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Abstract Depression questionnaire cutoffs are calibrated for screening accuracy and not to assess prevalence, but the Geriatric Depression Scale (GDS-15) is often used to estimate diagnostic prevalence among older adults, most commonly with scores of ≥ 5. We conducted an individual participant data meta-analysis to compare depression prevalence based on GDS-15 ≥ 5 to Structured Clinical Interview for Diagnostic and Statistical Manual (SCID) diagnoses and assessed whether an alternative cutoff could be more accurate. We used generalized linear mixed models to estimate prevalence. Data from 14 studies (3602 participants, 434 SCID major depression) were included. Pooled GDS-15 ≥ 5 prevalence was 34.2% (95% confidence interval [CI] 27.5–41.6%), and pooled SCID prevalence was 14.8% (95% CI 10.0–21.5%; difference of 17.6%, 95% CI 11.6–23.6%). GDS-15 ≥ 8 provided the closest estimate to SCID with mean difference of − 0.3% (95% prediction interval − 17.0–16.5%). Prevalence estimate differences were not associated with study or participant characteristics. In sum, GDS-15 ≥ 5 substantially overestimated depression prevalence. A cutoff of ≥ 8 was accurate overall, but heterogeneity was too high for implementation in practice. Validated diagnostic interviews should be used to estimate major depression prevalence among older adults.

Abstract Adipose tissue plays critical roles in an individual’s aging process. In this research, we use single-nucleus RNA sequencing to create highly detailed transcriptional maps of subcutaneous adipose tissue and visceral adipose tissue in young and aged mice. We comprehensively identify the various cell types within the white adipose tissue of mice, our study has elucidated seven distinct cell types within this tissue. Further analyses focus on adipocytes, fibro-adipogenic progenitors, and immune cells, revealing age-related declines in the synthetic metabolic activity of adipocytes, diminished immune regulation, and reduced maturation or proliferation of fibroblasts in undifferentiated adipocytes. We confirm the presence of distinct subpopulations of adipocytes, highlighting decreases in adipogenesis subgroups due to aging. Additionally, we uncover a reduction in immune cell subpopulations, driven by age-associated immune system dysregulation. Furthermore, pseudo-time analyses indicate that Adipocyte1 represents the 'nascent' phase of adipocyte development, while Adipocyte2 represents the 'mature' phase. We use cell–cell interaction to explore the age-dependent complexities of the interactions between FAPs and adipocytes, and observed increased expression of the inflammation-related Retn-Tlr4 interaction in older mice, while the anti-inflammatory Angpt1-Tek interaction was only detected in young mice. These transcriptional profiles serve as a valuable resource for understanding the functional genomics underlying metabolic disorders associated with aging in human adipose tissue.

Abstract. Background:. Life's Simple 7, the former construct of cardiovascular health (CVH) has been used to evaluate adverse non-communicable chronic diseases (NCDs). However, some flaws have been recognized in recent years and Life's Essential 8 has been established. In this study, we aimed to analyze the association between CVH defined by Life's Essential 8 and risk of 44 common NCDs and further estimate the population attributable fractions (PAFs) of low-moderate CVH scores in the 44 NCDs. Methods:. In the UK Biobank, 170,726 participants free of 44 common NCDs at baseline were included. The Life's Essential 8 composite measure consists of four health behaviours (diet, physical activity, nicotine exposure, and sleep) and four health factors (body mass index, non-high density lipoprotein cholesterol, blood glucose, and blood pressure), and the maximum CVH score was 100 points. CVH score was categorized into low, moderate, and high groups. Participants were followed up for 44 NCDs diagnosis across 10 human system disorders according to the International Classification of Diseases 10th edition (ICD-10) code using linkage to national health records until 2022. Cox proportional hazard models were used in this study. The hazard ratios (HRs) and PAFs of 44 NCDs associated with CVH score were examined. Results:. During the median follow-up of 10.85 years, 58,889 incident NCD cases were documented. Significant linear dose-response associations were found between higher CVH score and lower risk of 25 (56.8%) of 44 NCDs. Low-moderate CVH (

Abstract An equivalent analytical model of sloshing in a two-dimensional (2-D) rigid rectangular container equipped with multiple vertical baffles is presented. Firstly, according to the subdomain partition approach, the total liquid domain is partitioned into subdomains with the pure interface and boundary conditions. The separation of variables is utilized to achieve the velocity potential for subdomains. Then, sloshing characteristics are solved according to continuity and free surface conditions. According to the mode orthogonality of sloshing, the governing motion equation for sloshing under horizontal excitation is given by introducing generalized time coordinates. Besides, by producing the same hydrodynamic shear and overturning moment as those from the original container-liquid-baffle system, a mass-spring analytical model of the continuous liquid sloshing is established. The equivalent masses and corresponding locations are presented in the model. The feasibility of the present approach is verified by conducting comparative investigations. Finally, by utilizing normalized equivalent model parameters, the sloshing behaviors of the baffled container are investigated regarding baffle positions and heights as well as the liquid height, respectively.

Abstract. Background:. Prenatal and postnatal factors may have joint effects on cardiovascular health, and we aimed to assess the joint association of birth weight and ideal cardiovascular health metrics (ICVHMs) prospectively in adulthood with incident cardiovascular disease (CVD). Methods:. In the UK Biobank, 227,833 participants with data on ICVHM components and birth weight and without CVD at baseline were included. The ICVHMs included smoking, body mass index, physical activity, diet information, total cholesterol, blood pressure, and hemoglobin A1c. The Cox proportional hazards model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) in men and women. Results:. Over a median follow-up period of 13.0 years (2,831,236 person-years), we documented 17,477 patients with incident CVD. Compared with participants with birth weights of 2.5–4.0 kg, the HRs (95% CIs) of CVD among those with low birth weights was 1.08 (1.00–1.16) in men and 1.23 (1.16–1.31) in women. The association between having a birth weight

Abstract This study investigates the impact of geopolitical risk (GPR) on consumption-based carbon (CCO2) emissions as well as the moderating role of environmental policy stringency (EPS) on the above relationship. Based on data collected from 27 countries from 1990 to 2020, the basic results from the sample of the study indicate that GPR accelerates CCO2 emissions. Quantile regression results reveal that the effect of GPR is more pronounced in countries with higher CCO2 emissions. Moreover, EPS weakens the escalating effect of GPR on CCO2 emissions. The robust test results validate the findings reported in the basic regression model. The heterogeneity test indicates that the impact of GPR on CCO2 emissions is greater in developing countries compared in developed countries. The study also proposes these policy implications based on the findings: (1) countries should ensure a stable political environment, establish a robust legal system and promote energy transition; and (2) the scope of environmental taxes should be expanded where different tax rates should be imposed in order to be useful in reducing CCO2 emissions.

BackgroundSerious games (SGs) have emerged as engaging and instructional digital simulation tools that are increasingly being used for military medical training. SGs are often compared with traditional media in terms of learning outcomes, but it remains unclear which of the 2 options is more efficient and better accepted in the process of knowledge acquisition. ObjectiveThis study aimed to create and test a scenario-based system suitable for enhancing rescue reasoning skills in tactical combat casualty care. MethodsTo evaluate the effectiveness of the SGs, a randomized, observational, comparative trial was conducted. A total of 148 members from mobile medical logistics teams were recruited for training. Pre- and posttraining assessments were conducted using 2 different formats: a video-based online course (n=78) and a game simulation (n=70). We designed 3 evaluation instruments based on the first 2 levels of the Kirkpatrick model (reaction and learning) to measure trainees’ satisfaction, knowledge proficiency, and self-confidence. ResultsThere were 4 elements that made up the learning path for the SGs: microcourses (video-based online courses), self-test, game simulation, and record query. The knowledge test scores in both groups were significantly higher after the intervention (t154=–6.010 and t138=–7.867, respectively; P

Abstract Developing a mucosal vaccine against SARS-CoV-2 is critical for combatting the epidemic. Here, we investigated long-term immune responses and protection against SARS-CoV-2 for the intranasal vaccination of a triple receptor-binding domain (RBD) scaffold protein (3R-NC) adjuvanted with a flagellin protein (KFD) (3R-NC + KFDi.n). In mice, the vaccination elicited RBD-specific broad-neutralizing antibody responses in both serum and mucosal sites sustained at high level over a year. This long-lasting humoral immunity was correlated with the presence of long-lived RBD-specific IgG- and IgA-producing plasma cells, alongside the Th17 and Tfh17-biased T-cell responses driven by the KFD adjuvant. Based upon these preclinical findings, an open labeled clinical trial was conducted in individuals who had been primed with the inactivated SARS-CoV-2 (IAV) vaccine. With a favorable safety profile, the 3R-NC + KFDi.n boost elicited enduring broad-neutralizing IgG in plasma and IgA in salivary secretions. To meet the challenge of frequently emerged variants, we further designed an updated triple-RBD scaffold protein with mutated RBD combinations, which can induce adaptable antibody responses to neutralize the newly emerging variants, including JN.1. Our findings highlight the potential of the KFD-adjuvanted triple-RBD scaffold protein is a promising prototype for the development of a mucosal vaccine against SARS-CoV-2 infection.

