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Abstract Background and purpose Various deep learning auto-segmentation (DLAS) models have been proposed, some of which have been commercialized. However, the issue of performance degradation is notable when pretrained models are deployed in the clinic. This study aims to enhance precision of a popular commercial DLAS product in rectal cancer radiotherapy by localized fine-tuning, addressing challenges in practicality and generalizability in real-world clinical settings. Materials and methods A total of 120 Stage II/III mid-low rectal cancer patients were retrospectively enrolled and divided into three datasets: training (n = 60), external validation (ExVal, n = 30), and generalizability evaluation (GenEva, n = 30) datasets respectively. The patients in the training and ExVal dataset were acquired on the same CT simulator, while those in GenEva were on a different CT simulator. The commercial DLAS software was first localized fine-tuned (LFT) for clinical target volume (CTV) and organs-at-risk (OAR) using the training data, and then validated on ExVal and GenEva respectively. Performance evaluation involved comparing the LFT model with the vendor-provided pretrained model (VPM) against ground truth contours, using metrics like Dice similarity coefficient (DSC), 95th Hausdorff distance (95HD), sensitivity and specificity. Results LFT significantly improved CTV delineation accuracy (p

Osteosarcoma (OS) is one of the most common malignant tumors in children and young adults. As chemotherapy and other therapies are limited by low therapeutic efficiency, severe side effects and single therapeutic function, it is of high value to develop innovative therapies for precise and efficient treatment of OS. Herein, natural photosynthetic microalgae (C. vulgaris, CV) were utilized as carriers for the chemotherapeutic agent doxorubicin (DOX) to create a multifunctional therapeutic platform (CV@DOX) for the photo-modulation of the tumor microenvironment (TME) and synergistic chemo-photodynamic therapy of osteosarcoma. CV@DOX exhibited rapid drug release behavior in the acidic TME, improving the efficiency of chemotherapy against tumors and reducing side effects on other normal tissues. Under 650 nm laser irradiation, CV@DOX demonstrated the ability to effectively generate oxygen to alleviate tumor hypoxia and utilize the photosensitizing properties of chlorophyll in CV to produce an increased amount of reactive oxygen species (ROS), thereby enhancing photodynamic therapy (PDT). CV@DOX-mediated synergistic chemo-photodynamic therapy demonstrated efficacy in halting tumor progression in an orthotopic osteosarcoma mouse model by promoting tumor cell apoptosis, inhibiting tumor proliferation and angiogenesis. Moreover, chlorophyll-assisted fluorescence imaging enabled monitoring of the distribution of CV@DOX in osteosarcoma after administration. Finally, CV@DOX did not cause significant hematological and tissue toxicity, and prevented DOX-induced cardiotoxicity, showing good in vivo biocompatibility. Overall, this work presents a novel TME-responsive and TME-modulating platform for imaging-guided multimodal osteosarcoma treatment.

Micro/nanoplastics (MNPs) and heavy metals (HMs) coexist worldwide. Existing studies have reported different or even contradictory toxic effects of co-exposure to MNPs and HMs on plants, which may be related to various influencing factors. In this study, existing publications were searched and analyzed using CiteSpace, meta-analysis, and machine learning. CiteSpace analysis showed that this research field was still in the nascent stage, and hotspots in this field included accumulation, cadmium (Cd), growth, and combined toxicity. Meta-analysis revealed the differential association of seven influencing factors (MNP size, pollutant treatment duration, cultivation media, plant species, MNP type, HM concentration, and MNP concentration) and 8 physiological parameters receiving the most attention. Co-exposure of the two contaminants had stronger toxic effects than HM treatment alone, and phytotoxicity was generally enhanced with increasing concentrations and longer exposure durations, especially when using nanoparticles, hydroponic medium, dicotyledons producing stronger toxic effects than microplastics, soil-based medium, and monocotyledons. Dry and fresh weight analysis showed that co-exposure to MNPs and Cd resulted in significant phytotoxicity in all classifications. Concerning the MNP types, polyolefins partially attenuated plant toxicity, but both modified polystyrene (PS) and biodegradable polymers exacerbated joint phytotoxicity. Finally, machine learning was used to fit and predict plant HM concentrations, showing five classifications with an accuracy over 80 %, implying that the polynomial regression model could be used to predict HM content in plants under complex pollution conditions. Overall, this study identifies current knowledge gaps and provides guidance for future research.

Abstract Ultra‐thin 2D materials have great potential as electrodes for micro‐supercapacitors (MSCs) because of their facile ion transport channels. Here, a high‐precision controllable photonic‐synthesis strategy that provided 1 inch wafer‐scale ultra‐thin film arrays of alloyed WxMo2xSy with sulfur vacancies and expanded interlayer (13.2 Å, twice of 2H MoS2) is reported. This strategy regulates the nucleation and growth of transition metal dichalcogenides (TMDs) on the picosecond or even femtosecond scale, which induces Mo–W alloying, interlayer expansion, and sulfur loss. Therefore, the diffusion barrier of WxMo2xSy is reduced, with charge transfer and ion diffusion enhancing. The as‐prepared symmetric MSCs with the size of 100 × 100 µm2 achieve ultrahigh specific capacitance (242.57 mF cm−2 and 242567.83 F cm−3), and energy density (21.56 Wh cm−3 with power density of 485.13 W cm3). The established synthesis strategy fits numerous materials, which provides a universal method for the flexible synthesis of electrodes in microenergy devices.

Bacterial infections pose a significant clinical burden on global health. The growing incidence of drug-resistant pathogens highlights the critical necessity to identify and isolate bioactive compounds from marine resources. Marine-derived fungi could provide novel lead compounds against pathogenic bacteria. Due to the particularity of the marine environment, Aspergillus species derived from marine sources have proven to be potent producers of bioactive secondary metabolites and have played a considerable role in advancing drug development. This study reviews the structural diversity and activities against pathogenic bacteria of secondary metabolites isolated from marine-derived Aspergillus species over the past 14 years (January 2010–June 2024), and 337 natural products (including 145 new compounds) were described. The structures were divided into five major categories—terpenoids, nitrogen-containing compounds, polyketides, steroids, and other classes. These antimicrobial metabolites will offer lead compounds to the development and innovation of antimicrobial agents.

Abstract Suicidal behavior and non-suicidal self-injury (NSSI) are common in adolescent patients with major depressive disorder (MDD). Thus, delineating the unique characteristics of suicide attempters having adolescent MDD with NSSI is important for suicide prediction in the clinical setting. Here, we performed psychological and biochemical assessments of 130 youths having MDD with NSSI. Participants were divided into two groups according to the presence/absence of suicide attempts (SAs). Our results demonstrated that the age of suicide attempters is lower than that of non-attempters in participants having adolescent MDD with NSSI; suicide attempters had higher Barratt Impulsiveness Scale (BIS-11) impulsivity scores and lower serum CRP and cortisol levels than those having MDD with NSSI alone, suggesting levels of cortisol and CRP were inversely correlated with SAs in patients with adolescent MDD with NSSI. Furthermore, multivariate regression analysis revealed that NSSI frequency in the last month and CRP levels were suicidal ideation predictors in adolescent MDD with NSSI, which may indicate that the increased frequency of NSSI behavior is a potential risk factor for suicide. Additionally, we explored the correlation between psychological and blood biochemical indicators to distinguish suicide attempters among participants having adolescent MDD with NSSI and identified a unique correlation network that could serve as a marker for suicide attempters. Our research data further suggested a complex correlation between the psychological and behavioral indicators of impulsivity and anger. Therefore, our study findings may provide clues to identify good clinical warning signs for SA in patients with adolescent MDD with NSSI.

We herein report a rare case of simultaneous intrauterine molar pregnancy and tubal pregnancy. A woman of childbearing age who had never been pregnant underwent an ultrasound examination 70 days after the onset of menopause. She had a history of ovulation induction. The ultrasound findings suggested a partial hydatidiform mole. She was then pathologically confirmed to have a complete hydatidiform mole after uterine suction dilation and curettage. On postoperative day 4, an ultrasound examination before discharge showed an inhomogeneous mass in the left adnexal region with mild lower abdominal pain. On postoperative day 17, the blood human chorionic gonadotropin level did not drop as expected, and a follow-up examination still indicated a mass in the left adnexal region. We were unable to rule out an ectopic hydatidiform mole. Hysteroscopy with laparoscopic exploration of the left adnexal mass and salpingotomy suggested a diagnosis of intrauterine hydatidiform mole combined with left tubal pregnancy.

