host defense to C. albicans and S. aureus. Moreover, local neuron activation elicited type 17 responses and augmented host defense at adjacent, unstimulated skin through a nerve reflex arc. These data show the sufficiency of TRPV1 + neuron activation for host defense and demonstrate the existence of functional anticipatory innate immunity at sites adjacent to infection that depends on antidromic neuron activation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: We examined the longitudinal association between change in body composition directly measured by computed tomography (CT) and future insulin sensitivity., Methods: This was a prospective study with 10 years of follow-up with 297 Japanese-American without diabetes. Intra-abdominal fat area (IAFA) and abdominal subcutaneous fat area (SCFA), and thigh SCFA were measured by CT. Insulin sensitivity was calculated by HOMA-IR and the Matsuda index., Results: Baseline and change in IAFA were significantly and independently associated with change in HOMA-IR and Matsuda index during follow-up. In multivariate analysis, IAFA and 10-year change in IAFA (Δ IAFA) was significantly and positively associated with 10-year HOMA-IR (p < 0.001) and significantly and negatively associated with 10-year Matsuda index (p < 0.001). The association with Matsuda index though was non-linear and best modeled as a quadratic function (Δ IAFA + Δ IAFA 2 ). No significant associations in multivariate analyses were seen between thigh SCFA and insulin sensitivity or abdominal SCFA and HOMA-IR but an increase in abdominal SCFA was associated with diminished insulin sensitivity measured by the Matsuda index., Conclusions: An increase in visceral adiposity predicts diminished insulin sensitivity over 10 years of follow-up independent of the size of this adipose depot at baseline., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Noise-immune cavity enhanced optical heterodyne molecular spectroscopy (NICE-OHMS) is extremely sensitive in detecting weak absorption. However, the use of NICE-OHMS for metrology study was also hindered by its sensitivity to influence from various experimental conditions such as the residual amplitude modulation. Here we demonstrate to use NICE-OHMS for precision measurements of Lamb-dip spectra of molecules. After a dedicated investigation of the systematic uncertainties in the NICE-OHMS measurement, the transition frequency of a ro-vibrational line of C 2 H 2 near 789 nm was determined to be 379 639 280 915.3±1.2 kHz (fractional uncertainty 3.2 × 10 -12 ), agreeing well with, but more accurate than, the value determined from previous cavity ring-down spectroscopy measurements. The study indicates the possibility to implement the very sensitive NICE-OHMS method for frequency metrology of molecules, or a molecular clock, in the near-infrared.

Behavioural flexibility is crucial for adaptive behaviour, and recent evidence suggests that cholinergic interneurons of the striatum play a distinct role. Previous studies of cholinergic function have focused on strategy switching by the dorsomedial or ventral striatum. We here investigated whether cholinergic interneurons in the dorsolateral striatum play a similar role at the level of switching of habitual responses. Because the dorsolateral striatum is particularly involved in habitual responding, we developed a habit substitution task that involved switching habitual lever-press responses to one side to another. We first measured the effect of cholinergic activation in the dorsolateral striatum on this task. Chemogenetic activation of cholinergic interneurons caused an increase in the response rate for the substituted response that was significantly greater than the increase normally seen in control animals. The increase was due to burst-like responses with shorter inter-press intervals. However, there was no effect on inhibiting the old habit, or on habitual responding that did not require a switch. There was also no effect on lever-press performance and its reversal before lever-press responses became habitual. Conversely, neurochemically specific ablation of cholinergic interneurons did not significantly change habitual responding or response substitution. Thus, activation -but not ablation -of cholinergic interneurons in the dorsolateral striatum modulates expression of a new habit when an old habit is replaced by a new one. Together with previous work, this suggests that striatal cholinergic interneurons facilitate behavioural flexibility in both dorsolateral striatum in addition to dorsomedial and ventral striatum., (© 2018 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Precision spectroscopy of the hydrogen molecule is a test ground of quantum electrodynamics (QED), and it may serve for the determination of fundamental constants. Using a comb-locked cavity ring-down spectrometer, for the first time, we observed the Lamb-dip spectrum of the R(1) line in the overtone of hydrogen deuteride (HD). The line position was determined to be 217 105 182.79±0.03&#95;{stat}±0.08&#95;{syst}  MHz (δν/ν=4×10^{-10}), which is the most accurate rovibrational transition ever measured in the ground electronic state of molecular hydrogen. Moreover, from calculations including QED effects up to the order m&#95;{e}α^{6}, we obtained predictions for this R(1) line as well as for the HD dissociation energy, which are less accurate but signaling the importance of the complete treatment of nonadiabatic effects. Provided that the theoretical calculation reaches the same accuracy, the present measurement will lead to a determination of the proton-to-electron mass ratio with a precision of 1.3 parts per billion.