Abstract. Background:. The serum vitamin D level varies widely by population, and studies have linked vitamin D levels with the risk of type 2 diabetes mellitus (T2DM). However, the relationship is inconsistent and the impact of vitamin D on T2DM among East Chinese adults is unclear. The study aimed to investigate the association between serum 25-hydroxyvitamin D (25[OH]D) levels and the risk of T2DM and evaluated whether the association is modified by genetic predisposition. Methods:. In the Survey on Prevalence in East China for Metabolic Diseases and Risk Factors (SPECT-China) cohort, 1862 participants free of T2DM at baseline were included. A weighted genetic risk score was calculated with 28 variants associated with T2DM. Hierarchical logistic models were used to examine the association of serum 25(OH)D and genetic risk with T2DM. Results:. After a 5-year follow-up, 132 cases of T2DM were documented. We observed no significant association between quartiles of serum 25(OH)D and T2DM risk after multivariable adjustment (χ2 = 0.571, Pfor trend = 0.426). Compared to those in the lowest quartile of 25(OH)D, the odds ratios (ORs) (95% confidence interval [CI]) for participants with increased quartiles were 1.29 (0.74–2.25), 1.35 (0.77–2.36), and 1.27 (0.72–2.24), respectively. We observed a positive association of glycated hemoglobin (HbA1c) with 25(OH)D at baseline (β = 1.752, P = 0.001) and after follow-up (β = 1.385, P = 0.003), and a negative association of ln conversion homeostasis model assessment (HOMA)-β with 25(OH)D at baseline (β = -0.982, P = 0.021). There was no significant interaction between 25(OH)D and diabetes genetic predisposition on the risk of T2DM (χ2 = 2.710, Pfor interaction = 0.100). The lowest OR (95% CI) of T2DM was among participants with low genetic risk and the highest quartile of 25(OH)D (0.17 [0.05–0.62]). Conclusion:. Serum 25(OH)D may be irrelevant to the risk of incident T2DM among East Chinese adults regardless of genetic predisposition.

Abstract This study investigates the impact of macroprudential policies on ecological footprint (EF) in the top 11 largest countries. This study uses country-level panel data from these countries, covering the period from 1992 to 2020. Findings indicate that macroprudential policies alleviates ecological footprint in the sample. Macroprudential policies primarily reduce the ecological footprint before medium quantile (50%) while the environmental benefits of the policies end in the later quantiles. Moreover, environmental policy stringency (EPS) amplifies the positive influence of macroprudential policies on environmental sustainability. Estimate results stay the same with basic regression results in the post-global financial crisis (GFC) period while the impact is positive in the pre-GFC period. Finally, other robust tests validate the findings reported in basic regression model. This study suggests that governments should customize various types of macroprudential policies while also considering environmental concerns. The achievement of a sustainable environment can be facilitated by the combined effects of macroprudential policies and EPS.

Abstract Bacteriophage therapy is one potential strategy to treat antimicrobial resistant or persistent bacterial infections, and the year 2021 marked the centennial of Felix d’Hérelle’s first publication on the clinical applications of phages. At the Center for Phage Biology & Therapy at Yale University, a preparatory modular approach has been established to offer safe and potent phages for single-patient investigational new drug applications while recognizing the time constraints imposed by infection(s). This study provides a practical walkthrough of the pipeline with an Autographiviridae phage targeting Pseudomonas aeruginosa (phage vB_PaeA_SB, abbreviated to ΦSB). Notably, a thorough phage characterization and the evolutionary selection pressure exerted on bacteria by phages, analogous to antibiotics, are incorporated into the pipeline.

Abstract Activating transcription factor 6 (ATF6) is an endoplasmic reticulum stress responsive gene. We previously reported that conditional knockout of hepatic ATF6 exacerbated liver metabolic damage by repressing autophagy through mTOR pathway. However, the mechanism by which ATF6 influence liver metabolism has not been well established. Hydrogen sulfide (H2S) is a gaseous signaling molecule that plays an important role in regulating inflammation, and suppress nonalcoholic fatty liver in mice. Based on the previous study, we assumed that ATF6 may regulate H2S production to participate in liver metabolism. In order to clarify the mechanism by which ATF6 regulates H2S synthesis to ameliorate liver steatosis and inflammatory environment, we conducted the present study. We used the liver specific ATF6 knockout mice and fed on high-fat-diet, and found that H2S level was significantly downregulated in hepatic ATF6 knockout mice. Restoring H2S by the administration of slow H2S releasing agent GYY4137 ameliorated the hepatic steatosis and glucose tolerance. ATF6 directly binds to the promoter of cystathionine β synthetase (CBS), an important enzyme in H2S synthesis. Thus, ATF6 could upregulate H2S production through CBS. Sulfhydrated Sirtuin-1 (SIRT1) was downregulated in ATF6 knockout mice. The expression of pro-inflammatory factor IL-17A was upregulated and anti-inflammatory factor IL-10 was downregulated in ATF6 knockout mice. Our results suggest that ATF6 can transcriptionally enhance CBS expression as well as H2S synthesis. ATF6 increases SIRT1 sulfhydration and ameliorates lipogenesis and inflammation in the fatty liver. Therefore, ATF6 could be a novel therapeutic strategy for high-fat diet induced fatty liver metabolic abnormalities.

Background:. Tri-ponderal mass index (TMI) has been reported to be a more accurate estimate of body fat than body mass index (BMI). This study aims to compare the effectiveness of TMI and BMI in identifying hypertension, dyslipidemia, impaired fasting glucose (IFG), abdominal obesity, and clustered cardio-metabolic risk factors (CMRFs) in 3- to 17-year-old children. Methods:. A total of 1587 children aged 3 to 17 years were included. Logistic regression was used to evaluate correlations between BMI and TMI. Area under the curves (AUCs) were used to compare discriminative capability among indicators. BMI was converted to BMI-z scores, and accuracy was compared by false-positive rate, false-negative rate, and total misclassification rate. Results:. Among children aged 3 to 17 years, the mean TMI was 13.57 ± 2.50 kg/m3 for boys and 13.3 ± 2.33 kg/m3 for girls. Odds ratios (ORs) of TMI for hypertension, dyslipidemia, abdominal obesity, and clustered CMRFs ranged from 1.13 to 3.15, higher than BMI, whose ORs ranged from 1.08 to 2.98. AUCs showed similar ability of TMI (AUC: 0.83) and BMI (AUC: 0.85) in identifying clustered CMRFs. For abdominal obesity and hypertension, the AUC of TMI was 0.92 and 0.64, respectively, which was significantly better than that of BMI, 0.85 and 0.61. AUCs of TMI for dyslipidemia and IFG were 0.58 and 0.49. When 85th and 95th of TMI were set as thresholds, total misclassification rates of TMI for clustered CMRFs ranged from 6.5% to 16.4%, which was not significantly different from that of BMI-z scores standardized according to World Health Organization criteria. Conclusions:. TMI was found to have equal or even better effectiveness in comparison with BMI in identifying hypertension, abdominal obesity, and clustered CMRFs TMI was more stable than BMI in 3- to 17-year-old children, while it failed to identify dyslipidemia and IFG. It is worth considering the use of TMI for screening CMRFs in children and adolescents.

