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Background The prevalence of abnormal weight is on the rise, presenting serious health risks and socioeconomic problems. Nonetheless, there is a lack of consensus on the medical cost savings that can be attained through the mitigation of abnormal weight. The aim of this study was to estimate the impact of abnormal weight on health care costs in China. Methods The study employed a 5-wave panel data from China Family Panel Studies (CFPS) between 2012 and 2020 (8,847 participants in each wave). Inpatient, non-inpatient and total healthcare costs were outcome variables. Abnormal weight is categorized based on body mass index (BMI).Initially, the two-part model was employed to investigate the impact of overweight/obesity and underweight on healthcare utilisation and costs, respectively. Subsequently, the estimated results were utilised to calculate the overweight/obesity attributable fraction (OAF) and the underweight attributable fraction (UAF). Results In 2020, the total national healthcare cost of the overweight and obese population was estimated to be $189.99 billion and $ 62.54 billion, and the underweight population was $37.32 billion. In comparison to people of normal weight, individuals who were overweight/obese (OR=1.072, p0.1). Conclusions Abnormal weight imposes a huge economic burden on individuals, households and the society. Abnormal weight in Chinese adults significantly increased healthcare utilisation and costs, particular in non-inpatient care. It is recommended that government and relevant social agencies provide a better social environment to enhance individual self-perception and promote healthy weight.

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Immunologic checkpoint blockade has been proven effective in a variety of malignancies. However, high rates of resistance have substantially hindered its clinical use. Understanding the underlying mechanisms may lead to new strategies for improving therapeutic efficacy. Although a number of signaling pathways have been shown to be associated with tumor cell–mediated resistance to immunotherapy, T cell–intrinsic resistant mechanisms remain elusive. Here, we demonstrated that diacylglycerol kinase alpha (Dgka) mediated T-cell dysfunction during anti–PD-1 therapy by exacerbating the exhaustion of reinvigorated tumor-specific T cells. Pharmacologic ablation of Dgka postponed T-cell exhaustion and delayed development of resistance to PD-1 blockade. Dgka inhibition also enhanced the efficacy of anti–PD-1 therapy. We further found that the expression of DGKA in cancer cells promoted tumor growth via the AKT signaling pathway, suggesting that DGKA might be a target in tumor cells as well. Together, these findings unveiled a molecular pathway mediating resistance to PD-1 blockade and provide a potential therapeutic strategy with combination immunotherapy.

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PD-1/L1 and CTLA-4 blockade immunotherapies have been approved for 13 types of cancers and are being studied in diffuse large B-cell lymphoma (DLBCL), the most common aggressive B-cell lymphoma. However, whether both PD-1 and CTLA-4 checkpoints are active and clinically significant in DLBCL is unknown. Whether PD-1 ligands expressed by tumor cells or by the microenvironment of DLBCL are critical for the PD-1 immune checkpoint is unclear. We performed immunophenotypic profiling for 405 patients with de novo DLBCL using a MultiOmyx immunofluorescence platform and simultaneously quantitated expression/coexpression of 13 immune markers to identify prognostic determinants. In both training and validation cohorts, results demonstrated a central role of the tumor immune microenvironment, and when its functionality was impaired by deficiency in tumor-infiltrating T cells and/or natural killer cells, high PD-1 expression (but not CTLA-4) on CD8+ T cells, or PD-L1 expression on T cells and macrophages, patients had significantly poorer survival after rituximab–CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) immunochemotherapy. In contrast, tumor-cell PD-L2 expression was associated with superior survival, as well as PD-L1+CD20+ cells proximal (indicates interaction) to PD-1+CD8+ T cells in patients with low PD-1+ percentage of CD8+ T cells. Gene-expression profiling results suggested the reversibility of T-cell exhaustion in PD-1+/PD-L1+ patients with unfavorable prognosis and implication of LILRA/B, IDO1, CHI3L1, and SOD2 upregulation in the microenvironment dysfunction with PD-L1 expression. This study comprehensively characterized the DLBCL immune landscape, deciphered the differential roles of various checkpoint components in rituximab–CHOP resistance in DLBCL patients, and suggests targets for PD-1/PD-L1 blockade and combination immunotherapies.

Diffuse large B-cell lymphoma (DLBCL) is the major type of aggressive B-cell lymphoma. High-grade B-cell lymphoma (HGBCL) with MYC/BCL2 double-hit (DH) represents a distinct entity with dismal prognosis after standard immunochemotherapy in the current WHO lymphoma classification. However, whether TP53 mutation synergizes with MYC abnormalities (MYC rearrangement and/or Myc protein overexpression) contributing to HGBCL-like biology and prognosis is not well investigated. In this study, patients with DLBCL with MYC/TP53 abnormalities demonstrated poor clinical outcome, high-grade morphology, and distinct gene expression signatures. To identify more effective therapies for this distinctive DLBCL subset, novel MYC/TP53/BCL-2–targeted agents were investigated in DLBCL cells with MYC/TP53 dual alterations or HGBCL-MYC/BCL2-DH. A BET inhibitor INCB057643 effectively inhibited cell viability and induced apoptosis in DLBCL/HGBCL cells regardless of MYC/BCL2/TP53 status. Combining INCB057643 with a MDM2-p53 inhibitor DS3032b significantly enhanced the cytotoxic effects in HGBCL-DH without TP53 mutation, while combining with the BCL-2 inhibitor venetoclax displayed potent therapeutic synergy in DLBCL/HGBCL cells with and without concurrent TP53 mutation. Reverse-phase protein arrays revealed the synergistic molecular actions by INCB057643, DS3032b and venetoclax to induce cell-cycle arrest and apoptosis and to inhibit AKT/MEK/ERK/mTOR pathways, as well as potential drug resistance mechanisms mediated by upregulation of Mcl-1 and RAS/RAF/MEK/ERK pathways. In summary, these findings support subclassification of DLBCL/HGBCL with dual MYC/TP53 alterations, which demonstrates distinct pathobiologic features and dismal survival with standard therapy, therefore requiring additional targeted therapies.Implications:The clinical and pharmacologic studies suggest recognizing DLBCL with concomitant TP53 mutation and MYC abnormalities as a distinctive entity necessary for precision oncology practice.Visual Overview:http://mcr.aacrjournals.org/content/molcanres/19/2/249/F1.large.jpg.

