Elevated temperature as a dominant driver to aggravate cadmium toxicity: Investigations through toxicokinetics and omics.

Despite the great interest in the consequences of global change stressors on marine organisms, their interactive effects on cadmium (Cd) bioaccumulation/biotoxicity are very poorly explored, particularly in combination with the toxicokinetic model and molecular mechanism. According to the projections for 2100, this study investigated the impact of elevated pCO2 and increased temperature (isolated or joint) on Cd uptake dynamics and transcriptomic response in the marine copepod Tigriopus japonicus. Toxicokinetic results showed significantly higher Cd uptake in copepods under increased temperature and its combination with elevated pCO2 relative to the ambient condition, linking to enhanced Cd bioaccumulation. Transcriptome analysis revealed that, under increased temperature and its combination with elevated pCO2, up-regulated expression of Cd uptake-related genes but down-regulation of Cd exclusion-related genes might cause increased cellular Cd level, which not only activated detoxification and stress response but also induced oxidative stress and concomitant apoptosis, demonstrating aggravated Cd biotoxicity. However, these were less pronouncedly affected by elevated pCO2 exposure. Therefore, temperature seems to be a primary factor in increasing Cd accumulation and its toxicity in the future ocean. Our findings suggest that we should refocus the interactive effects between climate change stressors and Cd pollution, especially considering temperature as a dominant driver.

Programmable DNA Templates for Silver Nanoclusters Synthesis To Develop On-Demand FRET Aptasensor.

DNA-templated silver nanoclusters (AgNCs-DNA) can be synthesized via a one-pot method bypassing the tedious process of biomolecular labeling. Appending an aptamer to DNA templates results in dual-functionalized DNA strands that can be utilized for synthesizing aptamer-modified AgNCs, thereby enabling the development of label-free fluorescence aptasensors. However, a major challenge lies in the necessity to redesign the dual-functionalized DNA strand for each specific target, thus increasing the complexity and hindering widespread application of these aptasensors. To overcome this challenge, we designed six DNA strands (DNA1-DNA6) that incorporate the templates for AgNCs synthesis and A4-linker for further aptamer coupling. Among all the synthesized AgNCs-DNA samples, it was found that both AgNCs-DNA1 and AgNCs-DNA2 stood out for their excellent long-term stability. After capturing the T4-linker that connected with aptamer1 specific for aflatoxin B1 (AFB1), however, we found that only AgNCs-DNA1/aptamer1 maintained excellent long-term stability. This finding highlighted the potential of AgNCs-DNA1 as a versatile label-free fluorescence probe for the development of on-demand fluorescence aptasensors. To emphasize its benefits in aptasensing applications, we utilized AgNCs-DNA1/aptamer1 as the fluorescence probe and MoS2 nanosheets as the quencher to develop a FRET aptasensor for AFB1 detection. This aptasensor demonstrated remarkable sensitivity, enabling the detection of AFB1 within a wide concentration range of 0.03-120 ng/mL, with a limit of detection as low as 3.6 pg/mL (S/N = 3). The versatility of the aptasensor has been validated through the recognition of diverse targets, employing aptamer2 specific for ochratoxin A and aptamer3 specific for zearalenone, thereby showcasing its extensive applicability for on-demand detection. The universal applicability of this aptasensor holds great promise for future applications in diverse fields including food safety, environmental monitoring, and clinical diagnosis.

The efficacy and safety of local 5-aminolevulinic acid-based photodynamic therapy in the treatment of cervical high-grade squamous intraepithelial lesion: a single center retrospective observational study.

