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Breakthrough infection of SARS-CoV-2 is a serious challenge, as increased infections were documented in fully-vaccinated individuals. Recipients with poor antibody response are highly vulnerable to reinfection, whereas those with strong antibody responses achieve sterilizing immunity. Thus far, biomarkers associated with levels of vaccine-elicited antibody response are still lacking. Here, we studied the antibody response of age- and gender-controlled healthy cohort, who received inactivated SARS-CoV-2 vaccines and profiled the B cell receptor repertoires in longitudinally consecutive samples. Upon vaccination, all vaccinated individuals displayed a convergent antibody response with shared common antibody clones and public neutralizing antibodies. Strikingly, poor vaccine-responders are distinguishable from strong vaccine-responders by a biased V-usage before vaccination and IgG to IgM mRNA ratio. These findings reveal molecular signatures associated with the different levels of vaccine-induced antibody response, which could be further developed into biomarkers for the design of vaccination strategies.

The global incidence of childhood obesity is increasing. Currently, there are only few established drugs for treating adolescent obesity. Randomized clinical trials (RCTs) comparing pharmacological interventions in children with obesity are scarce; therefore, we aimed to analyze the relative efficacy and adverse reactions of these drugs and compare the effects of each drug on body mass index (BMI).This meta-analysis focused on the slimming effect, safety, and correlation of metformin, orlistat, exenatide, liraglutide, and topiramate in children with obesity. Several international databases were searched and clinical trials on the treatment of obesity in children in which the drug was administered for ≥ 6 months were included. Changes in BMI before and after treatment were analyzed using a Bayes framework, and the surface under the cumulative ranking was calculated.Of 2102 relevant articles retrieved, 21 RCTs were included in the study. Compared to other drugs, liraglutide reduced BMI the most in children with obesity. However, it was most associated with drug withdrawal due to adverse events while topiramate was least.Liraglutide had a higher probability of achieving clinically significant weight loss compared with other drugs while topiramate was superior in safety.

Advanced glycation end products (AGEs) that abnormally accumulate in diabetic patients have been reported to damage bone health. We aimed to investigate the association between skin autofluorescence (SAF)-AGEThis study was nested in the prospective REACTION (Risk Evaluation of Cancers in Chinese Diabetic Individuals) study and included 1214 eligible participants. SAF was used to measure skin AGEs (SAF-AGEs). Fracture events were determined by an in-person clinical follow-up. Binary logistic regression analysis, linear regression analysis, and a restricted cubic spline nested in logistic models were used to test outcomes.The overall prevalence of LBD/osteoporosis in middle-aged or elderly T2DM patients was 35.7% (n = 434), and the overall incidence of MOFs was 10.5% (n = 116). Logistic analysis showed a significantly positive relationship between quartiles of SAF-AGEIn conclusion, SAF-AGE背景: 糖基化终末产物(AGEs)在糖尿病患者体内异常积聚，已有报道会损害骨健康。本研究旨在探讨皮肤自发荧光(SAF)-AGE

OBJECTIVES Emergency transfers (ETs), deterioration events with late recognition requiring ICU interventions within 1 hour of transfer, are associated with adverse outcomes. We leveraged electronic health record (EHR) data to assess the association between ETs and outcomes. We also evaluated the association between intervention timing (urgency) and outcomes. METHODS We conducted a propensity-score-matched study of hospitalized children requiring ICU transfer between 2015 and 2019 at a single institution. The primary exposure was ET, automatically classified using Epic Clarity Data stored in our enterprise data warehouse endotracheal tube in lines/drains/airway flowsheet, vasopressor in medication administration record, and/or ≥60 ml/kg intravenous fluids in intake/output flowsheets recorded within 1 hour of transfer. Urgent intervention was defined as interventions within 12 hours of transfer. RESULTS Of 2037 index transfers, 129 (6.3%) met ET criteria. In the propensity-score-matched cohort (127 ET, 374 matched controls), ET was associated with higher in-hospital mortality (13% vs 6.1%; odds ratio, 2.47; 95% confidence interval [95% CI], 1.24–4.9, P = .01), longer ICU length of stay (subdistribution hazard ratio of ICU discharge 0.74; 95% CI, 0.61–0.91, P < .01), and longer posttransfer length of stay (SHR of hospital discharge 0.71; 95% CI, 0.56–0.90, P < .01). Increased intervention urgency was associated with increased mortality risk: 4.1% no intervention, 6.4% urgent intervention, and 10% emergent intervention. CONCLUSIONS An EHR measure of deterioration with late recognition is associated with increased mortality and length of stay. Mortality risk increased with intervention urgency. Leveraging EHR automation facilitates generalizability, multicenter collaboratives, and metric consistency.