T cell receptor (TCR) T cell therapies target tumor antigens in a human leukocyte antigen (HLA)-restricted manner. Biomarker-defined therapies require validation of assays suitable for determination of patient eligibility. For clinical trials evaluating TCR T cell therapies targeting melanoma-associated antigen A4 (MAGE-A4), screening in studies NCT02636855 and NCT04044768 assesses patient eligibility based on: (1) high-resolution HLA typing and (2) tumor MAGE-A4 testing via an immunohistochemical assay in HLA-eligible patients. The HLA/MAGE-A4 assays validation, biomarker data, and their relationship to covariates (demographics, cancer type, histopathology, tissue location) are reported here. HLA-A∗02 eligibility was 44.8% (2,959/6,606) in patients from 43 sites across North America and Europe. While HLA-A∗02:01 was the most frequent HLA-A∗02 allele, others (A∗02:02, A∗02:03, A∗02:06) considerably increased HLA eligibility in Hispanic, Black, and Asian populations. Overall, MAGE-A4 prevalence based on clinical trial enrollment was 26% (447/1,750) across 10 solid tumor types, and was highest in synovial sarcoma (70%) and lowest in gastric cancer (9%). The covariates were generally not associated with MAGE-A4 expression, except for patient age in ovarian cancer and histology in non-small cell lung cancer. This report shows the eligibility rate from biomarker screening for TCR T cell therapies and provides epidemiological data for future clinical development of MAGE-A4-targeted therapies.

Peptide medications have been more well-known in recent years due to their many benefits, including low side effects, high biological activity, specificity, effectiveness, and so on. Over 100 peptide medications have been introduced to the market to treat a variety of illnesses. Most of these peptide medications are developed on the basis of endogenous peptides or natural peptides, which frequently required expensive, time-consuming, and extensive tests to confirm. As artificial intelligence advances quickly, it is now possible to build machine learning or deep learning models that screen a large number of candidate sequences for therapeutic peptides. Therapeutic peptides, such as those with antibacterial or anticancer properties, have been developed by the application of artificial intelligence algorithms.The process of finding and developing peptide drugs is outlined in this review, along with a few related cases that were helped by AI and conventional methods. These resources will open up new avenues for peptide drug development and discovery, helping to meet the pressing needs of clinical patients for disease treatment. Although peptide drugs are a new class of biopharmaceuticals that distinguish them from chemical and small molecule drugs, their clinical purpose and value cannot be ignored. However, the traditional peptide drug research and development has a long development cycle and high investment, and the creation of peptide medications will be substantially hastened by the AI-assisted (AI+) mode, offering a new boost for combating diseases.

The rapid and accurate classification of Panax notoginseng leaf diseases is vital for timely disease control and reducing economic losses. Recently, image classification algorithms have shown great promise for plant disease diagnosis, but dataset quantity and quality are crucial. Moreover, classifying P. notoginseng leaf diseases faces severe challenges, including the small features of anthrax and the strong similarity between round spot and melasma diseases. In order to address these problems, we have proposed an ECA-based diffusion model and Inception-SSNet for the classification of the six major P. notoginseng leaf diseases, namely gray mold, powdery mildew, virus infection, anthrax, melasma, and round spot. Specifically, we propose an image generation scheme, in which the lightweight attention mechanism, ECA, is used to capture the dependencies between channels for improving the dataset quantity and quality. To extract disease features more accurately, we developed an Inception-SSNet hybrid model with skip connection, attention feature fusion, and self-calibrated convolutional. These innovative methods enable the model to make better use of local and global information, especially when dealing with diseases with similar features and small targets. The experimental results show that our proposed ECA-based diffusion model FID reaches 42.73, compared with the baseline model, which improved by 74.71%. Further, we tested the classification model using the data set of P. notoginseng leaf disease generation, and the accuracy of 11 mainstream classification models was improved. Our proposed Inception-SSNet classification model achieves an accuracy of 97.04% on the non-generated dataset, which is an improvement of 0.11% compared with the baseline model. On the generated dataset, the accuracy reached 99.44%, which is an improvement of 1.02% compared to the baseline model. This study provides an effective solution for the monitoring of Panax notoginseng diseases.

BackgroundAcute hematologic toxicity (HT) is a prevalent adverse tissue reaction observed in cervical cancer patients undergoing chemoradiotherapy (CRT), which may lead to various negative effects such as compromised therapeutic efficacy and prolonged treatment duration. Accurate prediction of HT occurrence prior to CRT remains challenging.MethodsA discovery dataset comprising 478 continuous cervical cancer patients (140 HT patients) and a validation dataset consisting of 205 patients (52 HT patients) were retrospectively enrolled. Both datasets were categorized into the CRT group and radiotherapy (RT)-alone group based on the treatment regimen, i.e., whether chemotherapy was administered within the focused RT duration. Radiomics features were derived by contouring three regions of interest (ROIs)—bone marrow (BM), femoral head (FH), and clinical target volume (CTV)—on the treatment planning CT images before RT. A comprehensive model combining the radiomics features as well as the demographic, clinical, and dosimetric features was constructed to classify patients exhibiting acute HT symptoms in the CRT group, RT group, and combination group. Furthermore, the time-to-event analysis of the discriminative ROI was performed on all patients with acute HT to understand the HT temporal progression.ResultsAmong three ROIs, BM exhibited the best performance in classifying acute HT, which was verified across all patient groups in both discovery and validation datasets. Among different patient groups in the discovery dataset, acute HT was more precisely predicted in the CRT group [area under the curve (AUC) = 0.779, 95% CI: 0.657–0.874] than that in the RT-alone (AUC = 0.686, 95% CI: 0.529–0.817) or combination group (AUC = 0.748, 95% CI: 0.655–0.827). The predictive results in the validation dataset similarly coincided with those in the discovery dataset: CRT group (AUC = 0.802, 95% CI: 0.669–0.914), RT-alone group (AUC = 0.737, 95% CI: 0.612–0.862), and combination group (AUC = 0.793, 95% CI: 0.713–0.874). In addition, distinct feature sets were adopted for different patient groups. Moreover, the predicted HT risk of BM was also indicative of the HT temporal progression.ConclusionsHT prediction in cervical patients is dependent on both the treatment regimen and ROI selection, and BM is closely related to the occurrence and progression of HT, especially for CRT patients.

Six new polyketides, which includes three new lactones (talarotones A–C) (1–3), one new polyketide (talarotide A) (4), two new polyenes (talaroyenes A, B) (5, 6), together with one new meroterpenoid (talaropenoid A) (7) and 13 known compounds (8–20) were isolated from the mangrove-derived fungus Talaromyces flavus TGGP35. The structure and configuration of the compounds 1–7 were elucidated from the data obtained from HR-ESI-MS, IR, 1D/2D NMR spectroscopy, Mo2 (OAc)4-induced electronic circular dichroism (ECD), CD spectroscopy, and modified Mosher's method. Compounds 5 and 20 displayed antioxidant activity with IC50 values of 0.40 and 1.36 mM, respectively. Compounds 3, 6, 11, 16, and 17 displayed cytotoxic activity against human cancer cells Hela, A549, and had IC50 values ranging from 28.89 to 62.23 μM. Compounds 7, 10–12, and 14–18 exhibited moderate or potent anti-insect activity against newly hatched larvae of Helicoverpa armigera Hubner, with IC50 values in the range 50–200 μg/mL. Compound 18 showed antibacterial activity against Ralstonia solanacearum with the MIC value of 50 μg/mL.