Background: Typical treatments for cervical high-grade squamous intraepithelial lesion (HSIL) are invasive procedures. However, these procedures often come with several severe side effects, despite their positive effects on cervical HSIL. 5-aminolevulinic acid photodynamic therapy (ALA-PDT) is a non-invasive treatment that has been successfully used to treat cervical low-grade squamous intraepithelial lesion (LSIL). In this study, we aimed to further investigate the clinical efficacy and safety of ALA-PDT in the treatment of patients with cervical HSIL. Methods: A total of 40 patients aged 20 - 41 years with cervical HSIL and high-risk Human Papilloma Virus (HR-HPV) infections were enrolled in this retrospective study from January 2019 to December 2022. Patients were treated with six times of ALA-PDT at intervals of 7-14 days. Three months after the treatment, the efficacy was evaluated through HPV genotyping and cervical cytology examination. If the cytological result was worse than ASC -US, the patient underwent colposcopy-directed biopsy immediately. Otherwise, patients would receive rigorous follow-up observation. Results: Three months after receiving ALA-PDT treatment, 65% (26/40) of cervical HSIL patients at our center showed complete regression (cytological result: normal; HR-HPV: negative). This rate increased to 82.5% (33/40) at the 12-month follow-up. None of the patients experienced disease progression after ALA-PDT therapy. The risk of persistent HR-HPV infection was 32.5% (13/40) at the 3-month follow-up after ALA-PDT. Multivariate analyses identified cervical canal involvement as an independent risk factor for persistent HR-HPV infection at the 3-month follow-up after ALA-PDT treatment. During the treatment of the 40 patients with ALA-PDT, there were no reports of severe adverse reactions. Only a limited number of patients experienced slight discomfort symptoms. Conclusion: ALA-PDT is safe and effective noninvasive therapy for patients with cervical HSIL and HR-HPV infections. It is particularly suitable for young women, who have been confirmed with cervical HSIL and have demand for fertility protection. Three months after ALA-PDT treatment, if a patient still has either ASC-US cervical cytological result and/or HR-HPV infection, rigorous observation is considered safe for her. Cervical canal involvement is an independent risk factor for persistent HR-HPV infection at the 3-month follow-up after ALA-PDT treatment.

Optimizing Gantry Breakpoint Angles in Proton Therapy: Enhancing Efficiency and Patient Experience.

Purpose: The breakpoint for a 360° radiotherapy gantry is typically positioned at 180°. This arbitrary setting has not been systematically evaluated for efficiency and may cause redundant gantry rotation and extended setup times. Our study aimed to identify an optimal gantry breakpoint angle for a full-gantry proton therapy system, with the goal of minimizing gantry movement. Materials and Methods: We analyzed 70 months of clinically delivered proton therapy plans (9152 plans, 131 883 fractions), categorizing them by treatment site and mapping the fields from a partial-gantry to full-gantry orientation. For each delivered fraction, we computed the minimum total gantry rotation angle as a function of gantry breakpoint position, which was varied between 0° and 360° in 1° steps. This analysis was performed separately within the entire plan cohort and individual treatment sites, both with and without the capability of over-rotating 10° past the breakpoint from either direction (20° overlap). The optimal gantry breakpoint was identified as one which resulted in a low average gantry rotation per fraction. Results: Considering mechanical constraints, 130° was identified as a reasonable balance between increased gantry-rotation efficiency and practical treatment considerations. With a 20° overlap, this selection reduced the average gantry rotation by 41.4° per fraction when compared to the standard 180° breakpoint. Disease site subgroups showed the following reduction in average gantry rotation: gastrointestinal 192.2°, thoracic 56.3°, pediatric 44.9°, genitourinary 19.9°, central nervous system 10.7°, breast 2.8°, and head and neck 0.1°. Conclusion: For a full-gantry system, a breakpoint of 130° generally outperforms the conventional 180° breakpoint. This reduction is particularly impactful for gastrointestinal, pediatric, and thoracic sites, which constitute a significant proportion of cases at our center. The adjusted breakpoint could potentially streamline patient delivery, alleviate mechanical wear, and enhance treatment precision by reducing the likelihood of patient movement during delivery.

Application progress of nanocellulose in food packaging: A review.

With the increasing environmental and ecological problems caused by petroleum-based packaging materials, the focus has gradually shifted to natural resources for the preparation of functional food packaging materials. In addition to biodegradable properties, nanocellulose (NC) mechanical properties, and rich surface chemistry are also fascinating and desired to be one of the most probable green packaging materials. In this review, we firstly introduce the recent progress of novel applications of NC in food packaging, including intelligent packaging, nano(bio)sensors, and nano-paper; secondly, we focus on the modification techniques of NC to summarize the properties (antimicrobial, mechanical, hydrophobic, antioxidant, and so on) that are required for food packaging, to expand the new synthetic methods and application areas. After presenting all the latest advances related to material design and sustainable applications, an overview summarizing the safety of NC is presented to promote a continuous and healthy movement of NC toward the field of truly sustainable packaging.