Chimeric antigen receptor (CAR) T-cell therapy can induce durable remissions of relapsed/refractory B-acute lymphoblastic leukemia (ALL). However, case reports suggested differential outcomes mediated by leukemia cytogenetics. We identified children and young adults with relapsed/refractory CD19+ ALL/lymphoblastic lymphoma treated on 5 CD19-directed CAR T-cell (CTL019 or humanized CART19) clinical trials or with commercial tisagenlecleucel from April 2012 to April 2019. Patients were hierarchically categorized according to leukemia cytogenetics: High-risk lesions were defined as KMT2A (MLL) rearrangements, Philadelphia chromosome (Ph+), Ph-like, hypodiploidy, or TCF3/HLF; favorable as hyperdiploidy or ETV6/RUNX1; and intermediate as iAMP21, IKZF1 deletion, or TCF3/PBX1. Of 231 patients aged 1 to 29, 74 (32%) were categorized as high risk, 28 (12%) as intermediate, 43 (19%) as favorable, and 86 (37%) as uninformative. Overall complete remission rate was 94%, with no difference between strata. There was no difference in relapse-free survival (RFS; P = .8112), with 2-year RFS for the high-risk group of 63% (95% confidence interval [CI], 52-77). There was similarly no difference seen in overall survival (OS) (P = .5488), with 2-year OS for the high-risk group of 70% (95% CI, 60-82). For patients with KMT2A-rearranged infant ALL (n = 13), 2-year RFS was 67% (95% CI, 45-99), and OS was 62% (95% CI, 40-95), with multivariable analysis demonstrating no increased risk of relapse (hazard ratio, 0.70; 95% CI, 0.21-2.90; P = .7040) but a higher proportion of relapses associated with myeloid lineage switch and a 3.6-fold increased risk of all-cause death (95% CI, 1.04-12.75; P = .0434). CTL019/huCART19/tisagenlecleucel are effective at achieving durable remissions across cytogenetic categories. Relapsed/refractory patients with high-risk cytogenetics, including KMT2A-rearranged infant ALL, demonstrated high RFS and OS probabilities at 2 years.

Drylands cover more than 40% of Earth's land surface and occur at the margin of forest distributions due to the limited availability of water for tree growth. Recent elevated temperature and low precipitation have driven greater forest declines and pulses of tree mortality on dryland sites compared to humid sites, particularly in temperate Eurasia and North America. Afforestation of dryland areas has been widely implemented and is expected to increase in many drylands globally to enhance carbon sequestration and benefits to the human environment, but the interplay of sometimes conflicting afforestation outcomes has not been formally evaluated yet. Most previous studies point to conflicts between additional forest area and water consumption, in particular water yield and soil conservation/desalinization in drylands, but were generally confined to local and regional scales. Our global synthesis demonstrates that additional tree cover can amplify water consumption through a nonlinear increase in evapotranspiration-depending on tree species, age, and structure-which will be further intensified by future climate change. In this review we identify substantial knowledge gaps in addressing the dryland afforestation dilemma, where there are trade-offs with planted forests between increased availability of some resources and benefits to human habitats versus the depletion of other resources that are required for sustainable development of drylands. Here we propose a method of addressing comprehensive vegetation carrying capacity, based on regulating the distribution and structure of forest plantations to better deal with these trade-offs in forest multifunctionality. We also recommend new priority research topics for dryland afforestation, including: responses and feedbacks of dryland forests to climate change; shifts in the ratio of ecosystem ET to tree cover; assessing the role of scale of afforestation in influencing the trade-offs of dryland afforestation; and comprehensive modeling of the multifunctionality of dryland forests, including both ecophysiological and socioeconomic aspects, under a changing climate.