Propylene glycol (PG) and vegetable glycerin (VG) are the most common solvents used in electronic cigarette liquids. No long-term inhalation toxicity assessments have been performed combining conventional and multi-omics approaches on the potential respiratory effects of the solvents in vivo. In this study, the systemic toxicity of aerosol generated from a ceramic heating coil-based e-cigarette was evaluated. First, the aerosol properties were characterized, including carbonyl emissions, the particle size distribution, and aerosol temperatures. To determine toxicological effects, rats were exposed, through their nose only, to filtered air or a propylene glycol (PG)/ glycerin (VG) (50:50, %W/W) aerosol mixture at the target concentration of 3 mg/L for six hours daily over a continuous 28-day period. Compared with the air group, female rats in the PG/VG group exhibited significantly lower body weights during both the exposure period and recovery period, and this was linked to a reduced food intake. Male rats in the PG/VG group also experienced a significant decline in body weight during the exposure period. Importantly, rats exposed to the PG/VG aerosol showed only minimal biological effects compared to those with only air exposure, with no signs of toxicity. Moreover, the transcriptomic, proteomic, and metabolomic analyses of the rat lung tissues following aerosol exposure revealed a series of candidate pathways linking aerosol inhalation to altered lung functions, especially the inflammatory response and disease. Dysregulated pathways of arachidonic acids, the neuroactive ligand-receptor interaction, and the hematopoietic cell lineage were revealed through integrated multi-omics analysis. Therefore, our integrated multi-omics approach offers novel systemic insights and early evidence of environmental-related health hazards associated with an e-cigarette aerosol using two carrier solvents in a rat model.

BackgroundHigh-quality primary care is associated with better health outcomes and more efficient and equitable health system performance. However, the rate of primary care attachment is falling, and timely access to primary care is worsening, driving many patients to use walk-in clinics for their comprehensive primary care needs. This study sought to explore the experiences and perceived roles and responsibilities of walk-in physicians in this current climate. Methods: Qualitative interviews were conducted with nineteen physicians currently providing walk-in care in Ontario, Canada between May and December 2022.ResultsLimited capacity for continuity and comprehensiveness of care were identified as major sources of professional tension for walk-in physicians. Divergent perspectives on their roles were anchored in how physicians viewed their professional identity. Some saw providing continuous and comprehensive care as an infringement on their professional role; others saw their professional role as more flexible and responsive to population needs. Regardless of their professional identity, participants reported feeling ill-equipped to manage the swell of unattached patients, citing a lack of time, resources, connectivity to the system, and remuneration flexibility. Conclusions: As practice demands of walk-in clinics change, an evolution in the professional roles and responsibilities of walk-in physicians follows. However, the resources, structure, and incentives of walk-in care have not evolved to reflect this, leaving physicians to set their own professional boundaries with patients. This results in increasing variations in care and confusion across the primary care sector around who is responsible for what, when, and how.

Summary: Large quantities of developmentally synchronized pupal intestines are required for biochemistry experiments. Here, we present a protocol for the mass isolation of staged pupal intestines during Drosophila melanogaster development based on buoyancy in sucrose for biochemical evaluation of protein ubiquitylation. We describe steps for crossing flies, preparation of samples, immunoprecipitation of proteins from staged isolated tissues, and analysis of samples by western blot. This protocol can be extended to investigate biochemical changes in other tissues.For complete details on the use and execution of this protocol, please refer to Wang et al. (2023).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

The high risk for anxiety and depression among individuals with stress has become a growing concern globally. Stress-related mental disorders are often accompanied by symptoms of metabolic dysfunction. Cordycepin is a Chinese herbal medicine commonly used for its metabolism-enhancing effects. We aimed to investigate the dose-dependent effects of cordycepin on psycho-metabolic disorders induced by stress. Our behavioral tests revealed that 12.5 mg/kg cordycepin by oral gavage significantly attenuated the anxiety- and depression-like behaviors induced by stress in mice. At 25 mg/kg, cordycepin restored the reduced weight and cell size of adipose tissues caused by stress. Besides ameliorating the metabolic dysbiosis of gut microbiota due to stress, cordycepin significantly reduced the elevated contents of 5-hydroxyindoleacetic acid in the serum and prefrontal cortex at 12.5 mg/kg and reversed the decrease in adipose induced by stress at 25 mg/kg. Correlation analyses further revealed that 12.5 mg/kg cordycepin reversed stress-induced changes in the intestinal microbiome of NK4A214_group and decreased serum Myristic acid and PC(15:0/18:1(11Z)) and cytokines, such as IFN-γ and IL-1β. 25 mg/kg cordycepin reversed stress-induced changes in the abundances of Prevoteaceae_UCG-001 and Desulfovibrio, increased serum L-alanine level, and decreased serum Inosine-5'-monophosphate level. Cordycepin thereby ameliorated the anxiety- and depression-like behaviors as well as disturbances in the adipose metabolism of mice exposed to stress. Overall, these findings offer evidence indicating that the prominent effects of cordycepin in the brain and adipose tissues are dose dependent, thus highlight the importance of evaluating the precise therapeutic effects of different cordycepin doses on psycho-metabolic diseases.

Background and aims: This study aimed to determine the prevalence of morbid thoughts and suicide attempts as well as their relationship with perceived health status, quality of life, and happiness in five low-middle-income countries. Methods: Data on 3373 men and women aged 40 years and above were collected from the World Health Organization’s (WHO’s) study on global AGEing and adult health (SAGE) survey on five countries: China (830), Ghana (438), India (1602), Russia (175), and South Africa (830). Outcome variables were morbid thoughts and suicide attempts, and the main explanatory variables were health status, quality of life, and happiness. Results: The findings indicated that among the five countries, India had the highest prevalence of both morbid thoughts 79.5% (95% CI: 73.4-84.5) and suicide attempts 75.4% (95% CI: 61.0-85.7), while Ghana had the lowest prevalence of both morbid thoughts 1.9% (95% CI: 1.3-2.7) and suicide attempts 2.5% (95% CI: 1.1-5.5). Furthermore, regression analysis revealed a significant association between perceived health, quality of life, and happiness with morbid thoughts and suicide attempts. However, the association between perceived health and happiness was significant only among women. Men and women reporting dissatisfaction with the quality of life had 1.521 times (95% CI: 1.126-2.056) and 1.762 times (95% CI: 1.406-2.209) higher odds of morbid thoughts compared with those who reported satisfaction with the quality of life. Conclusion: Perceived poor health, quality of life, and happiness are significantly associated with higher odds of morbid thoughts of suicidal ideation, especially among women. In line with the past findings, these findings support the importance of focusing on these perceived constructs of health and life for mental health promotion and suicide prevention programs.

BackgroundEmerging adults living with type 1 diabetes (T1D) face a series of challenges with self-management and decreased health system engagement, leading to an increased risk of acute complications and hospital admissions. Effective and scalable strategies are needed to support this population to transfer seamlessly from pediatric to adult care with sufficient self-management capability. While digital health interventions for T1D self-management are a promising strategy, it remains unclear which elements work, how, and for which groups of individuals. ObjectiveThis study aims to evaluate the design and implementation of a multicomponent SMS text message–based digital health intervention to support emerging adults living with T1D in real-world settings. The objectives are to identify the intervention components and associated mechanisms that support user engagement and T1D health care transition experiences and determine the individual characteristics that influence the implementation process. MethodsWe used a realist evaluation embedded alongside a randomized controlled trial, which uses a sequential mixed methods design to analyze data from multiple sources, including intervention usage data, patient-reported outcomes, and realist interviews. In step 1, we conducted a document analysis to develop a program theory that outlines the hypothesized relationships among “individual-level contextual factors, intervention components and features, mechanisms, and outcomes,” with special attention paid to user engagement. Among them, intervention components and features depict 10 core characteristics such as transition support information, problem-solving information, and real-time interactivity. The proximal outcomes of interest include user engagement, self-efficacy, and negative emotions, whereas the distal outcomes of interest include transition readiness, self-blood glucose monitoring behaviors, and blood glucose. In step 2, we plan to conduct semistructured realist interviews with the randomized controlled trial’s intervention-arm participants to test the hypothesized “context-intervention-mechanism-outcome” configurations. In step 3, we plan to triangulate all sources of data using a coincidence analysis to identify the necessary combinations of factors that determine whether and how the desired outcomes are achieved and use these insights to consolidate the program theory. ResultsFor step 1 analysis, we have developed the initial program theory and the corresponding data collection plan. For step 2 analysis, participant enrollment for the randomized controlled trial started in January 2023. Participant enrollment for this realist evaluation was anticipated to start in July 2023 and continue until we reached thematic saturation or achieved informational power. ConclusionsBeyond contributing to knowledge on the multiple pathways that lead to successful engagement with a digital health intervention as well as target outcomes in T1D care transitions, embedding the realist evaluation alongside the trial may inform real-time intervention refinement to improve user engagement and transition experiences. The knowledge gained from this study may inform the design, implementation, and evaluation of future digital health interventions that aim to improve transition experiences. International Registered Report Identifier (IRRID)PRR1-10.2196/46115