Supplementary Table S1. Clinicopathologic characteristics of patients with de novo DLBCL with dual MYC/TP53 aberrations Supplementary Table S2. Frequency of single or dual abnormal Myc protein, p53 protein, BCL2 protein, MYC gene, and TP53 gene in the studied patients with DLBCL treated with R-CHOP Supplementary Table S3. Prognostic factors by univariate analysis and multivariate analysis in DLBCL Supplementary Table S4. Gene expression signatures identified by comparing DLBCL patients with concurrent MYC-R Mut-TP53 or Mychigh Mut-TP53 alterations (double-positive) with DLBCL patients withSupplementary Table S5. Molecular, genetic and phenotypic status of 8 DLBCL/HGBCL cell lines by targeted next-generation sequencing, fluorescence in situ hybridization (FISH), and immunohistochemistry analysis none or the alterations (double-negative) Supplementary Figure S1. Morphologic and immunophenotypic features of DLBCL with MYC rearrangement (MYC-R) and TP53 mutation (Mut-TP53) dual-alterations and highgrade B-cell lymphoma (HGBCL) with MYC/BCL2 double-hit (DH) in representative patients. Supplementary Figure S2. Prognostic impact of p53 and Myc protein overexpression as single or double abnormalities in overall DLBCL and GCB/ABC subtypes. Supplementary Figure S3. Heatmap for gene expression signatures of MYC/TP53 dual alterations. Supplementary Figure S4. Representative figures of flow cytometric analysis indicating G2/M phase-cell cycle arrest by NCB057643 treatment for 24 hours in cells with MYC-R or Myc overexpression with Wt-TP53 (OCI-LY19) or Mut-TP53 (GR and TMD8). Supplementary Figure S5. Heatmap for significantly up- or downregulated proteins after INCB057643 treatment (5µM, 24 hours) in OCI-LY19 cells. Supplementary Figure S6. A MDM2 inhibitor DS3032b shows cytotoxic effects selectively in high-grade B-cell lymphoma (HGBCL) with MYC/BCL2 double-hit (DH) and wild-type (Wt) TP53. Supplementary Figure S7. Combined DS3032b and INCB057643 treatment has no synergistic cytotoxicity in DLBCL cell lines with MYC aberrations and TP53 mutation (MutTP53). Supplementary Figure S8. INCB057643 treatment (1.25 µM) alone or in combination with ABT-199 (venetoclax, 6.25 mM) for 24 hours induced p21 expression in TMD8 cells, whereas had no effect on p53 (mutant) expression levels.

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Purpose:Diffuse large B-cell lymphoma (DLBCL) is molecularly and clinically heterogeneous, and can be subtyped according to genetic alterations, cell-of-origin, or microenvironmental signatures using high-throughput genomic data at the DNA or RNA level. Although high-throughput proteomic profiling has not been available for DLBCL subtyping, MYC/BCL2 protein double expression (DE) is an established prognostic biomarker in DLBCL. The purpose of this study is to reveal the relative prognostic roles of DLBCL genetic, phenotypic, and microenvironmental biomarkers.Experimental Design:We performed targeted next-generation sequencing; IHC for MYC, BCL2, and FN1; and fluorescent multiplex IHC for microenvironmental markers in a large cohort of DLBCL. We performed correlative and prognostic analyses within and across DLBCL genetic subtypes and MYC/BCL2 double expressors.Results:We found that MYC/BCL2 double-high-expression (DhE) had significant adverse prognostic impact within the EZB genetic subtype and LymphGen-unclassified DLBCL cases but not within MCD and ST2 genetic subtypes. Conversely, KMT2D mutations significantly stratified DhE but not non-DhE DLBCL. T-cell infiltration showed favorable prognostic effects within BN2, MCD, and DhE but unfavorable effects within ST2 and LymphGen-unclassified cases. FN1 and PD-1–high expression had significant adverse prognostic effects within multiple DLBCL genetic/phenotypic subgroups. The prognostic effects of DhE and immune biomarkers within DLBCL genetic subtypes were independent although DhE and high Ki-67 were significantly associated with lower T-cell infiltration in LymphGen-unclassified cases.Conclusions:Together, these results demonstrated independent and additive prognostic effects of phenotypic MYC/BCL2 and microenvironment biomarkers and genetic subtyping in DLBCL prognostication, important for improving DLBCL classification and identifying prognostic determinants and therapeutic targets.