OBJECTIVE Digital subtraction angiography (DSA) is commonly performed after pial synangiosis surgery for pediatric moyamoya disease to assess the degree of neovascularization. However, angiography is invasive, and the risk of ionizing radiation is a concern in children. In this study, the authors aimed to identify whether arterial spin labeling (ASL) can predict postoperative angiogram grading. In addition, they sought to determine whether patients who underwent ASL imaging without DSA had similar postoperative outcomes when compared with patients who received ASL imaging and postoperative DSA. METHODS The medical records of pediatric patients who underwent pial synangiosis for moyamoya disease at a quaternary children’s hospital were reviewed during a 10-year period. ASL-only and ASL+DSA cohorts were analyzed. The frequency of preoperative and postoperative symptoms was analyzed within each cohort. Three neuroradiologists assigned a visual ASL grade for each patient indicating the change from the preoperative to postoperative ASL perfusion sequences. A postoperative neovascularization grade was also assigned for patients who underwent DSA. RESULTS Overall, 21 hemispheres of 14 patients with ASL only and 14 hemispheres of 8 patients with ASL+DSA were analyzed. The groups had similar rates of MRI evidence of acute or chronic stroke preoperatively (61.9% in the ASL-only group and 64.3% in the ASL+DSA group). In the entire cohort, transient ischemic attack (TIA) (p = 0.027), TIA composite (TIA or unexplained neurological symptoms; p = 0.0006), chronic headaches (p = 0.035), aphasia (p = 0.019), and weakness (p = 0.001) all had decreased frequency after intervention. The authors found a positive association between revascularization observed on DSA and the visual ASL grading (p = 0.048). The visual ASL grades in patients with an angiogram indicating robust neovascularization demonstrated improved perfusion when compared with the ASL grades of patients with a poor neovascularization. CONCLUSIONS Noninvasive ASL perfusion imaging had an association with postoperative DSA neoangiogenesis following pial synangiosis surgery in children. There were no significant postoperative stroke differences between the ASL-only and ASL+DSA cohorts. Both cohorts demonstrated significant improvement in preoperative symptoms after surgery. Further study in larger cohorts is necessary to determine whether the results of this study are validated in order to circumvent the invasive catheter angiogram.

Background: Triglyceride–glucose (TyG) index has been proposed to be a simple, economical, and reliable marker of insulin resistance. We aimed to investigate whether TyG is an independent predictor of hyperuricemia in diabetic kidney disease (DKD) populations by conducting a cross-sectional and longitudinal study.Methods: A total of 6,471 patients were enrolled in cross-sectional analysis, and 3,634 patients without hyperuricemia at the baseline were included in longitudinal analysis and were followed up for a median of 23.0 months. Hyperuricemia was categorized as a serum uric acid level ≥420 umol/L (7 mg/dL).Results: In this study, 19.58% of participants had hyperuricemia. In the cross-sectional analysis, multivariate logistics regression analysis showed that the ORs (95% CI) for hyperuricemia in the second, third, and fourth TyG quartiles were 1.29 (95% CI: 0.81–2.06), 1.35 (95% CI: 0.84–2.17), and 3.18 (95% CI:1.99–5.10), respectively, compared with the first quartile. Longitudinally, multivariate Cox regression model revealed that the hazard ratios for hyperuricemia in the upper quartiles of the TyG index were 1.13 (95% CI: 0.76-1.68), 1.73 (95% CI: 1.20-2.51), and 2.14 (95% CI: 1.47-3.10), respectively, compared with the first quartile. The Kaplan–Meier survival analysis showed that higher TyG levels predicted higher incidence of hyperuricemia. Moreover, the subgroup analyses revealed that the relationship between TyG levels and hyperuricemia was robust in DKD patients.Conclusion: Our findings indicate a significant independent correlation between the TyG index and the risk of hyperuricemia in DKD patients.

Hand, foot, and mouth disease (HFMD) is a common childhood infectious disease caused by human enteroviruses (EV). This study aimed to describe the epidemiological features of HFMD and the genetic characteristics of Coxsackievirus A16 (CVA16) in Taiyuan, Shanxi, China, from 2010 to 2021. Descriptive epidemiological methods were used to analyze the time and population distribution of HFMD and the genetic characteristics of CVA16. Except being affected by the COVID-19 epidemic in 2020, HFMD epidemics were sporadic from January to March each year, and began to increase in April, with a major epidemic peak from May to August, which declined in September, followed by a secondary peak from October to December. The prevalence of EV infection was the highest in children aged one to five years (84.42%), whereas its incidence was very low in children under one year of age (5.48%). Enterovirus nucleic acid was detected by real-time reverse transcription polymerase chain reaction in 6641 clinical specimens collected from patients with HFMD from 2010 to 2021, and 4236 EV-positive specimens were detected, including 988 enterovirus A71 (EV-A71), 1488 CVA16, and 1760 other enteroviruses. CVA16 remains prevalent and has co-circulated with other EVs in Taiyuan from 2010 to 2021. A phylogenetic tree constructed based on theVP1region showed that all CVA16 strains belonged to two different clades of the B1 genotype, B1a and B1b. They showed a nucleotide similarity of 86.5–100%, and an amino acid similarity of 96.9–100%. Overall, these findings add to the global genetic resources of CVA16, demonstrate the epidemiological characteristics of HFMD as well as the genetic features of CVA16 in Taiyuan City during 2010–2021, and provide supporting evidence for the prevention and control of HFMD.