Androgenetic alopecia (AGA) is an androgen-mediated alopecia affected by both genes and hormones. Medication is a relatively common treatment. As a new drug delivery method, microneedles (MNs) can effectively break through the stratum corneum barrier, deliver drugs more efficiently, and achieve better therapeutic effects. In this study, we develop a composite double-layer MN through multi-step casting fabrication using a polydimethylsiloxane mold. The needle tip was fabricated by mixed solution of chitosan and polyvinylpyrrolidone which was loaded with Polygonum multiflorum extract, and the base layer was prepared by mixed solution of polyvinyl alcohol and polyvinylpyrrolidone. In vitro mechanical tests showed that the maximum load of a single tip of the drug-loaded MN was about 3.5 ​N, which met the mechanical requirements of skin puncture (>1 ​N). The drug release experiment showed that the MN could achieve gradual drug release. In the animal experiment, pigmentation and hair regrowth occurred earlier in the Polygonum multiflorum-MN (Pm-MN) group than in the other groups, and hair growth finally appeared in almost the entire area. Compared with the AGA model mice, mice in the Pm-MN group achieved an increase in the number and diameter of hair follicles. In conclusion, the Pm-MN is scientific and feasible for treating AGA.

In order to control the influence of wind power generation incorporated into the power grid and keep the original power grid stable, this paper investigates the Takagi–Sugeno fuzzy model and the nonlinear switched system for permanent magnet synchronous generator in wind power generation system. By introducing fuzzy sliding mode control method, the stability of power system can be guaranteed. To do this, the integral sliding mode surface and fuzzy sliding mode control law are designed to reduce the influence of nonlinear disturbance on power system. In addition, the appropriate Lyapunov function is selected for derivation and proof. At the same time, the gain matrix is solved by linear matrix inequalities, which makes the model globally asymptotically stable. Finally, the stability of the system model is verified by simulation results.

Muscle contraction increases the level of reactive oxygen species (ROS), which has been acknowledged as key signaling entities in muscle remodeling and to underlie the healthy adaptation of skeletal muscle. ROS inevitably endows damage to various cellular molecules including DNA. DNA damage ought to be repaired to ensure genome integrity; yet, how DNA repair byproducts affect muscle adaptation remains elusive. Here, we showed that exercise elicited the generation of 8-oxo-7,8-dihydroguanine (8-oxoG), that was primarily found in mitochondrial genome of myofibers. Upon exercise, TA muscle's 8-oxoG excision capacity markedly enhanced, and in the interstitial fluid of TA muscle from the post-exercise mice, the level of free 8-oxoG base was significantly increased. Addition of 8-oxoG to myoblasts triggered myogenic differentiation via activating Ras-MEK-MyoD signal axis. 8-Oxoguanine DNA glycosylase1 (OGG1) silencing from cells or Ogg1 KO from mice decreased Ras activation, ERK phosphorylation, MyoD transcriptional activation, myogenic regulatory factors gene (MRFs) expression. In reconstruction experiments, exogenously added 8-oxoG base enhanced the expression of MRFs and accelerated the recovery of the injured skeletal muscle. Collectively, these data not only suggest that DNA repair metabolite 8-oxoG function as a signal entity for muscle remodeling and contribute to exercise-induced adaptation of skeletal muscle, but also raised the potential for utilizing 8-oxoG in clinical treatment to skeletal muscle damage-related disorders.

Abstract Background Peripartum depression in and after pregnancy are common, reported by 11.9% of women worldwide, and the proportion was even higher during the outbreak of coronavirus disease 2019 (COVID-19). We aimed to investigate the prevalence and risk factors of peripartum depression under the influence of COVID-19 in China. Methods Using a cross-sectional design, 2026 pregnant and postpartum women residing in Beijing, Wuhan, and Lanzhou of China were recruited from February 28 to April 9, 2020. The Patient Health Questionnaire-9 was used to assess their depressive symptoms. The women were divided into four subgroups based on pregnancy stage, and a binary logistic regression analysis was conducted on each subgroup. Results Under the influence of COVID-19, the prevalence rate of peripartum depression among Chinese women was 9.7%. It was 13.6, 10.8, 7.9 and 7.3% in the first, second, third trimester and puerperium, respectively. Regression analysis showed that the influence of current pregnancy status on movement (Mild vs. No, aORs were 3.89, P

The rostral ventromedial medulla (RVM) exerts bidirectional descending modulation of pain attributable to the activity of electrophysiologically identified pronociceptive ON and antinociceptive OFF neurons. Here, we report that GABAergic ON neurons specifically express G protein–coupled estrogen receptor (GPER). GPER+ neurons exhibited characteristic ON-like responses upon peripheral nociceptive stimulation. Optogenetic activation of GPER+ neurons facilitated, but their ablation abrogated, pain. Furthermore, activation of GPER caused depolarization of ON cells, potentiated pain, and ameliorated morphine analgesia through desensitizing μ-type opioid receptor–mediated (MOR-mediated) activation of potassium currents. In contrast, genetic ablation or pharmacological blockade of GPER attenuated pain, enhanced morphine analgesia, and delayed the development of morphine tolerance in diverse preclinical pain models. Our data strongly indicate that GPER is a marker for GABAergic ON cells and illuminate the mechanisms underlying hormonal regulation of pain and analgesia, thus highlighting GPER as a promising target for the treatment of pain and opioid tolerance.

Abstract Background Megaloblastic anemia or bone marrow changes could occur after prolonged nitrous oxide inhalation via vitamin B12 inactivation related DNA synthesis impairment. Previous researches have studied hematological changes with nitrous oxide exposure, but only in adults or adolescents. Pre-school age children with active hematopoietic red bone marrow are more vulnerable to potential side effects of nitrous oxide and might experience growth impairment. The purpose of our study was to analyze red blood cell morphology changes under nitrous oxide anesthesia in pre-school age children. Methods One hundred thirty-six children under 5 years old scheduled for hemivertebra resection were analyzed. According to fresh gas type in anesthesia records, 71 children who received nitrous oxide in oxygen during anesthesia maintenance were categorized into the nitrous oxide group and the other 65 who received air in oxygen were the air group. Complete blood counts in perioperative period were assessed for anemia, macrocytosis, microcytosis, anisocytosis, hyperchromatosis and hypochromatosis. The peak value and change percentage were calculated for mean corpuscular volume and red cell distribution width. Results Forty-two children in the air group (64.6%) and 30 in the nitrous oxide group (42.3%) developed anemia (P = 0.009). None developed macrocytosis in both groups. Postoperative mean corpuscular volume peaked (mean [95% confidence interval]) at 83.7(82.9–84.4) fL, and 83.2(82.4–83.9) fL and postoperative red cell distribution width at 13.8% (13.4–14.2%), and 13.9% (13.6–14.2%) for the air group and the nitrous oxide group. Both the relative change of mean corpuscular volume (P = 0.810) and red cell distribution width (P = 0.456) were similar between the two groups. Conclusions No megaloblastic red blood cell changes were observed with nitrous oxide exposure for 4 h in pre-school age children undergoing hemivertebra resection.

Abstract As an important part of smart city construction, traffic image denoising has been studied widely. Image denoising technique can enhance the performance of segmentation and recognition model and improve the accuracy of segmentation and recognition results. However, due to the different types of noise and the degree of noise pollution, the traditional image denoising methods generally have some problems, such as blurred edges and details, loss of image information. This paper presents an image denoising method based on BP neural network optimized by improved whale optimization algorithm. Firstly, the nonlinear convergence factor and adaptive weight coefficient are introduced into the algorithm to improve the optimization ability and convergence characteristics of the standard whale optimization algorithm. Then, the improved whale optimization algorithm is used to optimize the initial weight and threshold value of BP neural network to overcome the dependence in the construction process, and shorten the training time of the neural network. Finally, the optimized BP neural network is applied to benchmark image denoising and traffic image denoising. The experimental results show that compared with the traditional denoising methods such as Median filtering, Neighborhood average filtering and Wiener filtering, the proposed method has better performance in peak signal-to-noise ratio.