Abstract Background Apatinib, a highly selective VEGFR2 inhibitor, significantly improved efficacy versus placebo as a third- and later-line treatment for advanced gastric cancer in phase 2 and 3 trials. This prospective, single-arm, multicenter phase IV AHEAD study was conducted to verify the safety and efficacy of apatinib in patients with advanced or metastatic gastric or gastroesophageal adenocarcinoma after at least two lines of systematic therapy in clinical practice settings. Methods Patients with advanced gastric cancer who had previously failed at least two lines of chemotherapy received oral apatinib until disease progression, death or unacceptable toxicity. The primary endpoint was safety. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Adverse events were summarized by the incidence rate. Median OS and PFS were estimated using the Kaplan–Meier method. ORR, DCR, OS at 3 and 6 months, and PFS at 3 and 6 months were calculated, and their 95% CIs were estimated according to the Clopper-Pearson method. Results Between May 2015 and November 2019, a total of 2004 patients were enrolled, and 1999 patients who received at least one dose of apatinib were assessed for safety. In the safety population, 87.9% of patients experienced treatment-related adverse events (TRAEs), with the most common hypertension (45.2%), proteinuria (26.5%), and white blood cell count decreased (25.3%). Additionally, 51% of patients experienced grade ≥ 3 TRAEs. Fatal TRAEs occurred in 57 (2.9%) patients. No new safety concerns were reported. Among the 2004 patients included in the intention-to-treat population, the ORR was 4.4% (95% CI, 3.6–5.4%), and DCR was 35.8% (95% CI, 33.7–38.0%). The median PFS was 2.7 months (95% CI 2.2–2.8), and the median OS was 5.8 months (95% CI 5.4–6.1). Conclusions The findings in the AHEAD study confirmed the acceptable and manageable safety profile and clinical benefit of apatinib in patients with advanced gastric cancer as a third- or later-line of treatment. Trial registration This study was registered with ClinicalTrials.gov NCT02426034. Registration date was April 24, 2015.

Summary: Background: Cerebral Cavernous Malformation (CCM) is a rare cerebrovascular disease, characterized by the presence of multiple vascular malformations that may result in intracerebral hemorrhages (ICHs), seizure(s), or focal neurological deficits (FND). Familial CCM (fCCM) is due to loss of function mutations in one of the three independent genes KRIT1 (CCM1), Malcavernin (CCM2), or Programmed Cell death 10 (PDCD10/CCM3). The aim of this study was to identify plasma protein biomarkers of fCCM to assess the severity of the disease and predict its progression. Methods: Here, we have investigated plasma samples derived from n = 71 symptomatic fCCM patients (40 female/31 male) and n = 17 healthy donors (HD) (9 female/8 male) of the Phase 1/2 Treat_CCM trial, using multiplexed protein profiling approaches. Findings: Biomarkers as sCD14 (p = 0.00409), LBP (p = 0.02911), CXCL4 (p = 0.038), ICAM-1 (p = 0.02013), ANG2 (p = 0.026), CCL5 (p = 0.00403), THBS1 (p = 0.0043), CRP (p = 0.0092), and HDL (p = 0.027), were significantly different in fCCM compared to HDs. Of note, sENG (p = 0.011), THBS1 (p = 0.011) and CXCL4 (p = 0.011), were correlated to CCM genotype. sROBO4 (p = 0.014), TM (p = 0.026) and CRP (p = 0.040) were able to predict incident adverse clinical events, such as ICH, FND or seizure. GDF-15, FLT3L, CXCL9, FGF-21 and CDCP1, were identified as predictors of the formation of new MRI-detectable lesions over 2-year follow-up. Furthermore, the functional relevance of ang2, thbs1, robo4 and cdcp1 markers was validated by zebrafish pre-clinical model of fCCM. Interpretation: Overall, our study identifies a set of biochemical parameters to predict CCM progression, suggesting biological interpretations and potential therapeutic approaches to CCM disease. Funding: Italian Medicines Agency, Associazione Italiana per la Ricerca sul Cancro (AIRC), ERC, Leducq Transatlantic Network of Excellence, Swedish Research Council.

Abstract Background In recent years, there have been breakthroughs in the preclinical research of respiratory diseases, such as organoids and organ tissue chip models, but they still cannot provide insight into human respiratory diseases well. Human lung slices model provides a promising in vitro model for the study of respiratory diseases because of its preservation of lung structure and major cell types. Methods Human lung slices were manually prepared from small pieces of lung tissues obtained from lung cancer patients subjected to lung surgery. To evaluate the suitability of this model for lung fibrosis research, lung slices were treated with CdCl2 (30 μM), TGF-β1 (1 ng/ml) or CdCl2 plus TGF-β1 for 3 days followed by toxicity assessment, gene expression analysis and histopathological observations. Results CdCl2 treatment resulted in a concentration-dependent toxicity profile evidenced by MTT assay as well as histopathological observations. In comparison with the untreated group, CdCl2 and TGF-β1 significantly induces MMP2 and MMP9 gene expression but not MMP1. Interestingly, CdCl2 plus TGF-β1 significantly induces the expression of MMP1 but not MMP2, MMP7 or MMP9. Microscopic observations reveal the pathogenesis of interstitial lung fibrosis in the lung slices of all groups; however, CdCl2 plus TGF-β1 treatment leads to a greater alveolar septa thickness and the formation of fibroblast foci-like pathological features. The lung slice model is in short of blood supply and the inflammatory/immune-responses are considered minimal. Conclusions The results are in favor of the hypothesis that idiopathic pulmonary fibrosis (IPF) is mediated by tissue damage and abnormal repair. Induction of MMP1 gene expression and fibroblast foci-like pathogenesis suggest that this model might represent an early stage of IPF.

Abstract Item 10 of the Edinburgh Postnatal Depression Scale (EPDS) is intended to assess thoughts of intentional self-harm but may also elicit concerns about accidental self-harm. It does not specifically address suicide ideation but, nonetheless, is sometimes used as an indicator of suicidality. The 9-item version of the EPDS (EPDS-9), which omits item 10, is sometimes used in research due to concern about positive endorsements of item 10 and necessary follow-up. We assessed the equivalence of total score correlations and screening accuracy to detect major depression using the EPDS-9 versus full EPDS among pregnant and postpartum women. We searched Medline, Medline In-Process and Other Non-Indexed Citations, PsycINFO, and Web of Science from database inception to October 3, 2018 for studies that administered the EPDS and conducted diagnostic classification for major depression based on a validated semi-structured or fully structured interview among women aged 18 or older during pregnancy or within 12 months of giving birth. We conducted an individual participant data meta-analysis. We calculated Pearson correlations with 95% prediction interval (PI) between EPDS-9 and full EPDS total scores using a random effects model. Bivariate random-effects models were fitted to assess screening accuracy. Equivalence tests were done by comparing the confidence intervals (CIs) around the pooled sensitivity and specificity differences to the equivalence margin of δ = 0.05. Individual participant data were obtained from 41 eligible studies (10,906 participants, 1407 major depression cases). The correlation between EPDS-9 and full EPDS scores was 0.998 (95% PI 0.991, 0.999). For sensitivity, the EPDS-9 and full EPDS were equivalent for cut-offs 7–12 (difference range − 0.02, 0.01) and the equivalence was indeterminate for cut-offs 13–15 (all differences − 0.04). For specificity, the EPDS-9 and full EPDS were equivalent for all cut-offs (difference range 0.00, 0.01). The EPDS-9 performs similarly to the full EPDS and can be used when there are concerns about the implications of administering EPDS item 10. Trial registration: The original IPDMA was registered in PROSPERO (CRD42015024785).

Considerable evidence indicates the important role of gut microbiota in human health. Through the interaction with the host and diet, it secretes a myriad of metabolites to modulate biological processes essential for health. Cognitive impairment is a common feature of psychiatric and neurological disorders, which may seriously damage the quality of patients' life. Studies have found that cognitive impairment has a close relationship with gut microbiota, and plant polysaccharides intervention to maintain intestinal micro-ecological balance has a great impact on ameliorating cognitive impairment. This review introduced the interaction between gut microbiota and plant polysaccharides, and focused on signaling pathogenesis of gut microbiota in cognitive impairment. The effect of plant polysaccharides intervention on regulation of gut microbiota was also discussed, so as to provide a promising strategy for ameliorating cognitive impairment.

Abstract Background The realization of the “microbiota–gut–brain” axis plays a critical role in neuropsychiatric disorders, particularly depression, is advancing rapidly. Matrine is a natural bioactive compound, which has been found to possess potential antidepressant effect. However, the underlying mechanisms of regulation of the “microbiota–gut–brain” axis in the treatment of depression by oral matrine remain elusive. Methods Its antidepressant effects were initially evaluated by behavioral tests and relative levels of monoamine neurotransmitters, and matrine has been observed to attenuate the depression-like behavior and increase neurotransmitter content in CUMS-induced mice. Subsequently, studies from the “gut” to “brain” were conducted, including detection of the composition of gut microbiota by 16S rRNA sequencing; the metabolomics detection of gut metabolites and the analysis of differential metabolic pathways; the assessment of relative levels of diamine oxidase, lipopolysaccharide, pro-inflammatory cytokines, and brain-derived neurotrophic factor (BDNF) by ELISA kits or immunofluorescence. Results Matrine could regulate the disturbance of gut microbiota and metabolites, restore intestinal permeability, and reduce intestinal inflammation, thereby reducing the levels of pro-inflammatory cytokines in peripheral blood circulation and brain regions, and ultimately increase the levels of BDNF in brain. Conclusion Matrine may ameliorate CUMS-induced depression in mice by modulating the “microbiota–gut–brain” axis.