Dexmedetomidine improves mitophagy and pyroptosis through the ALKBH5/FUNDC1 axis during epidural-related maternal fever.

PURPOSE: Epidural analgesia has emerged as a commonly used method for relieving labor pain. However, epidural-related maternal fever (ERMF) is characterized by a high occurrence rate and can have detrimental consequences for the well-being of both the mother and the fetus. This study aimed to investigate the functional role and underlying mechanism of dexmedetomidine (DEX) in ERMF. MATERIALS AND METHODS: Ropivacaine (ROP)-induced human umbilical vein endothelial cells (HUVECs) were treated with DEX and/or transfected with ALKBH5 or FUNDC1 overexpression plasmid. qPCR and Western blot were adopted for mitophagy and pyroptosis marker protein detection. Autophagosomes were observed through electron microscopy, Caspase-1/PI double-positive cells were determined using flow cytometry. Inflammation-related factors were quantified using ELISA. The N6-methyladenosine (m6A) modification of FUNDC1 mRNA was examined using methylated RNA immunoprecipitation (MeRIP) and the binding between ALKBH5 and FUNDC1 mRNA was confirmed by RNA immunoprecipitation (RIP). RESULTS: In ROP-induced HUVECs, there was a significant upregulation in ALKBH5 and FUNDC1, resulting in a notable increase in inflammation, pyroptosis, and mitophagy. The administration of DEX demonstrated the ability to alleviate ROP-induced pyroptosis and promote protective mitophagy. Interestingly, DEX treatment significantly reduced the interaction between ALKBH5 and FUNDC1 mRNA, while simultaneously increasing the m6A level of FUNDC1 mRNA in ROP-treated cells. Moreover, the overexpression of FUNDC1 partially reversed the effects of ALKBH5 overexpression on mitophagy and pyroptosis in HUVECs. CONCLUSIONS: DEX can promote mitophagy and inhibit pyroptosis through the ALKBH5/FUNDC1 axis in ERMF, indicating its potential as a therapeutic strategy for clinical ERMF treatment.

Pro-CRISPR PcrIIC1-associated Cas9 system for enhanced bacterial immunity.

The CRISPR system is an adaptive immune system found in prokaryotes that defends host cells against the invasion of foreign DNA1. As part of the ongoing struggle between phages and the bacterial immune system, the CRISPR system has evolved into various types, each with distinct functionalities2. Type II Cas9 is the most extensively studied of these systems and has diverse subtypes. It remains uncertain whether members of this family can evolve additional mechanisms to counter viral invasions3,4. Here we identify 2,062 complete Cas9 loci, predict the structures of their associated proteins and reveal three structural growth trajectories for type II-C Cas9. We found that novel associated genes (NAGs) tended to be present within the loci of larger II-C Cas9s. Further investigation revealed that CbCas9 from Chryseobacterium species contains a novel ß-REC2 domain, and forms a heterotetrameric complex with an NAG-encoded CRISPR-Cas-system-promoting (pro-CRISPR) protein of II-C Cas9 (PcrIIC1). The CbCas9-PcrIIC1 complex exhibits enhanced DNA binding and cleavage activity, broader compatibility for protospacer adjacent motif sequences, increased tolerance for mismatches and improved anti-phage immunity, compared with stand-alone CbCas9. Overall, our work sheds light on the diversity and 'growth evolutionary' trajectories of II-C Cas9 proteins at the structural level, and identifies many NAGs-such as PcrIIC1, which serves as a pro-CRISPR factor to enhance CRISPR-mediated immunity.

Dose-Response Study of Phenylephrine for Preventing Spinal-Induced Hypotension During Cesarean Delivery with Combined Spinal-Epidural Anesthesia Under the Effect of Prophylactic Intravenous Ondansetron.