Abstract Background The gender pay gap in the United States (US) has narrowed over the last several decades, with the female/male earnings ratio in the US increased from about 60% before the 1980s to about 79% by 2014. However, the gender pay gap among the healthcare workforce persists. The objective of this study is to estimate the gender pay gap in the US federal governmental public health workforce during 2010–2018. Methods We used an administrative dataset including annual pay rates and job characteristics of employees of the US Department of Health and Human Services. Employees’ gender was classified based on first names. Regression analyses were used to estimate the gender pay gap using the predicted gender. Results Female employees of the DHHS earned about 13% less than men in 2010, and 9.2% less in 2018. Occupation, pay plan, and location explained more than half of the gender pay gap. Controlling for job grade further reduces the gap. The unexplained portion of the gender pay gap in 2018 was between 1.0 and 3.5%. Female employees had a slight advantage in terms of pay increase over the study period. Conclusions While the gender pay gap has narrowed within the last two decades, the pay gap between female and male employees in the federal governmental public health workforce persists and warrants continuing attention and research. Continued efforts should be implemented to reduce the gender pay gap among the health workforce.

Abstract Background Although more and more attention has been paid to the psychological consequences of the lockdown policy amongst pregnant women, the underlying mechanism linking the lockdown policy to maternal depression has not been studied in the context of China. This study aimed to explore the association between the lockdown policy and maternal depressive symptoms, and whether such association was mediated by internet use and/or family support. Methods This cross-sectional study used multi-stage sampling techniques in central and western China. Data were collected from 1266 pregnant women using a structtured questionnaire that measured internet use, family support, and depressive symptoms. The Patient Health Questionnaire-9 (PHQ-9) was used to measure depressive symptoms. Internet use was measured by length of usage and varierity of purpose for internet use. Family support was measureed by spousal support and parental support. The structural equation modelling was employed to conduct mediation analysis to test the specificity of the hypothetical paths. Results Overall, 527 respondents (41.63%) presented depressive symptoms. The lockdown policy was negatively associated with depressive symptoms in pregnant women (β = − 0.925, 95% CI = −1.510, − 0.360). The impact of the lockdown policy on depressive symptoms was partially mediated by internet use (β = 1.589, 95% CI = 0.730, 2.807) and family support (β = − 0.162, 95% CI = − 0.341, − 0.017), accounting for 42.67% of the total effect. Conclusions The lockdown policy was generally associated with fewer depressive symptoms in pregnant women. The lockdown policy increased maternal depressive symptoms through increased internet use, but decreased maternal depressive symptoms through enhanced family support. The findings suggest that the psychological consequence of the lockdown policy may vary across different populations, and warrant the need to take into consideration the features of subgroups.

Post-stroke patients exhibit distinct muscle activation electromyography (EMG) features in sit-to-stand (STS) due to motor deficiency. Muscle activation amplitude, related to muscle tension and muscle synergy activation levels, is one of the defining EMG features that reflects post-stroke motor functioning and motor impairment. Although some qualitative findings are available, it is not clear if and how muscle activation amplitude-related biomechanical attributes may quantitatively reflect during subacute stroke rehabilitation. To better enable a longitudinal investigation into a patient's muscle activation changes during rehabilitation or an inter-subject comparison, EMG normalization is usually applied. However, current normalization methods using maximum voluntary contraction (MVC) or within-task peak/mean EMG may not be feasible when MVC cannot be obtained from stroke survivors due to motor paralysis and the subject of comparison is EMG amplitude. Here, focusing on the paretic side, we first propose a novel, joint torque-based normalization method that incorporates musculoskeletal modeling, forward dynamics simulation, and mathematical optimization. Next, upon method validation, we apply it to quantify changes in muscle tension and muscle synergy activation levels in STS motor control units for patients in subacute stroke rehabilitation. The novel method was validated against MVC-normalized EMG data from eight healthy participants, and it retained muscle activation amplitude differences for inter- and intra-subject comparisons. The proposed joint torque-based method was also compared with the common static optimization based on squared muscle activation and showed higher simulation accuracy overall. Serial STS measurements were conducted with four post-stroke patients during their subacute rehabilitation stay (137 ± 22 days) in the hospital. Quantitative results of patients suggest that maximum muscle tension and activation level of muscle synergy temporal patterns may reflect the effectiveness of subacute stroke rehabilitation. A quality comparison between muscle synergies computed with the conventional within-task peak/mean EMG normalization and our proposed method showed that the conventional was prone to activation amplitude overestimation and underestimation. The contributed method and findings help recapitulate and understand the post-stroke motor recovery process, which may facilitate developing more effective rehabilitation strategies for future stroke survivors.

BackgroundADP-A2M10 specific peptide enhanced affinity receptor (SPEAR) T-cells are genetically engineered autologous T-cells that express a high-affinity melanoma-associated antigen (MAGE)-A10-specific T-cell receptor (TCR) targeting MAGE-A10-positive tumors in the context of human leukocyte antigen (HLA)-A*02. ADP-0022-004 is a phase 1, dose-escalation trial to evaluate the safety and anti-tumor activity of ADP-A2M10 in three malignancies (https://clinicaltrials.gov: NCT02989064).MethodsEligible patients were HLA-A*02 positive with advanced head and neck squamous cell carcinoma (HNSCC), melanoma, or urothelial carcinoma (UC) expressing MAGE-A10. Patients underwent apheresis; T-cells were isolated, transduced with a lentiviral vector containing the MAGE-A10 TCR, and expanded. Patients underwent lymphodepletion with fludarabine and cyclophosphamide prior to receiving ADP-A2M10. ADP-A2M10 was administered in two dose groups receiving 0.1×109 and >1.2 to 6×109 transduced cells, respectively, and an expansion group receiving 1.2 to 15×109 transduced cells.ResultsTen patients (eight male and two female) with HNSCC (four), melanoma (three), and UC (three) were treated. Three patients were treated in each of the two dose groups, and four patients were treated in the expansion group. The most frequently reported adverse events grade ≥3 were leukopenia (10), lymphopenia (10), neutropenia (10), anemia (nine), and thrombocytopenia (five). Two patients reported cytokine release syndrome (one each with grade 1 and grade 3), with resolution. Best response included stable disease in four patients, progressive disease in five patients, and not evaluable in one patient. ADP-A2M10 cells were detectable in peripheral blood from patients in each dose group and the expansion group and in tumor tissues from patients in the higher dose group and the expansion group. Peak persistence was greater in patients from the higher dose group and the expansion group compared with the lower dose group.ConclusionsADP-A2M10 has shown an acceptable safety profile with no evidence of toxicity related to off-target binding or alloreactivity in these malignancies. Persistence of ADP-A2M10 in the peripheral blood and trafficking of ADP-A2M10 into the tumor was demonstrated. Because MAGE-A10 expression frequently overlaps with MAGE-A4 expression in tumors and responses were observed in the MAGE-A4 trial (NCT03132922), this clinical program closed, and trials with SPEAR T-cells targeting the MAGE-A4 antigen are ongoing.

Abstract Background Despite the incremental implementation of the essential public health services (EPHS) during the last decade, the goal of EPHS’s equalization is impossible to cannot be achieved without appropriate policies targeting older migrants. Therefore, this study aims to examine whether the supply side meets the needs of older migrants and to explore the relationships among health status, the use of health services, and diverse factors. Methods The data were derived from a national cross-sectional dataset (N = 11,161) of the 2015 Chinese Migrant Dynamic Monitoring Survey. Mediating effects analysis and moderating effects analysis were conducted to explore the interactions between physical status and the use of EPHS in older migrants such as physical examination, health record, and follow-up services. Results The use of physical examination, health record, and follow-up services were correlated with each other. Household income, migrating for employment, and migrating for offspring were negatively associated with the use of EPHS. A positive association was observed between the use of EPHS and willingness for long-stay. The mediating effects of household income, migrating for employment, migrating for offspring, and willingness for long-stay were observed on the relationship between physical status and the use of EPHS. The moderating effects of household income and migrating for employment were discovered. Conclusion Public health policies that may be worthy of consideration include further enhancing the delivery capacity of primary health institutions, integrating professional clinical resources into the primary health system, and launching the target policies to improve the accessibility of EPHS in older migrants.