Abstract Background Programmed cell death protein-1 (PD-1) blockade therapies have demonstrated efficacy in nasopharyngeal carcinoma (NPC). Thyroid dysfunction is among the most common immune-related adverse events. This study aimed to explore the clinical pattern of thyroid dysfunction and its relationship with survival marker in nonmetastatic NPC after immunotherapy. Methods From January 1, 2019, to December 31, 2021, 165 pairs of nonmetastatic NPC patients (165 with and 165 without anti-PD-1 immunotherapy) matched by the propensity score matching method were included in this study. Thyroid function was assessed retrospectively before the first treatment and during each immunotherapy cycle. Results The spectrum of thyroid dysfunction was different between the immunotherapy and control groups (P < 0.001). Compared with the control group, patients in the immunotherapy group developed more hypothyroidism (14.545% vs. 7.273%), less hyperthyroidism (10.909% vs. 23.636%), and a distinct pattern, biphasic thyroid dysfunction (3.030% vs. 0%). Immunotherapy also accelerates the onset of hypothyroidism, which was earlier with a median onset time difference of 32 days (P < 0.001). Patients who acquired thyroid dysfunction during immunotherapy had better complete biological response to treatment (OR, 10.980; P = 0.042). Conclusions For nonmetastatic NPC, thyroid dysfunction was associated with better response to treatment in immunotherapy but not in routine treatment. Thyroid function could be used as a predictor for survival and should be under regular and intensive surveillance in clinical practice of anti-PD-1 immunotherapy for nonmetastatic NPC.

Abstract The cellulose of carex meyeriana kunth (CMKC) was used as raw material, and the spinning solution was prepared by combining with polyacrylonitrile (PAN). The nano-cellulose fiber of carex meyeriana kunth (CMKN) was prepared by electrospinning. Used to remove methylene blue dye (MB) in aqueous solution. In the electrospinning experiment, the addition of CMKC was in the range of 5% ~ 25%, the feed rate of spinning parameters was set in the range of 0.2 ~ 1.0 mL/h, the distance from the needle tip to the collecting plate was in the range of 10 ~ 25 cm, and the voltage was changed in the range of 15 ~ 25 kV. The obtained CMKN was characterized by scanning electron microscope, X-ray diffraction (XRD) and Fourier transform infrared spectroscopy. The MB removal rate was evaluated in the dye removal experiment, and the effects of CMKN on MB removal rate under the factors of CMKC dosage, temperature, shock time and MB initial concentration were discussed. The optimum process conditions were determined by response surface methodology. The results show that the prepared fibers are superfine fibers with nanometer diameter, and the spun nanofibers have smooth surface, high overall orientation and strong uniformity. The adsorption kinetics of prepared CMKN accords with quasi-second order model, and the adsorption isotherm accords with Langmuir model. The maximum dye removal rate of CMKN is 63.24%.

Abstract Background Significant intertumoral heterogeneity exists as antitumor treatment is introduced. Heterogeneous therapeutic responses are conventionally evaluated by imaging examinations based on Response Evaluation Criteria in Solid Tumors (RECIST); nevertheless, there are increasing recognitions that they do not fully capture patient clinical benefits. Currently, there is a paucity of data regarding the clinical implication of biological responses assessed by liquid biopsy of on-treatment circulating tumor DNA (ctDNA). Here, we investigated whether biological response evaluated by ctDNA kinetics added critical information to the RECIST, and whether integrating on-treatment biological response information refined risk stratification of cancer patients. Methods In this population-based cohort study, we included 821 patients with Epstein-Barr virus (EBV)-associated nasopharynx of head and neck cancer (NPC) receiving sequential neoadjuvant chemotherapy (NAC) and chemoradiotherapy (CRT), who had pretreatment and on-treatment cfEBV DNA and magnetic resonance imaging (MRI) surveillance. Biological responses evaluated by cfEBV DNA were profiled and compared with conventional MRI-based RECIST evaluation. The inverse probability weighting (IPW)-adjusted survival analysis was performed for major survival endpoints. The Cox proportional hazard regression [CpH]-based model was developed to predict the on-treatment ctDNA-based individualized survival. Results Of 821 patients, 71.4% achieved complete biological response (cBR) upon NAC completion. RECIST-based response evaluations had 25.3% discordance with ctDNA-based evaluations. IPW-adjusted survival analysis revealed that cfEBV DNApost-NAC was a preferential prognosticator for all endpoints, especially for distant metastasis. In contrast, radiological response was more preferentially associated with locoregional recurrence. Intriguingly, cfEBV DNApost-NAC further stratified RECIST-responsive and non-responsive patients; RECIST-based non-responsive patients with cBR still derived substantial clinical benefits. Moreover, detectable cfEBV DNApost-NAC had 83.6% prediction sensitivity for detectable post-treatment ctDNA, which conferred early determination of treatment benefits. Finally, we established individualized risk prediction models and demonstrated that introducing on-treatment ctDNA significantly refined risk stratification. Conclusions Our study helps advance the implementation of ctDNA-based testing in therapeutic response evaluation for a refined risk stratification. The dynamic and refined risk profiling would tailor future liquid biopsy-based risk-adapted personalized therapy.

The gut microbiota promotes host health by maintaining homeostasis and enhancing digestive efficiency. The gut microflora in wild birds affects host physiological characteristics, nutritional status, and stress response. The relict gull (Larus Relictus, a Chinese national first-class protected species) and the black-necked grebe (Podiceps Nigricollis, a secondary protected species) bred in the Ordos Relic Gull National Nature Reserve share similar feeding habits and living environments but are distantly related genetically. To explore the composition and differences in the gut microbiota of these two key protected avian species in Erdos Relic Gull National Nature Reserve and provide a basis for their protection, 16S rRNA gene high-throughput sequencing was performed and the gut microbial diversity and composition of the relict gull (L. Relictus) and black-necked grebe (P. Nigricollis) was characterized. In total, 445 OTUs (operational taxonomic units) were identified and classified into 15 phyla, 22 classes, 64 orders, 126 families, and 249 genera. Alpha diversity analysis indicates that the gut microbial richness of the relict gull is significantly lower than that of the black-necked grebe. Gut microbe composition differs significantly between the two species. The most abundant bacterial phyla in these samples were Proteobacteria, Firmicutes, Fusobacteria, and Bacteroidetes. The prominent phylum in the relict gull was Proteobacteria, whereas the prominent phylum in the black-necked grebe was Firmicutes. The average relative abundance of the 17 genera identified was greater than 1%. The dominant genus in the relict gull was Escherichia-Shigella, whereas Halomonas was dominant in the black-necked grebe. Microbial functional analyses indicate that environmental factors exert a greater impact on relict gulls than on black-necked grebes. Compared with the relict gull, the black-necked grebe was able to use food more efficiently to accumulate its nutrient requirements, and the gut of the relict gull harbored more pathogenic bacteria, which may be one reason for the decline in the relict gull population, rendering it an endangered species. This analysis of the gut microbial composition of these two wild avian species in the same breeding grounds is of great significance, offers important guidance for the protection of these two birds, especially relict gulls, and provides a basis for understanding the propagation of related diseases.

Summary: Background: Patients with auto-brewery syndrome (ABS) become inebriated after the ingestion of an alcohol-free, high-carbohydrate diet. Our previous work has shown that high-alcohol-producing (HiAlc) Klebsiella pneumoniae can generate excessive endogenous ethanol and cause non-alcoholic fatty liver disease (NAFLD). Therefore, it is reasonable to speculate that such bacteria might play an important role in the pathogenesis of ABS. Methods: The characteristics and metabolites of the intestinal flora from a clinical cohort of patients with ABS were analysed during different stages of disease and compared to a group of healthy controls. An in vitro culture system of relevant samples was used for screening drug sensitivity and ABS-inducing factors. Rabbit intestinal and murine models were established to verify if the isolated strains could induce ABS in vivo. Findings: We observed intestinal dysbiosis with decreased abundance of Firmicutes and increased of Proteobacteria in patients with ABS compared with healthy controls. The abundance of the genus Klebsiella in Enterobacteriaceae was strongly associated with fluctuations of patient's blood alcohol concentration. We isolated three species of HiAlc Klebsiella from ABS patients, which were able to induce ABS in mice. Monosaccharide content was identified as a potential food-related inducing factor for alcohol production. Treatments with antibiotics, a complex probiotic preparation and a low-carbohydrate diet not only alleviated ABS, but also erased ABS relapse during the follow-up observation of one of the patients. Interpretation: Excessive endogenous alcohol produced by HiAlc Klebsiella species was an underlying cause of bacterial ABS. Combined prescription of appropriate antibiotics, complex probiotic preparation and a controlled diet could be sufficient for treatment of bacteria-caused ABS. Funding: The funders are listed in the acknowledgement.