Background: Ondansetron reduces the median effective dose (ED50) of prophylactic phenylephrine to prevent spinal-induced hypotension (SIH) during cesarean delivery. However, the exact dose response of phenylephrine in combination with prophylactic ondansetron for preventing SIH is unknown. Therefore, this study aimed to determine the dose-response of phenylephrine to prevent SIH in cesarean delivery when 4 mg of ondansetron was used as a preventive method. Methods: A total of 80 parturients were enrolled and divided randomly into four groups (n = 20 in each group) who received either 0.2, 0.3, 0.4, or 0.5 µg/kg/min of prophylactic phenylephrine. Ten minutes before the initiation of spinal induction, 4 mg prophylactic ondansetron was administered. The effective dose of prophylactic phenylephrine was defined as the dose required to prevent hypotension after the period of intrathecal injection and up to neonatal delivery. The ED50 and ED90 of prophylactic phenylephrine and 95% confidence intervals (95% CI) were calculated using probit analysis. Results: The ED50 and ED90 for prophylactic phenylephrine to prevent SIH were 0.25 (95% CI, 0.15 to 0.30), and 0.45 (95% CI, 0.39 to 0.59) µg/kg/min, respectively. No significant differences were observed in the side effects and neonatal outcomes between the four groups. Conclusion: The administration of 4 mg of prophylactic ondansetron was associated with an ED50 of 0.25 (95% CI, 0.15~0.30) and ED90 of 0.45 (95% CI, 0.39~0.59) µg/kg/min for phenylephrine to prevent SIH.

On-Site Quantitative Visualization of Singlet Oxygen in Crops via an Organic Small Molecule-Based Ratiometric Fluorescent Probe and a Mobile Fluorescence Analysis Device.

Singlet oxygen (1O2) plays imperative roles in a variety of biotic or abiotic stresses in crops. The change of its concentration within a crop is closely related to the crop growth and development. Accordingly, there is an urgent need to develop an efficient analytical method for on-site quantitative detection of 1O2 in crops. Here, we judiciously constructed a novel ratiometric fluorescent probe, SX-2, for the detection of 1O2 in crops. Upon treating with 1O2, probe SX-2 displayed highly selective ratiometric fluorescence response, which is favorable for the quantitative detection of 1O2. Concurrently, the fluorescence solution color of probe SX-2 was varied, obviously from blue to yellow, indicating that the probe is beneficial for on-site detection by the naked eye. Sensing reaction mechanism studies showed that the 2,3-diphenyl imidazole group in SX-2 could function as a new selective recognition group for 1O2. Probe SX-2 was utilized for the detection of photoirradiation-induced 1O2 and endogenous 1O2 in living cells. The changes in the 1O2 level in zebrafish were also tracked by fluorescence imaging. In addition, the production of 1O2 in crop leaves under a light source of different wavelengths was studied. The results demonstrated more 1O2 were produced under a light source of 365 nm. Furthermore, to achieve on-site quantitative detection, a mobile fluorescence analysis device has been made. Probe SX-2 and mobile fluorescence analysis device were capable of on-site quantitative detecting of 1O2 in crops. The method developed herein will be convenient for the on-site quantitative measurement of 1O2 in distinct crops.

Deep learning based linear energy transfer calculation for proton therapy.