Supplementary Figure from Genetic Subtyping and Phenotypic Characterization of the Immune Microenvironment and MYC/BCL2 Double Expression Reveal Heterogeneity in Diffuse Large B-cell Lymphoma

Supplementary Data from Genetic Subtyping and Phenotypic Characterization of the Immune Microenvironment and MYC/BCL2 Double Expression Reveal Heterogeneity in Diffuse Large B-cell Lymphoma

Background Natural killer/T-cell lymphoma (NKTL) is a rare type of aggressive and heterogeneous non-Hodgkin's lymphoma (NHL) with a poor prognosis and limited therapeutic options. Therefore, there is an urgent need to exploit potential novel therapeutic targets for the treatment of NKTL. Histone deacetylase (HDAC) inhibitor chidamide was recently approved for treating relapsed/refractory peripheral T-cell lymphoma (PTCL) patients. However, its therapeutic efficacy in NKTL remains unclear. Methods We performed a phase II clinical trial to evaluate the efficacy of chidamide in 28 relapsed/refractory NKTL patients. Integrative transcriptomic, chromatin profiling analysis and functional studies were performed to identify potential predictive biomarkers and unravel the mechanisms of resistance to chidamide. Immunohistochemistry (IHC) was used to validate the predictive biomarkers in tumors from the clinical trial. Results We demonstrated that chidamide is effective in treating relapsed/refractory NKTL patients, achieving an overall response and complete response rate of 39 and 18%, respectively. In vitro studies showed that hyperactivity of JAK-STAT signaling in NKTL cell lines was associated with the resistance to chidamide. Mechanistically, our results revealed that aberrant JAK-STAT signaling remodels the chromatin and confers resistance to chidamide. Subsequently, inhibition of JAK-STAT activity could overcome resistance to chidamide by reprogramming the chromatin from a resistant to sensitive state, leading to synergistic anti-tumor effect in vitro and in vivo. More importantly, our clinical data demonstrated that combinatorial therapy with chidamide and JAK inhibitor ruxolitinib is effective against chidamide-resistant NKTL. In addition, we identified TNFRSF8 (CD30), a downstream target of the JAK-STAT pathway, as a potential biomarker that could predict NKTL sensitivity to chidamide. Conclusions Our study suggests that chidamide, in combination with JAK-STAT inhibitors, can be a novel targeted therapy in the standard of care for NKTL. Trial registration: ClinicalTrials.gov, NCT02878278. Registered 25 August 2016, https://clinicaltrials.gov/ct2/show/NCT02878278

Extensive clinical and experimental evidence suggests that macrophages play a crucial role in cancer immunotherapy. Cluster of differentiation (CD) 47, which is found on both healthy and malignant cells, regulates macrophage-mediated phagocytosis by sending a "don't eat me" signal to the signal regulatory protein alpha (SIRPα) receptor. Increasing evidence demonstrates that blocking CD47 interaction with SIRPα can enhance cancer cell clearance by macrophages. Additionally, inhibition of CD47/SIRPα interaction can increase antigen cross-presentation, leading to T-cell priming and an activated adaptive antitumor immune response. Therefore, inhibiting CD47/SIRPα axis has a significant impact on tumor immunotherapy. Studies on CD47 monoclonal antibodies are at the forefront of research, and impressive results have been obtained. Nevertheless, hematotoxicity, especially anemia, has become the most common adverse effect of the CD47 monoclonal antibody. More specific targeted drugs (i.e., bispecific antibodies, SIRPα/Fc fusion protein antibodies, and small-molecule inhibitors) have been developed to reduce hematotoxicity. Here, we review the present usage of CD47 antagonists for the treatment of lymphomas and hematologic neoplasms from the perspectives of structure, function, and clinical trials, including a comprehensive overview of the drugs in development.

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Individualized chemotherapy, which is at the forefront of acute myeloid leukemia (AML) treatment, has moderately improved outcomes over the past decade. Monitoring the peripheral blood blast burden during induction by flow cytometry has shown significant value in the evaluation of treatment responses. Our previous study reported the day 5 peripheral blast clearance rate (D5-PBCR) as an indicator of early treatment response, and D5-PBCR (+) patients showed poor outcomes. We performed the present phase 2 trial of early intervention in D5-PBCR (+) patients with homoharringtonine (HHT) introduced in the traditional induction regimen with anthracycline and cytarabine. The primary endpoint was complete remission (CR). This study enrolled 151 patients, 65 patients were D5-PBCR (+) and 55 patients completed induction with HHT addition. The overall CR rate after one course of induction was 84.4%, with 87.5% and 80.0% for the D5-PBCR (-) and D5-PBCR (+) groups, respectively. The incidence of grade 3/4 adverse events was comparable between the two groups. At the median follow-up of 53.1 months, median overall survival (OS) was not reached in the entire cohort, and median event-free survival (EFS) was 42.2 months. Neither the OS nor EFS showed significant differences between the D5-PBCR (-) and D5-PBCR (+) groups. Compared to historical data, significant improvements in both OS (p = .020) and EFS (p = .020) were observed in the D5-PBCR (+) group. In conclusion, optimization of induction chemotherapy with idarubicin and cytarabine according to D5-PBCR is feasible in patients with newly diagnosed AML. The addition of HHT demonstrated a good efficacy and safety profile.