Abstract Background Bereavement is the experience of an individual following the death of a person of significance to the individual, most often referring to the spouse. Increased morbidity, health care utilization, and mortality are known to be associated with bereavement. Given China’s growing population of older adults, there is a critical need to assess the health consequences of bereavement. Method We use data from the China Health and Retirement Longitudinal Study to examine the impact of bereavement on mental health and quality of life among a sample of mid- and older-aged adults. We use propensity score matching to construct a matching sample and difference-in-differences method to estimate the impact of bereavement on mental health and self-assessed health. Results We find bereavement is associated with increased depression symptoms among women (1.542 point or 0.229 standard deviations of Center for Epidemiologic Studies Depression (CES-D) 10 score) but not consistently for men over time. No statistically significant effect of bereavement on self-assessed health is found. Conclusions Our results show a harmful impact of bereavement on mental health among older women in China and point to the need for a comprehensive policy on survivor benefits in China, particularly for rural older women.

Root resorption is a common dental challenge that can lead to tooth loosening or even tooth loss. Among the cells involved in root resorption, cementoblasts are responsible for laying down the cementum, while macrophages with different phenotypes have also been shown to have bidirectional effects on root resorption. However, the relationship between macrophages and cementoblasts remains largely unknown. In this study, we examined the effect of macrophages with different polarization phenotypes on the mineralization of cementoblasts. Using the transwell coculture system and a conditioned medium-based coculture system, we found that compared with M0 (unpolarized macrophages), M1-polarized macrophages attenuated cementoblast mineralization, while M2-polarized macrophages enhanced cementoblast mineralization. Furthermore, by extracting M0/M1/M2 macrophage exosomes and examining their effects on the mineralization of cementoblasts, we found that the effects of macrophages on cementoblast mineralization were, at least partially, exerted by exosomes. Moreover, in vivo studies also indicated that an increased M1/M2 ratio could suppress cementoblast mineralization and bring about root resorption. During mechanical force-induced orthodontic tooth movement (OTM), root resorption was evident on the compression side of periodontal tissue, and a higher M1/M2 ratio and weaker cementoblast mineralization were observed on the compression side than on the tension side. We also used localized lipopolysaccharide (LPS) injection to increase the M1/M2 ratio around the roots of maxillary molars, where root resorption and decreased cementoblast mineralization were also observed. Furthermore, when we injected the exosomes from M0 and M1- and M2-polarized macrophages into mice, it was observed that the cementoblast mineralization was attenuated in the group injected with M1-polarized macrophage exosomes, while it was augmented in the group injected with M2-polarized macrophage exosomes.

Purpose: The aim of this study is to develop a practicable automatic clinical target volume (CTV) delineation method for radiotherapy of breast cancer after modified radical mastectomy.Methods: Unlike breast conserving surgery, the radiotherapy CTV for modified radical mastectomy involves several regions, including CTV in the chest wall (CTVcw), supra- and infra-clavicular region (CTVsc), and internal mammary lymphatic region (CTVim). For accurate and efficient segmentation of the CTVs in radiotherapy of breast cancer after modified radical mastectomy, a multi-scale convolutional neural network with an orientation attention mechanism is proposed to capture the corresponding features in different perception fields. A channel-specific local Dice loss, alongside several data augmentation methods, is also designed specifically to stabilize the model training and improve the generalization performance of the model. The segmentation performance is quantitatively evaluated by statistical metrics and qualitatively evaluated by clinicians in terms of consistency and time efficiency.Results: The proposed method is trained and evaluated on the self-collected dataset, which contains 110 computed tomography scans from patients with breast cancer who underwent modified mastectomy. The experimental results show that the proposed segmentation method achieved superior performance in terms of Dice similarity coefficient (DSC), Hausdorff distance (HD) and Average symmetric surface distance (ASSD) compared with baseline approaches.Conclusion: Both quantitative and qualitative evaluation results demonstrated that the specifically designed method is practical and effective in automatic contouring of CTVs for radiotherapy of breast cancer after modified radical mastectomy. Clinicians can significantly save time on manual delineation while obtaining contouring results with high consistency by employing this method.

The current accuracy of speech recognition can reach over 97% on different datasets, but in noisy environments, it is greatly reduced. Improving speech recognition performance in noisy environments is a challenging task. Due to the fact that visual information is not affected by noise, researchers often use lip information to help to improve speech recognition performance. This is where the performance of lip recognition and the effect of cross-modal fusion are particularly important. In this paper, we try to improve the accuracy of speech recognition in noisy environments by improving the lip reading performance and the cross-modal fusion effect. First, due to the same lip possibly containing multiple meanings, we constructed a one-to-many mapping relationship model between lips and speech allowing for the lip reading model to consider which articulations are represented from the input lip movements. Audio representations are also preserved by modeling the inter-relationships between paired audiovisual representations. At the inference stage, the preserved audio representations could be extracted from memory by the learned inter-relationships using only video input. Second, a joint cross-fusion model using the attention mechanism could effectively exploit complementary intermodal relationships, and the model calculates cross-attention weights on the basis of the correlations between joint feature representations and individual modalities. Lastly, our proposed model achieved a 4.0% reduction in WER in a −15 dB SNR environment compared to the baseline method, and a 10.1% reduction in WER compared to speech recognition. The experimental results show that our method could achieve a significant improvement over speech recognition models in different noise environments.

Graph neural networks have been widely used by multivariate time series-based anomaly detection algorithms to model the dependencies of system sensors. Previous studies have focused on learning the fixed dependency patterns between sensors. However, they ignore that the inter-sensor and temporal dependencies of time series are highly nonlinear and dynamic, leading to inevitable false alarms. In this paper, we propose a novel disentangled dynamic deviation transformer network (D3TN) for anomaly detection of multivariate time series, which jointly exploits multiscale dynamic inter-sensor dependencies and long-term temporal dependencies to improve the accuracy of multivariate time series prediction. Specifically, to disentangle the multiscale graph convolution, we design a novel disentangled multiscale aggregation scheme to better represent the hidden dependencies between sensors to learn fixed inter-sensor dependencies based on static topology. To capture dynamic inter-sensor dependencies determined by real-time monitoring situations and unexpected anomalies, we introduce a self-attention mechanism to model dynamic directed interactions in various potential subspaces influenced by various factors. In addition, complex temporal correlations across multiple time steps are simulated by processing the time series in parallel. Experiments on three real datasets show that the proposed D3TN significantly outperforms the state-of-the-art methods.

Background The phenomenon of male sterility widely occurs in Prunus sibirica and has a serious negative impact on yield. We identified the key stage and cause of male sterility and found differentially expressed genes related to male sterility in Prunus sibirica, and we analyzed the expression pattern of these genes. This work aimed to provide valuable reference and theoretical basis for the study of reproductive development and the mechanisms of male sterility in Prunus sibirica. Method The microstructures of male sterile flower buds and male fertile flower buds were observed by paraffin section. Transcriptome sequencing was used to screen genes related to male sterility in Prunus sibirica. Quantitative real-time PCR analysis was performed to verify the transcriptome data. Results Anther development was divided into the sporogenous cell stage, tetrad stage, microspore stage, and pollen maturity stage. Compared with male fertile flower buds, in the microspore stage, the pollen sac wall tissue in the male sterile flower buds showed no signs of degeneration. In the pollen maturity stage, the tapetum and middle layer were not fully degraded, and anther development stopped. Therefore, the microspore stage was the key stage for anther abortion , and the pollen maturity stage was the post stage for anther abortion. A total of 4,108 differentially expressed genes were identified by transcriptome analysis. Among them, 1,899 were up-regulated, and 2,209 were down-regulated in the transcriptome of male sterile flower buds. We found that “protein kinase activity”, “apoptosis process”, “calcium binding”, “cell death”, “cytochrome c oxidase activity”, “aspartate peptidase activity”, “cysteine peptidase activity” and other biological pathways such as “starch and sucrose metabolism” and “proteasome” were closely related to male sterility in Prunus sibirica. A total of 331 key genes were preliminarily screened. Conclusion The occurrence of male sterility in Prunus sibirica involved many biological processes and metabolic pathways. According to the results of microstructure observations, related physiological indexes determination and transcriptome analysis, we reveal that the occurrence of male sterility in Prunus sibirica may be caused by abnormal metabolic processes such as the release of cytochrome c in the male sterile flower buds, the imbalance of the antioxidant system being destroyed, and the inability of macromolecular substances such as starch to be converted into soluble small molecules at the correct stage of reproductive development, resulting in energy loss. As a result, the tapetum cannot be fully degraded, thereby blocking anther development, which eventually led to the formation of male sterility.