Objective.This study aims to address the limitations of traditional methods for calculating linear energy transfer (LET), a critical component in assessing relative biological effectiveness (RBE). Currently, Monte Carlo (MC) simulation, the gold-standard for accuracy, is resource-intensive and slow for dose optimization, while the speedier analytical approximation has compromised accuracy. Our objective was to prototype a deep-learning-based model for calculating dose-averaged LET (LETd) using patient anatomy and dose-to-water (DW) data, facilitating real-time biological dose evaluation and LET optimization within proton treatment planning systems.Approach. 275 4-field prostate proton Stereotactic Body Radiotherapy plans were analyzed, rendering a total of 1100 fields. Those were randomly split into 880, 110, and 110 fields for training, validation, and testing. A 3D Cascaded UNet model, along with data processing and inference pipelines, was developed to generate patient-specific LETddistributions from CT images and DW. The accuracy of the LETdof the test dataset was evaluated against MC-generated ground truth through voxel-based mean absolute error (MAE) and gamma analysis.Main results.The proposed model accurately inferred LETddistributions for each proton field in the test dataset. A single-field LETdcalculation took around 100 ms with trained models running on a NVidia A100 GPU. The selected model yielded an average MAE of 0.94 ± 0.14 MeV cm-1and a gamma passing rate of 97.4% ± 1.3% when applied to the test dataset, with the largest discrepancy at the edge of fields where the dose gradient was the largest and counting statistics was the lowest.Significance.This study demonstrates that deep-learning-based models can efficiently calculate LETdwith high accuracy as a fast-forward approach. The model shows great potential to be utilized for optimizing the RBE of proton treatment plans. Future efforts will focus on enhancing the model's performance and evaluating its adaptability to different clinical scenarios.

IRX4204 Induces Senescence and Cell Death in HER2-positive Breast Cancer and Synergizes with Anti-HER2 Therapy.

PURPOSE: Rexinoids, agonists of nuclear retinoid X receptor (RXR), have been used for the treatment of cancers and are well tolerated in both animals and humans. However, the usefulness of rexinoids in treatment of breast cancer remains unknown. This study examines the efficacy of IRX4204, a highly specific rexinoid, in breast cancer cell lines and preclinical models to identify a biomarker for response and potential mechanism of action. EXPERIMENTAL DESIGN: IRX4204 effects on breast cancer cell growth and viability were determined using cell lines, syngeneic mouse models, and primary patient-derived xenograft (PDX) tumors. In vitro assays of cell cycle, apoptosis, senescence, and lipid metabolism were used to uncover a potential mechanism of action. Standard anti-HER2 therapies were screened in combination with IRX4204 on a panel of breast cancer cell lines to determine drug synergy. RESULTS: IRX4204 significantly inhibits the growth of HER2-positive breast cancer cell lines, including trastuzumab and lapatinib-resistant JIMT-1 and HCC1954. Treatment with IRX4204 reduced tumor growth rate in the MMTV-ErbB2 mouse and HER2-positive PDX model by 49% and 44%, respectively. Mechanistic studies revealed IRX4204 modulates lipid metabolism and induces senescence of HER2-positive cells. In addition, IRX4204 demonstrates additivity and synergy with HER2-targeted mAbs, tyrosine kinase inhibitors, and antibody-drug conjugates. CONCLUSIONS: These findings identify HER2 as a biomarker for IRX4204 treatment response and demonstrate a novel use of RXR agonists to synergize with current anti-HER2 therapies. Furthermore, our results suggest that RXR agonists can be useful for the treatment of anti-HER2 resistant and metastatic HER2-positive breast cancer.

Knockdown of Ubiquitin-Conjugating Enzyme E2 T Abolishes the Progression of Head and Neck Squamous Cell Carcinoma by Inhibiting NF-Κb Signaling and inducing Ferroptosis.

BACKGROUND: Ubiquitin-conjugating enzyme 2T (UBE2T) has been reported to be associated with uncontrolled cell growth and tumorigenesis in multiple cancer types. However, the understanding of its regulatory role in the carcinogenesis of Head And Neck Squamous Cell Carcinoma (HNSC) is limited. METHODS: UBE2T expression in HNSC patient samples and the correlation between its expression and patients' survival rates were evaluated using The Cancer Genome Atlas (TCGA) database. Cell survival and proliferation were investigated in UM-SCC1 and UM-SCC15 cells infected with control and shUBE2T lentivirus. The xenograft mouse model was established using UM-SCC15 cells to examine HNSC tumorigenesis with or without UBE2T. Western blot, qRT-PCR, and ferroptosis assays were carried out to disclose the interaction between UBE2T and NF-κB signaling and ferroptosis. RESULTS: The increased expression of UBE2T was noted in tumor tissues of patients with HNSC, correlating with a significantly reduced overall survival time in this patient cohort. Knockdown of UBE2T inhibited HNSC tumorigenesis and tumor growth. Mechanistically, inhibition of UBE2T suppressed NF-ΚB signaling and induced ferroptosis in HNSC. CONCLUSION: Our study underscores the multifaceted role of UBE2T in HNSC, illuminating its potential as a biomarker and therapeutic target.