Abstract Women and gender-diverse individuals have faced disproportionate socioeconomic burden during COVID-19. There have been reports of greater negative mental health changes compared to men based on cross-sectional research that has not accounted for pre-COVID-19 differences. We compared mental health changes from pre-COVID-19 to during COVID-19 by sex or gender. MEDLINE (Ovid), PsycINFO (Ovid), CINAHL (EBSCO), EMBASE (Ovid), Web of Science Core Collection: Citation Indexes, China National Knowledge Infrastructure, Wanfang, medRxiv (preprints), and Open Science Framework Preprints (preprint server aggregator) were searched to August 30, 2021. Eligible studies included mental health symptom change data by sex or gender. 12 studies (10 unique cohorts) were included, all of which reported dichotomized sex or gender data. 9 cohorts reported results from March to June 2020, and 2 of these also reported on September or November to December 2020. One cohort included data pre-November 2020 data but did not provide dates. Continuous symptom change differences were not statistically significant for depression (standardized mean difference [SMD] = 0.12, 95% CI -0.09–0.33; 4 studies, 4,475 participants; I2 = 69.0%) and stress (SMD = − 0.10, 95% CI -0.21–0.01; 4 studies, 1,533 participants; I2 = 0.0%), but anxiety (SMD = 0.15, 95% CI 0.07–0.22; 4 studies, 4,344 participants; I2 = 3.0%) and general mental health (SMD = 0.15, 95% CI 0.12–0.18; 3 studies, 15,692 participants; I2 = 0.0%) worsened more among females/women than males/men. There were no significant differences in changes in proportions above cut-offs: anxiety (difference = − 0.05, 95% CI − 0.20–0.11; 1 study, 217 participants), depression (difference = 0.12, 95% CI -0.03–0.28; 1 study, 217 participants), general mental health (difference = − 0.03, 95% CI − 0.09–0.04; 3 studies, 18,985 participants; I2 = 94.0%), stress (difference = 0.04, 95% CI − 0.10–0.17; 1 study, 217 participants). Mental health outcomes did not differ or were worse by small amounts among women than men during early COVID-19.

Abstract This study aims to develop an assumption-free data-driven model to accurately forecast COVID-19 spread. Towards this end, we firstly employed Bayesian optimization to tune the Gaussian process regression (GPR) hyperparameters to develop an efficient GPR-based model for forecasting the recovered and confirmed COVID-19 cases in two highly impacted countries, India and Brazil. However, machine learning models do not consider the time dependency in the COVID-19 data series. Here, dynamic information has been taken into account to alleviate this limitation by introducing lagged measurements in constructing the investigated machine learning models. Additionally, we assessed the contribution of the incorporated features to the COVID-19 prediction using the Random Forest algorithm. Results reveal that significant improvement can be obtained using the proposed dynamic machine learning models. In addition, the results highlighted the superior performance of the dynamic GPR compared to the other models (i.e., Support vector regression, Boosted trees, Bagged trees, Decision tree, Random Forest, and XGBoost) by achieving an averaged mean absolute percentage error of around 0.1%. Finally, we provided the confidence level of the predicted results based on the dynamic GPR model and showed that the predictions are within the 95% confidence interval. This study presents a promising shallow and simple approach for predicting COVID-19 spread.

The development of efficient fungal vaccines is urgent for preventing life-threatening systemic fungal infections. In this study, we prepared a synthetic, cell-based fungal vaccine for preventing systemic fungal infections using synthetic biology techniques. The synthetic cell EmEAP1 was constructed by transforming the Escherichia coli chassis using a de novo synthetic fragment encoding the protein mChEap1 that was composed of the E. coli OmpA peptide, the fluorescence protein mCherry, the Candida albicans adhesin Eap1, and the C-terminally transmembrane region. The EmEAP1 cells highly exposed the mChEap1 on the cell surface under IPTG induction. The fungal vaccine was then prepared by mixing the EmEAP1 cells with aluminum hydroxide gel and CpG. Fluorescence quantification revealed that the fungal vaccine was stable even after 112 days of storage. After immunization in mice, the vaccine resided in the lymph nodes, inducing the recruitment of CD11c+ dendritic cells. Moreover, the vaccine strongly activated the CD4+ T splenocytes and elicited high levels of anti-Eap1 IgG. By the prime-boost immunization, the vaccine prolonged the survival time of the mice infected by the C. albicans cells and attenuated fungal colonization together with inflammation in the kidneys. This study sheds light on the development of synthetic biology-based fungal vaccines for the prevention of life-threatening fungal infections.

In humans, odors are detected by ~400 functional olfactory receptor (OR) genes. The superfamily of functional OR genes can be further divided into tens of families. In large part, the OR genes have experienced extensive tandem duplications, which have led to gene gains and losses. However, whether different OR gene families have experienced distinct modes of gene duplication has yet to be reported. We conducted comparative genomic and evolutionary analyses for human functional OR genes. Based on analysis of human-mouse 1-1 orthologs, we found that human functional OR genes show higher-than-average evolutionary rates, and there are significant differences among families of functional OR genes. Via comparison with seven vertebrate outgroups, families of human functional OR genes show different extents of gene synteny conservation. Although the superfamily of human functional OR genes is enriched in tandem and proximal duplications, there are particular families which are enriched in segmental duplications. These findings suggest that human functional OR genes may be governed by different evolutionary mechanisms and that large-scale gene duplications have contributed to the early evolution of human functional OR genes.

BackgroundLiver tumor remains an important cause of cancer-related death. Nanosecond pulsed electric fields (nsPEFs) are advantageous in the treatment of melanoma and pancreatic cancer, but their therapeutic application on liver tumors need to be further studied.MethodsHep3B cells were treated with nsPEFs. The biological behaviors of cells were detected by Cell Counting Kit-8, 5-ethynyl-20-deoxyuridine, and transmission electron microscopy (TEM) assays. In vivo, rabbit VX2 liver tumor models were ablated by ultrasound-guided nsPEFs and radiofrequency ablation (RFA). Contrast-enhanced ultrasound (CEUS) was used to evaluate the ablation effect. HE staining and Masson staining were used to evaluate the tissue morphology after ablation. Immunohistochemistry was performed to determine the expression of Ki67, proliferating cell nuclear antigen, and α-smooth muscle actin at different time points after ablation.ResultsThe cell viability of Hep3B cells was continuously lower than that of the control group within 3 days after pulse treatment. The proliferation of Hep3B cells was significantly affected by nsPEFs. TEM showed that Hep3B cells underwent significant morphological changes after pulse treatment. In vivo, CEUS imaging showed that nsPEFs could completely ablate model rabbit VX2 liver tumors. After nsPEFs ablation, the area of tumor fibrosis and the expression of Ki67, proliferating cell nuclear antigen, and α-smooth muscle actin were decreased. However, after RFA, rabbit VX2 liver tumor tissue showed complete necrosis, but the expression of PCNA and α-smooth muscle actin did not decrease compared to the tumor group.ConclusionsnsPEFs can induce Hep3B cells apoptosis and ablate rabbit VX2 liver tumors in a non-thermal manner versus RFA. The ultrasound contrast agent can monitor immediate effect of nsPEF ablation. This study provides a basis for the clinical study of nsPEFs ablation of liver cancer.