Background Unhealthy gestational weight gain is a modifiable risk factor for adverse maternal and child health. Appropriate and effective intervention strategies that focus on behavioral change or maintenance are critical in weight management during pregnancy. Our aim was to uncover the influencing factors and psychosocial mechanisms of gestational weight control behavior, and to construct a behavioral model suitable for intervention based on Information-Motivation-Behavioral skills (IMB) model. Methods A sample of 559 pregnant women from a municipal maternal and child healthcare facility in Jiangsu Province, China was enrolled in this cross-sectional empirical study. Partial least square structural equation modelling was used to verify the hypothesized model, and post hoc analyses was used to test the effect of parity and pre-pregnancy BMI on the model. Results The IMB model elements can predict gestational weight management (GWM) behavior well, with information being the most influential factor. As predicted, information affects GWM directly (β = 0.325, p p p p p Conclusion Findings from this study supported the predictions of the IMB model for GWM behavior, and identified its modifiable determinants. The tested behavior model for GWM can serve as a new validated intervention strategy in weight management among pregnant women.

Pancreatic cancer (PC) is a malignant tumor with high malignancy that is difficult to diagnose and treat. PC is a major medical problem because of its low early diagnosis rate, high surgical mortality rate, low cure rate, and expensive related testing cost. Therefore, the significance of finding new markers for PC is self-evident. Semaphorins (Semas) have been shown to affect angiogenesis and lymphangiogenesis and can also directly affect the behavior of tumor cells. The expression and related action targets of its family members on PC are summarized in this review.

Breast cancer is the most common cancer in women, and first-degree relatives (FDRs) of breast cancer patients have a significantly higher risk of developing breast cancer. However, the factors affecting breast cancer screening behavior of FDRs in China remain unclear.The aim of this study was to determine the social cognitive theory factors influencing screening behaviors of FDRs.A cross-sectional survey was conducted, and 430 FDRs were recruited. Data were collected using demographic information and self-reported questionnaire based on the social cognitive theory. The structural equation modeling method was used to analyze the influence of social cognitive factors on breast cancer screening behavior.The model showed a good fit (goodness of fit = 0.462). Goal setting and self-regulation (β = 0.631, P.001) and positive outcome expectation (β = 0.098, P = .042) were positively related to breast cancer screening behavior. Negative outcome expectation was negatively related to breast cancer screening behavior (β = -0.102, P = .024). In addition, positive outcome expectation, negative outcome expectation, and goal setting and self-regulation are mediators of self-efficacy (β = 0.475, P.001) to breast cancer screening behavior.Goal setting and self-regulation are important influences on breast cancer screening behavior. The social cognitive theory is both applicable to and effective in explaining and predicting breast cancer screening behavior.Health professionals can develop appropriate intervention strategies based on the social cognitive theory among FDRs. It is necessary to focus on the people who influence women, such as spouses, mothers, or daughters.

Programmed cell death protein 1(PD-1) is a type of immune-inhibitory checkpoint protein, which delivers inhibitory signals to cytotoxic T cells by binding to the programmed death ligand-1 (PD-L1) displayed on the surface of cancer cells. Antibodies blocking PD-1/PD-L1 interaction have been extensively used in treatment of human malignancies and have achieved promising outcomes in recent years. However, gradual development of resistance to PD-1/PD-L1 blockade has decreased the effectiveness of this immunotherapy in cancer patients. The underlying epigenetic mechanisms need to be elucidated for application of novel strategies overcoming this immunotherapy resistance. Epigenetic aberrations contribute to cancerogenesis by promoting different hallmarks of cancer. Moreover, these alterations may lead to therapy resistance, thereby leading to poor prognosis. Recently, the epigenetic regulatory drugs have been shown to decrease the resistance to PD-1/PD-L1 inhibitors in certain cancer patients. Inhibitors of the non-coding RNAs, DNA methyltransferases, and histone deacetylases combined with PD-1/PD-L1 inhibitors have shown considerable therapeutic efficacy against carcinomas as well as blood cancers. Importantly, DNA methylation-mediated epigenetic silencing can inhibit antigen processing and presentation, which promotes cancerogenesis and aggravates resistance to PD-1/PD-L1 blockade immunotherapy. These observations altogether suggest that the combination of the epigenetic regulatory drugs with PD-1/PD-L1 inhibitors may present potential solution to the resistance caused by monotherapy of PD-1/PD-L1 immunotherapy.

BackgroundThe burden of disease and economic losses caused by aging populations and non-communicable chronic diseases (NCD) are significant public health concerns. Estimates of healthcare costs attributed to chronic diseases in the senior population can inform the creation of disease preventive and control policies. This study therefore utilized an econometric method to estimate the chronic disease attributable fraction (CDAF) of yearly per capita healthcare costs in older persons, which includes all potential costs.MethodsThis study employed the three waves of panel data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). The data evaluate the annual per capita utilization and cost of outpatient and inpatient healthcare for the elderly. A two-part model was utilized to estimate outpatient, inpatient, and healthcare costs associated to the six selected chronic conditions.ResultsThe top six chronic diseases of the surviving elderly in China are hypertension, arthritis, heart disease, cataract, chronic lung disease, stroke or cardiovascular disease (CVD). The CDAF for outpatient costs, inpatient costs, and healthcare costs were 44.99%, 64.73%, and 55.18%, respectively. Among them, the CDAFs of hypertension in outpatient costs and total healthcare costs were 12.53% and 12.50%; the CDAF of arthritis in outpatient costs was 5.95%; the CDAFs of heart disease in outpatient costs, hospitalization costs and healthcare costs were 17.85 %, 33.84%, and 24.49% respectively; the CDAFs of cataract in outpatient costs and healthcare costs were 4.60% and 5.67%; the CDAFs of chronic lung disease in outpatient costs, inpatient costs, and healthcare costs were 7.50%, 17.03%, and 11.96%; CDAFs of stroke or CVD in outpatient cost, inpatient cost, and healthcare cost were 7.96%, 23.54%, and 16.94%. In addition, gender, place of residence, and degree of education affect the cost attribute to chronic disease in older persons.ConclusionIn the healthcare service cost of the elderly, the attributed cost of chronic diseases has significant differences, mainly reflected in the elderly's gender, living environment, and preference for outpatient or inpatient treatment. Based on this, the prevention and treatment policies formulated for specific chronic diseases can help reduce the health and economic burden of the society.