Monocyte HLA-DR level on admission predicting in-hospital mortality rate in exertional heatstroke: A 12-year retrospective study.

BACKGROUND: Exertional heatstroke (EHS), a fatal illness, pronounces multiple organ dysfunction syndrome (MODS) and high mortality rate. Currently, no ideal factor prognoses EHS. Decreased monocyte human leukocyte-DR antigen (mHLA-DR) has been observed in critically ill individuals, particularly in those with sepsis. While most research focus on the pro-inflammatory response exploration in EHS, there are few studies related to immunosuppression, and no report targeted on mHLA-DR in EHS. The present study tried to explore the prognostic value of mHLA-DR levels in EHS patients. METHODS: This was a single-center retrospective study. Clinical data of EHS patients admitted to the intensive care unit of the General Hospital of Southern Theatre Command between January 1, 2008, and December 31, 2020, were recorded and analyzed. RESULTS: Seventy patients with 54 survivors and 16 nonsurvivors were ultimately enrolled. Levels of mHLA-DR in the nonsurvivors (41.8% [38.1-68.1]%) were significantly lower than those in the survivors (83.1% [67.6-89.4]%, p < 0.001). Multivariate logistic regression indicated that mHLA-DR (odds ratio [OR] = 0.939; 95% confidence interval [CI]: 0.892-0.988; p = 0.016) and Glasgow coma scale (GCS) scores (OR = 0.726; 95% CI: 0.591-0.892; p = 0.002) were independent risk factors related with in-hospital mortality rate in EHS. A nomogram incorporated mHLA-DR with GCS demonstrated excellent discrimination and calibration abilities. Compared to the traditional scoring systems, the prediction model incorporated mHLA-DR with GCS had the highest area under the curve (0.947, 95% CI: [0.865-0.986]) and Youden index (0.8333), with sensitivity of 100% and specificity of 83.33%, and a greater clinical net benefit. CONCLUSION: Patients with EHS were at a risk of early experiencing decreased mHLA-DR early. A nomogram based on mHLA-DR with GCS was developed to facilitate early identification and timely treatment of individuals with potentially poor prognosis.

Genetic Characterization, Pathogenicity, and Epidemiology Analysis of Three Sub-Genotype Pigeon Newcastle Disease Virus Strains in China.

Pigeon Newcastle disease (ND) is a serious infectious illness caused by the pigeon Newcastle disease virus (NDV) or Paramyxovirus type 1 (PPMV-1). Genotype VI NDV is a primary factor in ND among Columbiformes (such as pigeons and doves). In a recent study, eight pigeon NDV strains were discovered in various provinces in China. These viruses exhibited mesogenic characteristics based on their MDT and ICPI values. The complete genome sequences of these eight strains showed a 90.40% to 99.19% identity match with reference strains of genotype VI, and a 77.86% to 80.45% identity match with the genotype II vaccine strain. Additionally, analysis of the F gene sequence revealed that these NDV strains were closely associated with sub-genotypes VI.2.2.2, VI.2.1.1.2.1, and VI.2.1.1.2.2. The amino acid sequence at the cleavage site of the F protein indicated virulent characteristics, with the sequences 112KRQKRF117 and 112RRQKRF117 observed. Pigeons infected with these sub-genotype strains had a low survival rate of only 20% to 30%, along with lesions in multiple tissues, highlighting the strong spread and high pathogenicity of these pigeon NDV strains. Molecular epidemiology data from the GenBank database revealed that sub-genotype VI.2.1.1.2.2 strains have been prevalent since 2011. In summary, the findings demonstrate that the prevalence of genotype VI NDV is due to strains from diverse sub-genotypes, with the sub-genotype VI.2.1.1.2.2 strain emerging as the current epidemic strain, highlighting the significance of monitoring pigeon NDV in China.