Background:Cancer poses a serious threat to one’s health, which caused significant economic burden on the family and society. Poor availability and affordability resulted in some essential medicines failing to meet the basic health needs of this group of patients. The objective of this study was to evaluate the availability, prices and affordability of 32 anticancer essential medicines in Hubei Province, China.Methods: Data on the availability and price related information of 32 essential anticancer medicines in the capital and five other cities of Hubei Province were collected. A total of 28 hospitals were sampled, which included 13 tertiary hospitals and 15 secondary hospitals. We used the standard methods developed by the World Health Organization and Health Action International to compare the differences in drug price, availability and affordability between secondary hospitals and tertiary hospitals.Results: Overall, the availability of medicine was higher in tertiary hospitals. The average availability of originator brand (OBs) was 13.70% (tertiary hospitals) VS 6.67% (secondary hospitals), and lowest-priced generic (LPGs) was 62.83% (tertiary hospitals) VS 42.92% (secondary hospitals). The MPR value of most sampled medicines in secondary hospitals were less than 1. In contrast, the MPR of Cytarabine (17.15), Oxaliplatin (12.73) were significantly higher than the international reference price. The top three OBs’ total expenses for 30-days treatment were Irinotecan, Oxaliplatin, Bicalutamide. Further, their affordability was relative low, as the costs for one course using these medicines were much higher than 20% of the minimum family monthly income.Conclusion: Though the “Zero Mark-Up” and “Centralized procurement policy of anti-tumor drugs” policies have been implemented in China, the availability issue yet to be addressed. High price and low affordability were the major barriers to the access of essential anticancer medicines. Measures should be taken to provide sufficient, available and affordable medicines to patients in need.

Tumorigenesis is highly correlated with the accumulation of mutations. The abundant and extensive DNA oxidation product, 8-Oxoguanine (8-oxoG), can cause mutations if it is not repaired by 8-oxoG repair systems. Therefore, the accumulation of 8-oxoG plays an essential role in tumorigenesis. To avoid the accumulation of 8-oxoG in the genome, base excision repair (BER), initiated by 8-oxoguanine DNA glycosylase1 (OGG1), is responsible for the removal of genomic 8-oxoG. It has been proven that 8-oxoG levels are significantly elevated in cancer cells compared with cells of normal tissues, and the induction of DNA damage by some antitumor drugs involves direct or indirect interference with BER, especially through inducing the production and accumulation of reactive oxygen species (ROS), which can lead to tumor cell death. In addition, the absence of the core components of BER can result in embryonic or early post-natal lethality in mice. Therefore, targeting 8-oxoG repair systems with inhibitors is a promising avenue for tumor therapy. In this study, we summarize the impact of 8-oxoG accumulation on tumorigenesis and the current status of cancer therapy approaches exploiting 8-oxoG repair enzyme targeting, as well as possible synergistic lethality strategies involving exogenous ROS-inducing agents.

Objective Hepatitis B and hepatitis C cause a heavy disease burden in China. This paper aims to investigate the public’s knowledge on hepatitis B and hepatitis C in Chongqing municipality and Chengdu City, China.Design A cross-sectional study was conducted from December 2016 to April 2017.Setting Two communities from Chongqing and Chengdu were involved in this study.Participants Data from 928 community residents were analysed.Outcome Demographic characteristics, knowledge on hepatitis B and hepatitis C and sources of hepatitis knowledge were obtained from questionnaires. The participants’ scores ranged from 0 to 24, and a test score about more than 14.4 (60% of the total score) was defined as sufficient knowledge.Results Among the participants, only 36.10% presented sufficient knowledge on hepatitis B and hepatitis C, and about 40% were unaware of the two antidiscrimination policies in China. The sources of information about hepatitis were mainly from doctors and the internet. Unmarried individuals, people with secondary education and above and those with an annual income above US$2108 tended to exhibit a higher level of knowledge on hepatitis B and hepatitis C.Conclusions The community members demonstrated limited awareness and level of knowledge on hepatitis B and hepatitis C, particularly in relation to the antidiscrimination policies. Extensive health education should be provided to the public, particularly to those with low educational status and income.

Abstract Background Gene-modified autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) reactive against the NY-ESO-1-specific HLA-A*02-restricted peptide SLLMWITQC (NY-ESO-1 SPEAR T-cells; GSK 794), have demonstrated clinical activity in patients with advanced synovial sarcoma (SS). The factors contributing to gene-modified T-cell expansion and the changes within the tumor microenvironment (TME) following T-cell infusion remain unclear. These studies address the immunological mechanisms of response and resistance in patients with SS treated with NY-ESO-1 SPEAR T-cells. Methods Four cohorts were included to evaluate antigen expression and preconditioning on efficacy. Clinical responses were assessed by RECIST v1.1. Engineered T-cell persistence was determined by qPCR. Serum cytokines were evaluated by immunoassay. Transcriptomic analyses and immunohistochemistry were performed on tumor biopsies from patients before and after T-cell infusion. Gene-modified T-cells were detected within the TME via an RNAish assay. Results Responses across cohorts were affected by preconditioning and intra-tumoral NY-ESO-1 expression. Of the 42 patients reported (data cut-off 4June2018), 1 patient had a complete response, 14 patients had partial responses, 24 patients had stable disease, and 3 patients had progressive disease. The magnitude of gene-modified T-cell expansion shortly after infusion was associated with response in patients with high intra-tumoral NY-ESO-1 expression. Patients receiving a fludarabine-containing conditioning regimen experienced increases in serum IL-7 and IL-15. Prior to infusion, the TME exhibited minimal leukocyte infiltration; CD163+ tumor-associated macrophages (TAMs) were the dominant population. Modest increases in intra-tumoral leukocytes (≤5%) were observed in a subset of subjects at approximately 8 weeks. Beyond 8 weeks post infusion, the TME was minimally infiltrated with a TAM-dominant leukocyte infiltrate. Tumor-associated antigens and antigen presentation did not significantly change within the tumor post-T-cell infusion. Finally, NY-ESO-1 SPEAR T cells trafficked to the TME and maintained cytotoxicity in a subset of patients. Conclusions Our studies elucidate some factors that underpin response and resistance to NY-ESO-1 SPEAR T-cell therapy. From these data, we conclude that a lymphodepletion regimen containing high doses of fludarabine and cyclophosphamide is necessary for SPEAR T-cell persistence and efficacy. Furthermore, these data demonstrate that non-T-cell inflamed tumors, which are resistant to PD-1/PD-L1 inhibitors, can be treated with adoptive T-cell based immunotherapy. Trial registration ClinicalTrials.gov, NCT01343043, Registered 27 April 2011.