Objectives The aim of this study is to address the difficulties encountered by public health workers in the early and middle stages of their efforts to combat COVID-19, compare the gaps among different types of institutions, and identify shortcomings in epidemic control. Methods Using multi-stage sampling, a survey of public health workers involved in the prevention and control of COVID-19 was conducted from 18 February to 1 March 2020 through a self-administered questionnaire. These public health workers were from the primary health care center (defined as “primary-urban” and “primary-rural” for those in urban and rural areas, respectively) and the center for disease control and prevention (defined as “non-primary”) in five provinces including Hubei, Guangdong, Sichuan, Jiangsu and Gansu, China. Results A total of 9,475 public health workers were surveyed, of which 40.0 %, 27.0 % and 33.0 % were from the primary-rural, primary-urban and non-primary, respectively. The resources shortage were reported by 27.9 % participants, with the primary-rural being the worst affected (OR = 1.201, 95 %CI: 1.073–1.345). The difficulties in data processing were reported by 31.5 % participants, with no significant differences among institutions. The difficulties in communication and coordination were reported by 29.8 % participants, with the non-primary being the most serious (primary-rural: OR = 0.520, 95 %CI: 0.446–0.606; primary-urban: OR = 0.533, 95 %CI: 0.454–0.625). The difficulties with target audiences were reported by 20.2 % participants, with the primary-urban being the worst (OR = 1.368, 95 %CI: 1.199–1.560). The psychological distress were reported by 48.8 % participants, with no significant differences among institutions. Conclusions Psychological distress is the most serious problem in the prevention and control of COVID-19. Resources shortage in primary-rural, difficulties in communication and coordination in non-primary, and difficulties with target audiences in the primary-urban deserve attention. This study will provide scientific evidences for improving the national public health emergency management system, especially for reducing the urban-rural differences in emergency response capacity.

The donor–acceptor (D–A) hybrid crystals are an emerging class of crystalline hybrid complexes composed of semiconductive organic and inorganic components at the molecular level. These unique cryst...

Supramolecular isomerism in coordination compounds, an ideal platform for understanding the self-assembly and structure–property relationships, has received extensive research interest in the past ...

Immunologic checkpoint blockade has been proven effective in a variety of malignancies. However, high rates of resistance have substantially hindered its clinical use. Understanding the underlying mechanisms may lead to new strategies for improving therapeutic efficacy. Although a number of signaling pathways have been shown to be associated with tumor cell–mediated resistance to immunotherapy, T cell–intrinsic resistant mechanisms remain elusive. Here, we demonstrated that diacylglycerol kinase alpha (Dgka) mediated T-cell dysfunction during anti–PD-1 therapy by exacerbating the exhaustion of reinvigorated tumor-specific T cells. Pharmacologic ablation of Dgka postponed T-cell exhaustion and delayed development of resistance to PD-1 blockade. Dgka inhibition also enhanced the efficacy of anti–PD-1 therapy. We further found that the expression of DGKA in cancer cells promoted tumor growth via the AKT signaling pathway, suggesting that DGKA might be a target in tumor cells as well. Together, these findings unveiled a molecular pathway mediating resistance to PD-1 blockade and provide a potential therapeutic strategy with combination immunotherapy.

Pudendal neuralgia (PN) is one of the most common forms of genital pain. Only 42.2% of PN patients respond to the first-line treatment. Novel neuromodulation techniques in the treatment of refractory PN patients are urgently required.The aim of this study was to evaluate the treatment effects and adverse events of sacral nerve stimulation (SNS) for patients with refractory PN.A prospective nonrandomized study.This prospective analysis included 33 patients who received the phase II surgical implantation.A total of 55 eligible PN patients were recruited for SNS treatment after informed consent, and 33 of 55 patients with a minimum 50% improvement were candidates for surgical implantation. Visual Analog Scale (VAS) scores, Self-rating Anxiety and Depression Scale, Quality of life score (SF-36), and sleep monitoring indicators before and after surgery were used to assess the effects of SNS on patients with refractory PN.Thirty-three patients were included in the final analysis, involving 24 women and 9 men with a mean age of 49.5 years (26-70 years). There was a favorable decrease in pain severity (VAS scores) from 7.1 ± 1.1 at baseline to 6.1 ± 1.0 on postoperative day 1, and 2.8 ± 0.7 at 1 week, 1.7 ± 0.5 at 1 month, 1.1 ± 0.7 at 6 months, and 1.0 ± 0.6 at 12 months after surgery, respectively (P0.05). The mean score of each section of SF-36 after SNS was significantly higher than that at baseline (P0.05). Total sleep time and sleep time in each period were significantly prolonged after SNS implantation compared with that before surgery (6 months vs Pre, total: 5.32 ± 1.49 hours vs 3.66 ± 1.19 hours, deep: 2.52 ± 0.63 hours vs 1.36 ± 0.43 hours, light: 1.78 ± 0.42 hours vs 0.99 ± 0.30 hours, rapid eye movement: 1.41 ± 0.29 hours vs 0.89 ± 0.27 hours, P0.05). No serious device complications were reported during the follow-up period.Large-scale randomized clinical trials are warranted to evaluate the risk factors for prediction of refractory PN.These data imply that SNS can have beneficial effects on patients with refractory PN.