Abstract Background The optimal posttreatment surveillance strategy for nasopharyngeal carcinoma (NPC) remains unclear. Circulating cell-free Epstein-Barr virus (cfEBV) DNA has been recognized as a promising biomarker to facilitate early detection of NPC recurrence. Therefore, we aim to determine whether integrating circulating cfEBV DNA into NPC follow-up is cost-effective. Methods For each stage of asymptomatic nonmetastatic NPC patients after complete remission to primary NPC treatment, we developed a Markov model to compare the cost-effectiveness of the following surveillance strategies: routine follow-up strategy, i.e., (1) routine clinical physical examination; routine imaging strategies, including (2) routine magnetic resonance imaging plus computed tomography plus bone scintigraphy (MRI + CT + BS); and (3) routine 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT); cfEBV DNA-guided imaging strategies, including (4) cfEBV DNA-guided MRI + CT + BS and (5) cfEBV DNA-guided PET/CT. Clinical probabilities, utilities, and costs were derived from published studies or databases. Sensitivity analyses were performed. Results For all disease stages, cfEBV DNA-guided imaging strategies demonstrated similar survival benefits but were considerably more economical than routine imaging strategies. They only required approximately one quarter of the number of imaging studies compared with routine imaging strategies to detect one recurrence. Specifically, cfEBV DNA-guided MRI + CT + BS was most cost-effective for stage II (incremental cost-effectiveness ratio [ICER] $57,308/quality-adjusted life-year [QALY]) and stage III ($46,860/QALY) patients, while cfEBV DNA-guided PET/CT was most cost-effective for stage IV patients ($62,269/QALY). However, routine follow-up was adequate for stage I patients due to their low recurrence risk. Conclusions The cfEBV DNA-guided imaging strategies are effective and cost-effective follow-up methods in NPC. These liquid biopsy-based strategies offer evidence-based, stage-specific surveillance modalities for clinicians and reduce disease burden for patients.

Objectives To evaluate the extent to which marriage influences cancer-specific survival (CSS) by influencing the insurance status among patients with common solid cancers and the feasibility of reducing the survival gap caused by marriage by increasing private insurance coverage for unmarried patients.Setting A retrospective cohort study with patients retrieved from the Surveillance, Epidemiology and End Results programme.Participants Patients with nine common solid cancers diagnosed between 2007 and 2016 were included. Patients were excluded if their marital status, insurance status, socioeconomical status, stage or cause of death was unavailable, if survival time was less than 1 month, or if they were younger than 18 years at the time of diagnosis.Primary and secondary outcome measures The primary outcome was CSS, which was compared between married and unmarried individuals. Mediation analyses were conducted to determine the contribution of insurance status to the association between marriage and CSS.Results Married patients had better CSS than those unmarried (time ratio 1.778; 95% CI 1.758 to 1.797). Private health insurance was a key factor mediating the association between marital status and CSS (proportion mediated (PM), 17%; 95% CI 17% to 17.1%). The PM ranges from 10.7% in prostate cancer to 20% in kidney cancer. The contribution of private insurance to the association between marital status and CSS was greater among women than among men (PM 18.5% vs 16.7%). The mediating effect of private insurance was the greatest for the comparison between married and separated individuals (PM 25.6%; 95% CI 25.3% to 25.8%) and smallest for the comparison between married and widowed individuals (PM 11.0%; 95% CI 10.9% to 11.1%).Conclusions 17% of the marital disparities in CSS are mediated by private insurance coverage. Increasing private insurance coverage for unmarried patients may reduce the survival gap related to marital status and sex. However, it is unclear whether better publicly funded insurance would have the same effect.

Abstract Objective To address the challenge of computational identification of cell type-specific regulatory elements on a genome-wide scale. Results We propose SeqEnhDL, a deep learning framework for classifying cell type-specific enhancers based on sequence features. DNA sequences of “strong enhancer” chromatin states in nine cell types from the ENCODE project were retrieved to build and test enhancer classifiers. For any DNA sequence, positional k-mer (k = 5, 7, 9 and 11) fold changes relative to randomly selected non-coding sequences across each nucleotide position were used as features for deep learning models. Three deep learning models were implemented, including multi-layer perceptron (MLP), Convolutional Neural Network (CNN) and Recurrent Neural Network (RNN). All models in SeqEnhDL outperform state-of-the-art enhancer classifiers (including gkm-SVM and DanQ) in distinguishing cell type-specific enhancers from randomly selected non-coding sequences. Moreover, SeqEnhDL can directly discriminate enhancers from different cell types, which has not been achieved by other enhancer classifiers. Our analysis suggests that both enhancers and their tissue-specificity can be accurately identified based on their sequence features. SeqEnhDL is publicly available at https://github.com/wyp1125/SeqEnhDL .

Abstract Phytophthora nicotianae is highly pathogenic to Solanaceous crops and is a major problem in tobacco production. The tobacco cultivar Beihart1000-1 (BH) is resistant, whereas the Xiaohuangjin 1025 (XHJ) cultivar is susceptible to infection. Here, BH and XHJ were used as models to identify resistant and susceptible genes using RNA sequencing (RNA-seq). Roots were sampled at 0, 6, 12, 24, and 60 h post infection. In total, 23,753 and 25,187 differentially expressed genes (DEGs) were identified in BH and XHJ, respectively. By mapping upregulated DEGs to the KEGG database, changes of the rich factor of “plant pathogen interaction pathway” were corresponded to the infection process. Of all the DEGs in this pathway, 38 were specifically regulated in BH. These genes included 11 disease-resistance proteins, 3 pathogenesis-related proteins, 4 RLP/RLKs, 2 CNGCs, 7 calcium-dependent protein kinases, 4 calcium-binding proteins, 1 mitogen-activated protein kinase kinase, 1 protein EDS1L, 2 WRKY transcription factors, 1 mannosyltransferase, and 1 calmodulin-like protein. By combining the analysis of reported susceptible (S) gene homologs and DEGs in XHJ, 9 S gene homologs were identified, which included 1 calmodulin-binding transcription activator, 1 cyclic nucleotide-gated ion channel, 1 protein trichome birefringence-like protein, 1 plant UBX domain-containing protein, 1 ADP-ribosylation factor GTPase-activating protein, 2 callose synthases, and 2 cellulose synthase A catalytic subunits. qRT-PCR was used to validate the RNA-seq data. The comprehensive transcriptome dataset described here, including candidate resistant and susceptible genes, will provide a valuable resource for breeding tobacco plants resistant to P. nicotianae infections.

Abstract. Background. The classification criteria and staging groups for nasopharyngeal carcinoma described in the Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) staging system have been revised over time. This study assessed the proportion of patients whose staging and treatment strategy have changed due to revisions of the UICC/AJCC staging system over the past 10 years (ie, from the sixth edition to the eighth edition), to provide information for further refinement. Methods. We retrospectively reviewed 1901 patients with non-metastatic nasopharyngeal carcinoma treated in our cancer center between November 2009 and June 2012. The Akaike information criterion and Harrell concordance index were applied to evaluate the performance of the staging system. Results. In total, 25 (1.3%) of the 1901 patients who were staged as T2a according to the sixth edition system were downgraded to T1 in the eighth edition; 430 (22.6%) staged as N0 in the sixth edition were upgraded to N1 in the eighth edition; 106 (5.6%) staged as N1/2 in the sixth edition were upgraded to N3 in the eighth edition. In addition, 51 (2.7%) and 25 (1.3%) of the study population were upstaged from stage I to stage II and stage II to stage IVa, respectively; 10 (0.5%) was downgraded from stage II to stage I. The survival curves of adjacent N categories and staging groups defined by eighth classification system were well-separated. However, there was no significant difference in the locoregional failure-free survival (P = 0.730) and disease-free survival (P = 0.690) rates between the T2 and T3 categories in the eighth edition classification system. Conclusions. Modifications to the tumor-node-metastasis staging system over the past 10 years have resulted in N classification changes in numerous cases. Although the eighth edition tumor-node-metastasis staging system better predicts survival outcomes, the T classification could be simplified in future revisions.

Abstract Background Radiation-induced oral mucositis (OM) is one of the most common acute complications for head and neck cancer. Severe OM is associated with radiation treatment breaks, which harms successful tumor management. Radiogenomics studies have indicated that genetic variants are associated with adverse effects of radiotherapy. Methods A large-scale genome-wide scan was performed in 1467 nasopharyngeal carcinoma patients, including 753 treated with 2D-CRT from Genetic Architecture of the Radiotherapy Toxicity and Prognosis (GARTP) cohort and 714 treated with IMRT (192 from the GARTP and 522 newly recruited). Subgroup analysis by radiotherapy technique was further performed in the top associations. We also performed physical and regulatory mapping of the risk loci and gene set enrichment analysis of the candidate target genes. Results We identified 50 associated genomic loci and 64 genes via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping and gene-based analysis, and 36 of these loci were replicated in subgroup analysis. Interestingly, one of the top loci located in TNKS, a gene relevant to radiation toxicity, was associated with increased OM risk with OR = 3.72 of the lead SNP rs117157809 (95% CI 2.10–6.57; P = 6.33 × 10−6). Gene set analyses showed that the 64 candidate target genes were enriched in the biological processes of regulating telomere capping and maintenance and telomerase activity (Top P = 7.73 × 10−7). Conclusions These results enhance the biological understanding of radiotherapy toxicity. The association signals enriched in telomere function regulation implicate the potential underlying mechanism and warrant further functional investigation and potential individual radiotherapy applications.