Background: Few studies have directly compared preemptive therapy (PET) and antiviral prophylaxis (AP) for prevention of cytomegalovirus (CMV) disease in CMV seropositive (R+) orthotopic liver transplant (OLT) recipients., Methods: We prospectively assessed CMV disease and clinical outcomes among 160 consecutive R+ OLT recipients who received PET (weekly plasma CMV PCR for 3 months, oral valganciclovir 900 mg twice daily for CMV viremia >250 IU/mL, until 2 consecutive negative weekly PCR results) and compared them with a historical cohort of 156 R+ recipients who received AP (valganciclovir, 900 mg daily for 3 months)., Results: Patient characteristics were similar between PET and AP cohorts (P > 0.05 all comparisons). In the PET group, 24% (39/160) developed CMV viremia greater than 250 IU/mL at a median of 42 (range, 7-93) days post-OLT. CMV monitoring adherence in the PET cohort was 85% (1488/1760 required tests) and 86% (30/36) initiated PET within 3 days of the CMV result. By 12 months post-OLT, the incidence of CMV disease, acute allograft rejection, major infection, or death in the PET and AP cohorts was not significantly different: 2% versus 2%, 19% versus 16%, 10.5% versus 10.8%, and 5% versus 8%, respectively (P > 0.05 all comparisons). The estimated proportion of drug-exposed patients and average antiviral drug exposure were significantly lower with PET versus AP: 24% versus 100%, P < 0.001, and 15.8 versus 81 g per patient, P < 0.001, respectively., Conclusions: PET is feasible in a nonresearch setting and is associated with similar CMV disease rates and other clinically relevant outcomes to AP in CMV seropositive liver transplant recipients.

Gelatin embedding of whole brains for sectioning is a critical procedure used in neuroscience to ensure all morphological and spatial details are preserved intact. Here, we describe an inexpensive, reproducible and efficient means to embed post-fixed brains ready for sectioning in gelatin within a week's time. The sections obtained are distortion-free and their fragile internal structures preserved which can be used for serial reconstructions for lesion studies and mapping of viral expression after stereotaxic injections. In addition, the separation of adjacent slices into a series of 3-4 vials facilitates subsequent organization and assembly of serial sections at the mounting step., (Copyright © 2017 The Authors; exclusive licensee Bio-protocol LLC.)

Precise molecular transition frequencies are needed in various studies including the test of fundamental physics. Two well isolated ro-vibrational transitions of 12 C 16 O at 1.57 μm, R(9) and R(10) in the second overtone band, were measured by a comb-locked cavity ring-down spectrometer. Despite the weakness of the lines (Einstein coefficient A≃0.008 s -1 ), Lamb-dip spectra were recorded with a signal-to-noise ratio over 1000, and the line positions were determined to be 191 360 212 761.1 and 191 440 612 662.2 kHz, respectively, with an uncertainty of 0.5 kHz (δν/ν=2.6×10 -12 ). The present work demonstrates the possibility to explore extensive molecular lines in the near-infrared with sub-kHz accuracy.