Cardiac resynchronization therapy (CRT) for heart failure requires transvenous insertion of a left ventricular pacing lead through the coronary sinus. However, repeated intraoperative dislocations often occur. Therefore, we describe a novel technique that uses the loop technique to treat patients with repeated intraoperative dislocations during transvenous left ventricular lead implantation to stabilize the lead in its final position. In five patients with repeated intraoperative dislocation during transvenous left ventricular lead implantation, the loop technique was successfully used to stabilize the lead in its final position. The pacing and sensing parameters were satisfactory in all patients at implantation and 12 months post-operatively. Compared with the pre-operative values, the 12-month post-operative values for the left ventricular ejection fraction were significantly increased and the left ventricular end systolic dimension and left ventricular end diastolic dimension were significantly decreased (P < 0.05). The left ventricular ejection fraction of these 5 patients increased by more than 15%. CRT significantly improved the left ventricular structure and function of these 5 patients. During the 1-, 3-, 6-, and 12-month follow-ups, no left ventricular lead dislocations were observed. This loop technique is safe and effective and can be considered for repeated intraoperative dislocation during transvenous left ventricular lead implantation through the coronary sinus of a CRT device.

Follicular lymphoma (FL) is the second most frequent non-Hodgkin lymphoma accounting for 10-20% of all lymphomas in western countries. As a clinically heterogeneous cancer, FL occasionally undergoes histological transformation to more aggressive B cell lymphoma types that are associated with poor prognosis. Here we evaluated the potential of circulating cell-free DNA (cfDNA) to improve the diagnosis and prognosis of follicular lymphoma patients. Twenty well-characterized FL cases (13 symptomatic and 7 asymptomatic) were prospectively included in this study. Plasma cfDNA, formalin-fixed paraffin-embedded (FFPE) tumor tissue DNA, and patient-matched granulocyte genomic DNA samples were obtained from 20 treatment-naive FL cases. Ultra-deep targeted next-generation sequencing was performed with these DNA samples by using a custom-designed platform including exons and exon-intron boundaries of 110 FL related genes. Using a strict computational bioinformatics pipeline, we identified 91 somatic variants in 31 genes in treatment-naive FL cases. Selected variants were cross-validated by using PCR-Sanger sequencing. We observed higher concentrations of cfDNA and a higher overlap of somatic variants present both in cfDNA and tumor tissue DNA in symptomatic FL cases compared to asymptomatic ones. Variants known to be associated with FL pathogenesis such as STAT6 p.D419 or EZH2 p.Y646 were observed in patient-matched cfDNA and tumor tissue samples. Consistent with previous observations, high Ki-67 staining, elevated LDH levels, FDG PET/CT positivity were associated with poor survival. High plasma cfDNA concentrations or the presence of BCL2 mutations in cfDNA showed significant association with poor survival in treatment-naive patients. BCL2 mutation evaluations in cfDNA improved the prognostic utility of previously established variables. In addition, we observed that a FL patient who had progressive disease contained histological transformation-associated gene (i.e. B2M and BTG1) mutations only in cfDNA. Pre-treatment concentrations and genotype of plasma cfDNA may be used as a liquid biopsy to improve diagnosis, risk stratification, and prediction of histological transformation. Targeted therapies related to oncogenic mutations may be applied based on cfDNA genotyping results. However, the results of this study need to be validated in a larger cohort of FL patients as the analyses conducted in this study have an exploratory nature.

Background: The prognostic roles of ferroptosis-related mRNAs (FG) and lncRNAs (FL) in pediatric acute myeloid leukemia (P-AML) patients remain unclear.Methods: RNA-seq and clinical data of P-AML patients were downloaded from the TARGET project. Cox and LASSO regression analyses were performed to identify FG, FL, and FGL (combination of FG and FL) prognostic models, and their performances were compared. Tumor microenvironment, functional enrichment, mutation landscape, and anticancer drug sensitivity were analyzed.Results: An FGL model of 22 ferroptosis-related signatures was identified as an independent parameter, and it showed performance better than FG, FL, and four additional public prognostic models. The FGL model divided patients in the discovery cohort (N = 145), validation cohort (N = 111), combination cohort (N = 256), and intermediate-risk group (N = 103) defined by the 2017 European LeukemiaNet (ELN) classification system into two groups with distinct survival. The high-risk group was enriched in apoptosis, hypoxia, TNFA signaling via NFKB, reactive oxygen species pathway, oxidative phosphorylation, and p53 pathway and associated with low immunity, while patients in the low-risk group may benefit from anti-TIM3 antibodies. In addition, patients within the FGL high-risk group might benefit from treatment using SB505124_1194 and JAK_8517_1739.Conclusion: Our established FGL model may refine and provide a reference for clinical prognosis judgment and immunotherapies for P-AML patients.