Agarwood, a non-wood product from the endangered Aquilaria and Gyrinops tress, is highly prized for its use in fragrances and medicines. The special formation process of agarwood is closely related to external injury and fungal infection. In this study, we demonstrate that infection of Aquilaria sinensis by Fusarium oxysporum, a soilborne fungus that causes vascular wilt diseases in diverse plants, induces agarwood formation. Based on these findings, an efficient method, termed F. oxysporum infection-induced formation of agarwood (FOIFA), was developed for the rapid production of quality agarwood. The agarwood formed in response to F. oxysporum infection was similar in structure and chemical composition to wild agarwood according to TLC (Thin-layer chromatography), HPLC (high performance liquid chromatography), and GC-MS (gas chromatography-mass spectrometry) analyses, except that the contents of alcohol-soluble extract, chromones, and essential oils (mainly sesquiterpenes) were higher in the formed agarwood.

Background: No-reflow phenomenon (NRP) in ST-segment elevation myocardial infarction (STEMI) patients is not infrequent. The predictive value of red blood-cell distribution width (RDW) on NRP has not been explored. Methods: STEMI patients undergoing primary percutaneous coronary intervention (pPCI) were enrolled. Plasma samples were obtained at admission. Participants were divided into two groups according to RDW. Logistic regression and receiver operating characteristic (ROC) curve were performed to evaluate the relationship between RDW and NRP. Subgroup analysis was made between the diabetes mellitus (DM) group and the No-DM group. Results: The high RDW group had a higher NRP compared to the low group. In multivariate logistic regression analysis, DM (adjusted odds ratio [AOR]:1.847; 95% confidence interval [CI]: 1.209–2.822; p = 0.005) and hemoglobin (AOR: 0.986; 95% CI: 0.973–0.999; p < 0.05), other than RDW, were independent predictors of NRP. RDW (AOR: 2.679; 95% CI: 1.542–4.655; p < 0.001) was an independent predictor of NRP in the DM group, but not in the No-DM group. In the DM group, area under the ROC curve value for RDW predicting NRP was 0.707 (77.3% sensitivity, 56.3% specificity (p < 0.001)). Conclusions: RDW is a predictor of NRP in DM patients with STEMI, which provides further assistance in clinicians’ decision making.

Objective(s): This study is aimed to design and synthesize a prodrug of 5-aminosalicylic acid and evaluate its ameliorative effect on experimental ulcerative colitis (UC).Materials and Methods: 5-Aminosalicylic acid-alanine (5-ASA-ALA) was synthesized and characterized. Its stability study was conducted in rat plasma and in the gastrointestinal tract environment, its transport characteristic was assessed using the Caco-2 cells. Its colon-targeting property was evaluated by the pharmacokinetic study, and incubation studies. A series of indicators were used to investigate its therapeutic effect on experimental colitis, including the survival rate and body weight of mice, the disease activity index (DAI), the colonic damage score and colon index, the myeloperoxidase (MPO) activity and the levels of malondialdehyde (MDA), total superoxide dismutase (SOD), glutathione (GSH) and glutathione peroxidase (GSH-Px) in colonic tissues.Results: 5-ASA-ALA was barely absorbed in the Caco-2 monolayer or into the rat blood. It was remarkably stable when incubated in the upper gastrointestinal tract, while gradually hydrolyzed in the colon of rats. When orally administered to mice, 5-ASA-ALA had significantly greater therapeutic effect on colitis than the positive control. Conclusion: 5-ASA-ALA is demonstrated to be a promising oral colon-targeting prodrug of 5-ASA and has potential application in UC treatment.

Abstract Background In locoregionally advanced nasopharyngeal carcinoma (LANPC) patients, variance of tumor response to induction chemotherapy (ICT) was observed. We developed and validated a novel imaging biomarker to predict which patients will benefit most from additional ICT compared with chemoradiotherapy (CCRT) alone. Methods All patients, including retrospective training (n = 254) and prospective randomized controlled validation cohorts (a substudy of NCT01245959, n = 248), received ICT+CCRT or CCRT alone. Primary endpoint was failure-free survival (FFS). From the multi-parameter magnetic resonance images of the primary tumor at baseline, 819 quantitative 2D imaging features were extracted. Selected key features (according to their interaction effect between the two treatments) were combined into an Induction Chemotherapy Outcome Score (ICTOS) with a multivariable Cox proportional hazards model using modified covariate method. Kaplan-Meier curves and significance test for treatment interaction were used to evaluate ICTOS, in both cohorts. Results Three imaging features were selected and combined into ICTOS to predict treatment outcome for additional ICT. In the matched training cohort, patients with a high ICTOS had higher 3-year and 5-year FFS in ICT+CCRT than CCRT subgroup (69.3% vs. 45.6% for 3-year FFS, and 64.0% vs. 36.5% for 5-year FFS; HR = 0.43, 95% CI = 0.25–0.74, p = 0.002), whereas patients with a low ICTOS had no significant difference in FFS between the subgroups (p = 0.063), with a significant treatment interaction (p interaction

Abstract. Background. Gestational diabetes mellitus (GDM) is usually diagnosed between 24th and 28th gestational week using the 75-g oral glucose tolerance test (OGTT). It is difficult to predict GDM before 24th gestational week because fast plasma glucose (FPG) decreases as the gestational age increases. It is controversial that if FPG ≥5.1 mmol/L before 24th gestational week should be intervened or not. The aim of this study was to evaluate the value of FPG to screen GDM before 24th gestational week in women with different pre-pregnancy body mass index (BMI). Methods. This was a multi-region retrospective cohort study in China. Women who had a singleton live birth between June 20, 2013 and November 30, 2014, resided in Beijing, Guangzhou and Chengdu, and received prenatal care in 21 selected hospitals, were included in this study. Pre-pregnancy BMI, FPG before the 24th gestational week, and one-step GDM screening with 75 g-OGTT at the 24th to 28th gestational weeks were extracted from medical charts and analyzed. The pregnant women were classified into four groups based on pre-pregnancy BMI: Group A (underweight, BMI < 18.5 kg/m2), Group B (normal, BMI 18.5–23.9 kg/m2), Group C (overweight, BMI 24.0–27.9 kg/m2) and Group D (obesity, BMI ≥28.0 kg/m2). The trend of FPG before 24th week of gestation was described, and the sensitivity and specificity of using FPG before the 24th gestational week to diagnose GDM among different pre-pregnancy BMI groups were reported. Differences in the means between groups were evaluated using independent sample t-test and analysis of variance. Pearson Chi-square test was used for categorical variables. Results. The prevalence of GDM was 20.0% (6806/34,087) in the study population. FPG decreased gradually as the gestational age increased in all pre-pregnancy BMI groups until the 19th gestational week. FPG was higher in women with higher pre-pregnancy BMI. FPG before the 24th gestational week and pre-pregnancy BMI could be used to predict GDM. The incidence of GDM in women with FPG ≥5.10 mmol/L in the 19th to 24th gestational weeks and pre-pregnancy overweight or obesity was significantly higher than that in women with FPG ≥5.10 mmol/L and pre-pregnancy BMI

Background: To identify a radiomics signature to predict local recurrence in patients with non-metastatic T4 nasopharyngeal carcinoma (NPC). Methods: A total of 737 patients from Sun Yat-sen University Cancer Center (training cohort: n = 360; internal validation cohort: n = 120) and Wuzhou Red Cross Hospital (external validation cohort: n = 257) underwent feature extraction from the largest axial area of the tumor on pretreatment magnetic resonance imaging scans. Feature selection was based on the prognostic performance and feature stability in the training cohort. Radscores were generated using the Cox proportional hazards regression model with the selected features in the training cohort and then validated in the internal and external validation cohorts. We also constructed a nomogram for predicting local recurrence-free survival (LRFS). Findings: Eleven features were selected to construct the Radscore, which was significantly associated with LRFS. For the training, internal validation, and external validation cohorts, the Radscore (C-index: 0.741 vs. 0.753 vs. 0.730) outperformed clinical prognostic variables (C-index for primary gross tumor volume: 0.665 vs. 0.672 vs. 0.577; C-index for age: 0.571 vs. 0.629 vs. 0.605) in predicting LRFS. The generated radiomics nomogram, which integrated the Radscore and clinical variables, exhibited a satisfactory prediction performance (C-index: 0.810 vs. 0.807 vs. 0.753). The nomogram-defined high-risk group had a shorter LRFS than did the low-risk group (5-year LRFS: 73.6% vs. 95.3%, P