Comparison of the dural puncture epidural and the standard epidural techniques in patients having labor analgesia maintained using programmed epidural boluses: a prospective double-blinded randomized clinical trial.

BACKGROUND: The dural puncture epidural technique has been shown in some studies to improve the onset and quality of the initiation of labor analgesia compared with the standard epidural technique. However, few studies have investigated whether this technique confers advantages during the maintenance of analgesia. This randomized double-blinded controlled study compared dural puncture epidural analgesia with standard epidural analgesia when analgesia was maintained using programmed intermittent epidural boluses. METHODS: 400 parturients requesting epidural labor analgesia were randomized to have analgesia initiated with a test dose of 3 mL lidocaine 1.5% with epinephrine 15 µg, followed by 12 mL ropivacaine 0.15% mixed with sufentanil 0.5 µg/mL using the dural puncture epidural or the standard epidural technique. After confirming satisfactory analgesia, analgesia was maintained with ropivacaine 0.1% and sufentanil 0.5 µg/mL via programmed intermittent epidural boluses (fixed volume 8 mL, intervals 40 min). We compared local anesthetic consumption, pain scores, obstetric and neonatal outcomes and patient satisfaction. RESULTS: A total of 339 patients completed the study and had data analyzed. There were no differences between the dural puncture epidural and standard epidural groups in ropivacaine consumption (mean difference -0.724 mg, 95% CI of difference -1.450 to 0.001 mg, p=0.051), pain scores, time to first programmed intermittent epidural bolus, the number of programmed intermittent epidural boluses, the number of manual epidural boluses, obstetric outcome or neonatal outcome. Patient satisfaction scores were statistically higher in the dural puncture epidural group but the absolute difference in scores was small. CONCLUSION: Our findings suggest that when labor analgesia is maintained using the programmed intermittent epidural bolus method, there is no significant advantage to initiating analgesia using the dural puncture epidural compared with the standard epidural technique. TRIAL REGISTRATION NUMBER: ChiCTR2200062349.

Remote Monitoring and Data Collection for Decentralized Clinical Trials.

Importance: Less than 5% of patients with cancer enroll in a clinical trial, partly due to financial and logistic burdens, especially among underserved populations. The COVID-19 pandemic marked a substantial shift in the adoption of decentralized trial operations by pharmaceutical companies. Objective: To assess the current global state of adoption of decentralized trial technologies, understand factors that may be driving or preventing adoption, and highlight aspirations and direction for industry to enable more patient-centric trials. Design, Setting, and Participants: The Bloomberg New Economy International Cancer Coalition, composed of patient advocacy, industry, government regulator, and academic medical center representatives, developed a survey directed to global biopharmaceutical companies of the coalition from October 1 through December 31, 2022, with a focus on registrational clinical trials. The data for this survey study were analyzed between January 1 and 31, 2023. Exposure: Adoption of decentralized clinical trial technologies. Main Outcomes and Measures: The survey measured (1) outcomes of different remote monitoring and data collection technologies on patient centricity, (2) adoption of these technologies in oncology and all therapeutic areas, and (3) barriers and facilitators to adoption using descriptive statistics. Results: All 8 invited coalition companies completed the survey, representing 33% of the oncology market by revenues in 2021. Across nearly all technologies, adoption in oncology trials lags that of all trials. In the current state, electronic diaries and electronic clinical outcome assessments are the most used technology, with a mean (SD) of 56% (19%) and 51% (29%) adoption for all trials and oncology trials, respectively, whereas visits within local physician networks is the least adopted at a mean (SD) of 12% (18%) and 7% (9%), respectively. Looking forward, the difference between the current and aspired adoption rate in 5 years for oncology is large, with respondents expecting a 40% or greater absolute adoption increase in 8 of the 11 technologies surveyed. Furthermore, digitally enabled recruitment, local imaging capabilities, and local physician networks were identified as technologies that could be most effective for improving patient centricity in the long term. Conclusions and Relevance: These findings may help to galvanize momentum toward greater adoption of enabling technologies to support a new paradigm of trials that are more accessible, less burdensome, and more inclusive.