BackgroundThe national essential public health service (NEPHS) has been in operation for more than a decade. Numerous studies examined the utilization of NEPHS by migrants and the factors that influence it, but few examined the effect of NEPHS awareness and utilization on the health of inhabitants, particularly migrants. The purpose of this study is to ascertain the level of awareness and utilization of NEPHS, as well as to examine their health-improving effects on migrants.MethodsBased on the data from the 2017 China Migrants Dynamic Survey, linear probability model, ordered logit model and the propensity score matching methods were employed to investigate impact of awareness and utilization of NEPHS on the health among Chinese migrants. Mediating effect model were used to identify the mechanism of the impact of NEPHS on health.ResultsThe findings indicated that migrants' awareness and utilization of NEPHS are still insufficient. After adjusting for other factors, the study discovered that increased awareness and use of NEPHS had a beneficial influence on migrants' self-rated health. Further heterogeneity analysis revealed significant disparities in the health consequences of NEPHS awareness and utilization across subgroups. The effect of increased awareness and usage of NEPHS on health is stronger for middle-aged and elderly people, women, and low-educated migrants with urban household registration. The estimated results of the mediating effect model supported the mechanism that increased NEPHS awareness among the floating population could encourage its utilization and further improve the floating population's health.ConclusionsGiven that migrants' NEPHS utilization is still low and that NEPHS utilization has a positive effect on health, some targeted strategies, such as a variety of new media communication methods, health education related to occupational disease and tuberculosis prevention, and targeted NEPHS projects for specific groups, such as men, young and middle-aged groups, those with a high level of education, and rural migrants, should be conducted to improve the health of migrants.

Background Public health workers at the Chinese Centre for Disease Control and Prevention (China CDC) and primary health care institutes (PHIs) were among the main workers who implemented prevention, control, and containment measures. However, their efforts and health status have not been well documented. We aimed to investigate the working conditions and health status of front line public health workers in China during the COVID-19 epidemic. Methods Between 18 February and 1 March 2020, we conducted an online cross-sectional survey of 2,313 CDC workers and 4,004 PHI workers in five provinces across China experiencing different scales of COVID-19 epidemic. We surveyed all participants about their work conditions, roles, burdens, perceptions, mental health, and self-rated health using a self-constructed questionnaire and standardised measurements (i.e., Patient Health Questionnaire and General Anxiety Disorder scale). To examine the independent associations between working conditions and health outcomes, we used multivariate regression models controlling for potential confounders. Results The prevalence of depression, anxiety, and poor self-rated health was 21.3, 19.0, and 9.8%, respectively, among public health workers (27.1, 20.6, and 15.0% among CDC workers and 17.5, 17.9, and 6.8% among PHI workers). The majority (71.6%) made immense efforts in both field and non-field work. Nearly 20.0% have worked all night for more than 3 days, and 45.3% had worked throughout the Chinese New Year holiday. Three risk factors and two protective factors were found to be independently associated with all three health outcomes in our final multivariate models: working all night for >3 days (multivariate odds ratio [ORm]=1.67~1.75, pppp=0.002~0.008), and ability to persist for > 1 month at the current work intensity (ORm=0.44~0.55, p Conclusions Chinese public health workers made immense efforts and personal sacrifices to control the COVID-19 epidemic and faced the risk of mental health problems. Efforts are needed to improve the working conditions and health status of public health workers and thus maintain their morale and effectiveness during the fight against COVID-19.

D–A hybrid heterostructures are an emerging class of crystalline hybrid materials composed of semiconductive inorganic donors and organic acceptors. However, due to the steric effects of the inorganic coordination sites, it is difficult for the large organic molecules to form compact packing at the molecular level, resulting in the poor efficiency of photoinduced charge transfers. To achieve an effective carrier separation and transfer, herein we incorporated third donors into a copper(I) halide/thiazolo[5,4-d] thiazole D–A heterostructure to construct three novel three-component complexes (Me2-Py2TTz)Cu4I6·(I2) (1), (Me2-Py2TTz)Cu3I5·(pyrene) (2) and (Me2-Py2TTz)Cu3I5·(perylene) (3) (Py2TTz = 2,5-bis(4-pyridyl) thiazolo[5,4-d] thiazole), respectively. Due to the spatial distances as well as the orbital energies between the copper(I) halide and thiazolo[5,4-d] thiazole units bridged by third donors, they are excellent three-component charge-transfer complexes (CTCs) with enhanced electrical properties.

With the introduction of 2,2′-bipyridine (2,2′-bipy) agent, two new zinc coordination polymers (CPs), {[Zn6(HL-H)4(2,2′-bipy)4]·¼H2O}n 1 and {[Zn3(HL-H)2(H2O)4]·6H2O}n 2, have been hydrothermally obtained derived from diphosphonic acid, 1-hydroxy-2-(3-pyridyl)ethylidene-1,1-diphosphonic acid (H5L = (H4C5N)CH2C(OH)(PO3H2)2, HL-H = (H4C5N–H)CH2C(OH)(PO3)2), and determined by single-crystal X-ray diffractions, elemental analysis, IR, powder X-ray diffractions (PXRD). The single-crystal X-ray diffractions reveal that compound 1 owns a novel 1-D fishbone-like inorganic chain structure built from binuclear building blocks [Zn2(O–P–O)2]n via [ZnO4]n tetrahedron linkers. It is the first example that N-heterlcyclic amine 2,2′-bipy is used as the second ligand to construct the compound 1 with the diphosphonic acid ligand H5L. Both hydrogen bonding and π–π stacking interactions further extend the 1-D chain to the 3-D supramolecular network. Compound 2 exhibits a 2-D reticulate layer structure containing 4-, 8- and 16-membered rings created from 1-D ladder-like inorganic chain, and the organic pyridine rings in the structure point to voids defined by the 16-membered rings. Moreover, the room-temperature fluorescence measurements show that both the compounds display two fluorescent emissions centered at 379, 424 nm for 1 and 380, 424 nm for 2, respectively, caused by intraligand π*–π emission state of organic pyridine ring (λex = 235 nm). With the introduction of 2,2′-bipyridine (2,2′-bipy) agent, two new Zn(II)-phosphonate CPs, 1-D {[Zn6(HL-H)4(2,2′-bipy)4]·¼H2O}n 1 and 2-D {[Zn3(HL-H)2(H2O)4]·6H2O}n 2 (H5L = (H4C5N)CH2C(OH)(PO3H2)2, HL-H = (H4C5N–H)CH2C(OH)(PO3)2), have been hydrothermally obtained and characterized. The thermal stabilities and fluorescent properties of them have been investigated.