Abstract Background Depression symptom questionnaires are commonly used to assess symptom severity and as screening tools to identify patients who may have depression. They are not designed to ascertain diagnostic status and, based on published sensitivity and specificity estimates, would theoretically be expected to overestimate prevalence. Meta-analyses sometimes estimate depression prevalence based on primary studies that used screening tools or rating scales rather than validated diagnostic interviews. Our objectives were to determine classification methods used in primary studies included in depression prevalence meta-analyses, if pooled prevalence differs by primary study classification methods as would be predicted, whether meta-analysis abstracts accurately describe primary study classification methods, and how meta-analyses describe prevalence estimates in abstracts. Methods We searched PubMed (January 2008–December 2017) for meta-analyses that reported pooled depression prevalence in the abstract. For each meta-analysis, we included up to one pooled prevalence for each of three depression classification method categories: (1) diagnostic interviews only, (2) screening or rating tools, and (3) a combination of methods. Results In 69 included meta-analyses (81 prevalence estimates), eight prevalence estimates (10%) were based on diagnostic interviews, 36 (44%) on screening or rating tools, and 37 (46%) on combinations. Prevalence was 31% based on screening or rating tools, 22% for combinations, and 17% for diagnostic interviews. Among 2094 primary studies in 81 pooled prevalence estimates, 277 (13%) used validated diagnostic interviews, 1604 (77%) used screening or rating tools, and 213 (10%) used other methods (e.g., unstructured interviews, medical records). Classification methods pooled were accurately described in meta-analysis abstracts for 17 of 81 (21%) prevalence estimates. In 73 meta-analyses based on screening or rating tools or on combined methods, 52 (71%) described the prevalence as being for “depression” or “depressive disorders.” Results were similar for meta-analyses in journals with impact factor ≥ 10. Conclusions Most meta-analyses combined estimates from studies that used screening tools or rating scales instead of diagnostic interviews, did not disclose this in abstracts, and described the prevalence as being for “depression” or “depressive disorders ” even though disorders were not assessed. Users of meta-analyses of depression prevalence should be cautious when interpreting results because reported prevalence may exceed actual prevalence.

Advances in remote sensing and machine learning enable increasingly accurate, inexpensive, and timely estimation of poverty and malnutrition indicators to guide development and humanitarian agencies' programming. However, state of the art models often rely on proprietary data and/or deep or transfer learning methods whose underlying mechanics may be challenging to interpret. We demonstrate how interpretable random forest models can produce estimates of a set of (potentially correlated) malnutrition and poverty prevalence measures using free, open access, regularly updated, georeferenced data. We demonstrate two use cases: contemporaneous prediction, which might be used for poverty mapping, geographic targeting, or monitoring and evaluation tasks, and a sequential nowcasting task that can inform early warning systems. Applied to data from 11 low and lower-middle income countries, we find predictive accuracy broadly comparable for both tasks to prior studies that use proprietary data and/or deep or transfer learning methods.

The determination of the relation between a number and a numerical interval is one of the core problems in the scientific calculation of privacy protection. The calculation of the relationship between two numbers and a numerical interval to protect privacy is also the basic problem of collaborative computing. It is widely used in data queries, location search and other fields. At present, most of the solutions are still fundamentally limited to the integer level, and there are few solutions at the real number level. To solve these problems, this paper first uses Bernoulli inequality generalization and a monotonic function property to extend the solution to the real number level and designs two new protocols based on the homomorphic encryption scheme, which can not only protect the data privacy of both parties involved in the calculation, but also extend the number domain to real numbers. In addition, this paper designs a solution to the confidential cooperative determination problem between real numbers by using the sign function and homomorphism multiplication. Theoretical analysis shows that the proposed solution is safe and efficient. Finally, some extension applications based on this protocol are given.

Background: Enzyme replacement therapy (ERT) can positively affect the visceral manifestations of lysosomal storage diseases (LSDs). However, the exclusion of the intravenous ERT agents from the central nervous system (CNS) prevents direct therapeutic effects. Methods: Using a neuronopathic Gaucher disease (nGD) mouse model, CNS-ERT was created using a systemic, non-invasive, and CNS-selective delivery system based on nanovesicles of saposin C (SapC) and dioleoylphosphatidylserine (DOPS) to deliver to CNS cells and tissues the corrective, functional acid β-glucosidase (GCase). Findings: Compared to free GCase, human GCase formulated with SapC-DOPS nanovesicles (SapC-DOPS-GCase) was more stable in serum, taken up into cells, mostly by a mannose receptor-independent pathway, and resulted in higher activity in GCase-deficient cells. In contrast to free GCase, SapC-DOPS-GCase nanovesicles penetrated through the blood-brain barrier into the CNS. The CNS targeting was mediated by surface phosphatidylserine (PS) of blood vessel and brain cells. Increased GCase activity and reduced GCase substrate levels were found in the CNS of SapC-DOPS-GCase-treated nGD mice, which showed profound improvement in brain inflammation and neurological phenotypes. Interpretation: This first-in-class CNS-ERT approach provides considerable promise of therapeutic benefits for neurodegenerative diseases. Funding: This study was supported by the National Institutes of Health grants R21NS 095047 to XQ and YS, R01NS 086134 and UH2NS092981 in part to YS; Cincinnati Children's Hospital Medical Center Research Innovation/Pilot award to YS and XQ; Gardner Neuroscience Institute/Neurobiology Research Center Pilot award to XQ and YS, Hematology-Oncology Programmatic Support from University of Cincinnati and New Drug State Key Project grant 009ZX09102-205 to XQ.

Gaucher disease is caused by a deficiency in glucocerebrosidase that can result in non-neuronal as well as neuronal symptoms. Common visceral symptoms are an increased organ size, specifically of the spleen, and glucosylceramide as well as glucosylsphingosine substrate accumulations as a direct result of the glucocerebrosidase deficiency. Neuronal symptoms include motor deficits and strong alterations in the cerebellum. To evaluate the effect of new compounds for the treatment of this devastating disease, animal models are needed that closely mimic the human phenotype. The 4L/PS-NA mouse as model of Gaucher disease is shown to present reduced glucocerebrosidase activity similar to human cases but an in-depth characterization of the model was still not performed. We therefore analyzed 4L/PS-NA mice for visceral alterations, motor deficits and also neuronal changes like glucocerebrosidase activity, substrate levels and neuroinflammation. A special focus was set at pathological changes of the cerebellum. Our results show that 4L/PS-NA mice have strongly enlarged visceral organs that are infiltrated by enlarged leukocytes and macrophages. Furthermore, animals present strong motor deficits that are accompanied by increased glucosylceramide and glucosylsphingosine levels in the brain, astrocytosis and activated microglia in the cortex and hippocampus as well as reduced calbindin levels in the cerebellum. The latter was directly related to a strong Purkinje cell loss. Our results thus provide a detailed characterization of the 4L/PS-NA mouse model over age showing the translational value of the model and validating its usefulness for preclinical efficiency studies to evaluate new compounds against Gaucher disease.

Abstract Background Alternative polyadenylation (APA) is a widespread phenomenon in the posttranscriptional regulation of gene expression that generates mRNAs with alternative 3′-untranslated regions (3’UTRs). APA contributes to the pathogenesis of various diseases, including cancer. However, the potential role of APA in the development of nasopharyngeal carcinoma (NPC) remains largely unknown. Methods A strategy of sequencing APA sites (SAPAS) based on second-generation sequencing technology was carried out to explore the global patterns of APA sites and identify genes with tandem 3’UTRs in samples from 6 NPC and 6 normal nasopharyngeal epithelial tissue (NNET). Sequencing results were then validated using quantitative RT-PCR in a larger cohort of 16 NPC and 16 NNET samples. Results The sequencing data showed that the use of tandem APA sites was prevalent in NPC, and numerous genes with APA-switching events were discovered. In total, we identified 195 genes with significant differences in the tandem 3’UTR length between NPC and NNET; including 119 genes switching to distal poly (A) sites and 76 genes switching to proximal poly (A) sites. Several gene ontology (GO) terms were enriched in the list of genes with switched APA sites, including regulation of cell migration, macromolecule catabolic process, protein catabolic process, proteolysis, small conjugating protein ligase activity, and ubiquitin-protein ligase activity. Conclusions APA site-switching events are prevalent in NPC. APA-mediated regulation of gene expression may play an important role in the development of NPC, and more detailed studies targeting genes with APA-switching events may contribute to the development of novel future therapeutic strategies for NPC.