Proton versus photon craniospinal irradiation for adult medulloblastoma: A dosimetric, toxicity, and exploratory cost analysis.

Background: This study aimed to determine whether proton craniospinal irradiation (CSI) decreased the dose to normal tissue and resulted in less toxicity than photon CSI for adult patients. Methods: This single-institution retrospective analyzed differences in radiation doses, acute toxicity, and cost between proton and CSI for adult medulloblastoma patients. Results: Of 39 total patients, 20 were treated with photon CSI prior to 2015, and 19 were treated with proton CSI thereafter. Median age was 28 years (range 18-66). The molecular subtype was most commonly sonic hedgehog (68%). Patients most commonly received 36 Gy CSI in 20 fractions with a boost to 54-55.8 Gy (92%). Proton CSI delivered significantly lower mean doses to cochleae, lacrimal glands, lens, parotid glands, pharyngeal constrictors, esophagus, lungs, liver, and skin (all P < .001). Patients receiving proton CSI had significantly lower rates of acute dysphagia of any grade (5% versus 35%, P = .044) and decreased median weight loss during radiation (+1.0 versus -2.8 kg, P = .011). Weight loss was associated with acute hospitalization (P = .009). Median follow-up was 2.9 and 12.9 years for proton and photon patients, respectively, limiting late toxicity and outcome comparisons. At the last follow-up, 5 photon patients had died (2 of progressive disease, 3 without recurrence ages 41-63) and 21% had experienced major cardiovascular events. At 10 years, 89% were alive and 82% were recurrence free. Conclusions: This study demonstrates dosimetric improvements with proton CSI, potentially leading to decreased acute toxicity including dysphagia and weight loss during treatment.

Co-occurrence of ozone and PM2.5 pollution in urban/non-urban areas in eastern China from 2013 to 2020: Roles of meteorology and anthropogenic emissions.

We applied a three-dimensional (3-D) global chemical transport model (GEOS-Chem) to evaluate the influences of meteorology and anthropogenic emissions on the co-occurrence of ozone (O3) and fine particulate matter (PM2.5) pollution day (O3-PM2.5PD) in urban and non-urban areas of the Beijing-Tianjin-Hebei (BTH) and Yangtze River Delta (YRD) regions during the warm season (April-October) from 2013 to 2020. The model captured the observed O3-PM2.5PD trends and spatial distributions well. From 2013 to 2020, with changes in both anthropogenic emissions and meteorology, the simulated values of O3-PM2.5PD in the urban (non-urban) areas of the BTH and YRD regions were 424.8 (330.1) and 309.3 (286.9) days, respectively, suggesting that pollution in non-urban areas also warrants attention. The trends in the simulated values of O3-PM2.5PD were -0.14 and -0.15 (+1.18 and +0.81) days yr-1 in the BTH (YRD) urban and non-urban areas, respectively. Sensitivity simulations revealed that changes in anthropogenic emissions decreased the occurrence of O3-PM2.5PD, with trends of -0.99 and -1.23 (-1.47 and -1.92) days yr-1 in the BTH (YRD) urban and non-urban areas, respectively. Conversely, meteorological conditions could exacerbate the frequency of O3-PM2.5PD, especially in the urban YRD areas, but less notably in the urban BTH areas, with trends of +2.11 and +0.30 days yr-1, respectively, owing to changes in meteorology only. The increases in T2m_max and T2m were the main meteorological factors affecting O3-PM2.5PD in most BTH and YRD areas. Furthermore, by conducting sensitivity experiments with different levels of pollutant precursor reductions in 2020, we found that volatile organic compound (VOC) reductions primarily benefited O3-PM2.5PD decreases in urban areas and that NOx reductions more notably influenced those in non-urban areas, especially in the YRD region. Simultaneously, reducing VOC and NOx emissions by 50 % resulted in considerable O3-PM2.5PD decreases (58.8-72.6 %) in the urban and non-urban areas of the BTH and YRD regions. The results of this study have important implications for the control of O3-PM2.5PD in the urban and non-urban areas of the BTH and YRD regions.