Quarantine plays a key role in controlling the pandemic of 2019 coronavirus disease (COVID-19). This study investigated (a) the associations between mandatory quarantine status and negative cognitions (perceived discrimination because of COVID-19 and perceived risk of COVID-19 infection)/mental health status (emotional distress because of COVID-19, probable depression, and self-harm/suicidal ideation), (b) the associations between the negative cognitions and mental health status, and (c) potential mediations between quarantined status and probable depression and self-harm/suicidal ideation via COVID-19-related negative cognitions/emotional distress. An online cross-sectional survey was conducted among 24,378 students of 26 universities in 16 Chinese cities (February 1-10, 2020). Correlation coefficients, odds ratios (OR), structural equation modeling, and other statistics were used for data analysis. Mandatory quarantined status was significantly and positively associated with perceived discrimination (Cohen's d = 0.62), perceived high/very high risk of infection (OR = 1.61), emotional distress (Cohen's d = 0.46), probable depression (OR = 2.54), and self-harm/suicidal ideation (OR = 4.98). Perceived discrimination was moderately and positively associated with emotional distress (Spearman correlation = 0.44). Associations between perceived risk of infection and mental health variables were significant but relatively weak. Cross-sectional mediation models showed good model fit, but the overall indirect paths via COVID-19-related negative cognitions/emotional distress only accounted for 12-15% of the total effects between quarantined status and probable depression and self-harm/suicidal ideation. In conclusion, quarantined participants were more likely than others to perceive discrimination and exhibit mental distress. It is important to integrate mental health care into the planning and implementation of quarantine measures. Future longitudinal studies to explore mechanisms underlying the mental health impact of quarantines are warranted. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Primary central nervous system lymphoma (PCNSL), a rare variant of non-Hodgkin's lymphoma, is characterized by distinct biological characteristics and clinical behaviors, and patient prognosis is not satisfactory. The advent of high-dose (HD) methotrexate (HD-MTX) therapy has significantly improved PCNSL prognosis. Currently, HD-MTX-based chemotherapy regimens are recognized as first-line treatment. PCNSL is sensitive to radiotherapy, and whole-brain radiotherapy (WBRT) can consolidate response to chemotherapy; however, WBRT-associated delayed neurotoxicity leads to neurocognitive impairment, especially in elderly patients. Other effective approaches include rituximab, temozolomide, and autologous stem-cell transplantation (ASCT). In addition, new drugs against PCNSL such as those targeting the B-cell receptor signaling pathway, are undergoing clinical trials. However, optimal therapeutic approaches in PCNSL remain undefined. This review provides an overview of advances in surgical approaches, induction chemotherapy, radiotherapy, ASCT, salvage treatments, and novel therapeutic approaches in immunocompetent patients with PCNSL in the past 5 years. Additionally, therapeutic progress in elderly patients and in those with relapsed/refractory PCNSL is also summarized based on the outcomes of recent clinical studies.

BackgroundMethamphetamine (METH) abuse causes serious health problems, including injury to the immune system, leading to increased incidence of infections and even making withdrawal more difficult. Of course, immune cells, an important part of the immune system, are also injured in methamphetamine abuse. However, due to different research models and the lack of bioinformatics, the mechanism of METH injury to immune cells has not been clarified.MethodsWe examined the response of three common immune cell lines, namely Jurkat, NK-92 and THP-1 cell lines, to methamphetamine by cell viability and apoptosis assay in vitro, and examined their response patterns at the mRNA level by RNA-sequencing. Differential expression analysis of two conditions (control and METH treatment) in three types of immune cells was performed using the DESeq2 R package (1.20.0). And some of the differentially expressed genes were verified by qPCR. We performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis of differentially expressed genes by the clusterProfiler R package (3.14.3). And gene enrichment analysis was also performed using MetaScape (www.metascape.org).ResultsThe viability of the three immune cells was differentially affected by methamphetamine, and the rate of NK-cell apoptosis was significantly increased. At the mRNA level, we found disorders of cholesterol metabolism in Jurkat cells, activation of ERK1 and ERK2 cascade in NK-92 cells, and disruption of calcium transport channels in THP-1 cells. In addition, all three cells showed changes in the phospholipid metabolic process.ConclusionsThe results suggest that both innate and adaptive immune cells are affected by METH abuse, and there may be commonalities between different immune cells at the transcriptome level. These results provide new insights into the potential effects by which METH injures the immune cells.