Abstract: This study in patients with relapsed, refractory, or high-risk multiple myeloma (MM) evaluated the safety and activity of autologous T cells engineered to express an affinity-enhanced T-cell receptor (TCR) that recognizes a peptide shared by cancer antigens New York esophageal squamous cell carcinoma-1 (NY-ESO-1) and L-antigen family member 1 (LAGE-1) and presented by HLA-A*02:01. T cells collected from 25 HLA-A*02:01-positive patients with MM expressing NY-ESO-1 and/or LAGE-1 were activated, transduced with self-inactivating lentiviral vector encoding the NY-ESO-1c259TCR, and expanded in culture. After myeloablation and autologous stem cell transplant (ASCT), all 25 patients received an infusion of up to 1 × 1010 NY-ESO-1 specific peptide enhanced affinity receptor (SPEAR) T cells. Objective response rate (International Myeloma Working Group consensus criteria) was 80% at day 42 (95% confidence interval [CI], 0.59-0.93), 76% at day 100 (95% CI, 0.55-0.91), and 44% at 1 year (95% CI, 0.24-0.65). At year 1, 13/25 patients were disease progression-free (52%); 11 were responders (1 stringent complete response, 1 complete response, 8 very good partial response, 1 partial response). Three patients remained disease progression-free at 38.6, 59.2, and 60.6 months post-NY-ESO-1 SPEAR T-cell infusion. Median progression-free survival was 13.5 months (range, 3.2-60.6 months); median overall survival was 35.1 months (range, 6.4-66.7 months). Infusions were well tolerated; cytokine release syndrome was not reported. No fatal serious adverse events occurred during study conduct. NY-ESO-1 SPEAR T cells expanded in vivo, trafficked to bone marrow, demonstrated persistence, and exhibited tumor antigen-directed functionality. In this MM patient population, NY-ESO-1 SPEAR T-cell therapy in the context of ASCT was associated with antitumor activity. This trial was registered at www.clinicaltrials.gov as #NCT01352286.

Abstract Background Community-based blood pressure (BP) monitoring plays an important role in national hypertension management in China. However, the utilisation of this service, together with its associations on hypertension treatment and BP control has not been fully investigated. Methods The study population was from the China Health and Retirement Longitudinal Study (CHARLS) in 2015. Cross-sectional data of 2487 hypertensive persons were included as subjects. Stratified sample households were selected from 450 villages or communities of 150 counties from 28 provinces. Finally, 21,097 individuals were interviewed successfully. The main outcome was hypertension control (having average BP under 140-90 mmHg). The main independent variable was utilisation of community-based BP monitoring service (having BP examination once a season or more). The mediators were hypertension treatment (currently taking any antihypertensive medicine) and lifestyle factors (alcohol intake, physical activity, smoke). We performed chi-square and binary logistic regression to analyse associations of BP monitoring with hypertension treatment and blood pressure control. The mediation model was examined by the Sobel test. Results Mean age of the population was 64.2 (0.24). The percentage of males was 42.8%. Prevalence of community-based BP monitoring was 32.1%. Patients who used this service had higher odds of hypertension treatment (β = 1.259, P

Background: Previous systematic review indicated the prevalence of prenatal anxiety as 14–54%. Pregnant women are a high-risk population for COVID-19. However, the prevalence of anxiety symptoms and related factors is unknown in Chinese pregnant women during COVID-19 outbreak.Objective: To investigate the prevalence of anxiety symptoms and the related factors in Chinese pregnant women who were attending crisis intervention during the COVID-19 pandemic.Methods: The data of this cross-sectional study were collected in about 2 months (February 28 to April 26, 2020). Data analysis was performed from April to May 2020. Participants completed a set of questionnaires via the Wechat Mini-program before starting the online self-help crisis intervention for COVID-19 epidemic. A total of 2,120 Chinese pregnant women who were attending a self-help crisis intervention participated in this study. A survey was developed to address possible stress-related factors in pregnant women during the COVID-19 outbreak, including demographic, socioeconomic, and pregnancy-related factors, as well as COVID-19 related factors. Generalized Anxiety Disorder-7 (GAD-7) scale and the 10-item perceived stress scale were, respectively, employed to measure anxiety and stress-related factors.Results: A total of 21.7% (459) of pregnant women reported at least mild anxiety (≥5 on the GAD-7 scale), and only 82 women reported moderate to severe anxiety (≥10 on the GAD-7 scale). Factors associated with at least mild anxiety included living in Hubei province (OR = 1.68, 95% CI = 1.32–2.13), nobody providing everyday life support (OR = 1.81, 95% CI = 1.18–2.77), pelvic pain or vaginal bleeding (OR = 1.67, 95% CI = 1.32–2.09), and higher perceived stress (OR = 6.87, 95% CI = 5.42–9.02). Having relatives or neighbors with a diagnosis of COVID-19 was not associated with anxiety (p > 0.05).Conclusions and Relevance: Our findings indicate that evaluation and intervention for maternal and infant health are necessary in pregnant women with anxiety during COVID-19 epidemic, especially those with higher perceived stress, less everyday life support, or vaginal bleeding. Interactions among these related medical, social and psychological factors need to be investigated in future studies.

Objectives In order to understand the influencing factors of the medication-taking behaviour in patients with chronic diseases, reveal the deep-seated causes underlying the phenomenon of polypharmacy, explore the formation rules of the risk perception of polypharmacy and how risk perception affect the medication decision-making behaviour of patients with chronic diseases.Design A qualitative descriptive design was used. Study data were collected through semi-structured interviews with patients and physicians. We used the grounded theory approach to refine influencing factors, followed by interpretative structural modelling that analysed the interaction between these factors.Setting Patients from two hospitals, two nursing homes and two communities. Physicians from two community hospitals in Wuhan, China.Participants Patients with chronic diseases with high willingness to cooperate and good communication ability. Physicians with rich experience in the treatment of chronic diseases.Results Twenty-nine interviews were conducted (20 patients and 9 physicians). A total of 35 influencing factors of the medication-taking behaviours in patients with chronic diseases were extracted from the interview data, further integrated into 10 integrated influencing factors and ultimately clustered into three aspects: ‘medication benefit’, ‘medication risk’ and ‘medication strategy’. Medication risk can be divided into four specific dimensions: economic risk, physical risk, psychosocial risk and time risk. 10 integrated influencing factors constituted the interpretative structural model of the medication decision-making behaviours in patients with chronic diseases.Conclusions The causes underlying the medication decision-making behaviour of patients with chronic diseases are complex, involving a series of influencing factors such as their risk perception of the medication-taking behaviour. In order to alleviate the adverse effects of polypharmacy on patients’ health and medical costs, further safety measures should be proposed to improve the medication-taking behaviour in patients with chronic diseases based on the relationship and internal mechanism of the influencing factors of the medication decision-making behaviour.

Objectives With about one-third of the population living below the poverty line, Jordan faces major healthcare, social and national development issues. Low insurance coverage among the poor and high out-of-pocket expenditure worsens the financial insecurity especially for the marginalised population. The Government of Jordan aims to achieve universal coverage of health insurance—a bold plan that requires research evidence for successful implementation. In this study, we aimed to assess the proportion of the population covered by any health insurance, and the determinants owing a health insurance.Design A population-based prospective cohort study.Setting Jordan.Methods Data for this study were derived from the Jordan Population and Family Health Survey, which was implemented by the Department of Statistics from early October 2017 to January 2018. Sample characteristics were described as percentages with 95% CIs. Binary logistic regression models were used to estimate OR of health insurance ownership. Parsimonious model was employed to assess the sex and geographical differences.Results Data revealed that in 2017–2018, 73.13% of the 12 992 men and women had health insurance. There was no indication of age of sex difference in health insurance ownership; however, marital status and socioeconomic factors such as wealth and education as well as internet access and geographical location appeared to be the important predictors of non-use of health insurance. The associations differed by sex and urbanicity for certain variables. Addressing these inequities may help achieve universal coverage in health insurance ownership in the population.Conclusions More than one-quarter of the population in Jordan were not insured. Efforts to decrease disparities in insurance coverage should focus on minimising socioeconomic and geographical disparities to promote equity in terms of healthcare services.

Bone marrow mesenchymal stem cells (BMSCs) are intraosseous stem cells, and the effects of tensile strain on BMSC differentiation mediate several bone-related treatments. To study the response of BMSCs under tension, we designed and developed a small cellular tension instrument, iStrain. When iStrain applied tension on BMSCs, these cells exhibited convergence in the alignment direction and lengthening of the cell processes and cell body. Real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting demonstrated that iStrain-mediated cyclic tension promotes the differentiation of BMSCs toward osteogenesis and fibrogenesis. And the mRNA and protein expression of differentiation-related genes changes with the extension of tension time.