Reservoir sediment contamination with heavy metals produced by mining activities has aroused widespread global concern owing to its potential threat to human health. In this study, the total concentrations and speciation of heavy metals (Cd, Pb, Zn) in the Lexi (LX) and Maoshui (MS) reservoirs around the historical artisanal zinc smelting area in Southwest China were determined, and pollution indices were applied to assess the pollution levels and potential ecological risks of the two reservoirs. The results showed that all the detected samples in the two reservoirs presented significant metal accumulation, especially for Cd, as compared with the soil background values in Guizhou Province. Between the two reservoirs, the vertical distribution characteristics of each metal in sediment columns were similar. The heavy metal concentrations of the three columns in the LX reservoir reached their maxima at 35, 15, and 10 cm and showed a trend of first increasing and then decreasing overall. However, the heavy metal contents of the three columns in the MS reservoir all exhibited wave-like characteristics in the vertical direction, and all of them reached a relatively obvious high point at approximately 5 and 30 cm. The geoaccumulation index (Igeo) and potential ecological risk index (RI) indicated that Cd was strongly enriched and represented the main risk factor, and the pollution level of the MS reservoir was significantly higher than that of the LX reservoir. Furthermore, the effect coefficients (ERMQ) confirmed that the two reservoirs are likely to have toxic impacts on aquatic organisms and need to be controlled and mitigated. The speciation analysis of heavy metals revealed that Cd was primarily in the acid-extractable fraction (69.57%, 68.28%), Pb was chiefly in the reducible fraction (55.24%, 42.18%) and oxidizable fraction (22.60%, 38.02%), and Zn was mainly in the oxidizable fraction (32.54%, 37.65%) in the LX and MS reservoirs, respectively. The ratios of the secondary phase and primary phase (RSP) and risk assessment code (RAC) evaluation demonstrated that Cd in the sediments of the two reservoirs presents a very high potential ecological risk, and Pb and Zn were at medium to high ecological risk levels. This study highlighted that the artisanal zinc smelting activities had caused serious heavy metal pollution in reservoir sediments, posing a threat to the local ecological environment.

This article devises a photograph-based monitoring model to estimate the real-time PM2.5 concentrations, overcoming currently popular electrochemical sensor-based PM2.5 monitoring methods’ shortcomings such as low-density spatial distribution and time delay. Combining the proposed monitoring model, the photographs taken by various camera devices (e.g., surveillance camera, automobile data recorder, and mobile phone) can widely monitor PM2.5 concentration in megacities. This is beneficial to offering helpful decision-making information for atmospheric forecast and control, thus reducing the epidemic of COVID-19. To specify, the proposed model fuses Information Abundance measurement and Wide and Deep learning, dubbed as IAWD, for PM2.5 monitoring. First, our model extracts two categories of features in a newly proposed DS transform space to measure the information abundance (IA) of a given photograph since the growth of PM2.5 concentration decreases its IA. Second, to simultaneously possess the advantages of memorization and generalization, a new wide and deep neural network is devised to learn a nonlinear mapping between the above-mentioned extracted features and the groundtruth PM2.5 concentration. Experiments on two recently established datasets totally including more than 100 000 photographs demonstrate the effectiveness of our extracted features and the superiority of our proposed IAWD model as compared to state-of-the-art relevant computing techniques.

Cytosine base editor (CBE) enables targeted C-to-T conversions at single base-pair resolution and thus has potential therapeutic applications in humans. However, the low efficiency of the system limits practical use of this approach. We reported a high-throughput human cells-based reporter system that can be harnessed for quickly measuring editing activity of CBE. Screening of 1813 small-molecule compounds resulted in the identification of Ricolinostat (an HDAC6 inhibitor) that can enhance the efficiency of BE3 in human cells (2.45- to 9.21-fold improvement). Nexturastat A, another HDAC6 inhibitor, could also increase BE3-mediated gene editing by 2.18- to 9.95-fold. Ricolinostat and Nexturastat A also boost base editing activity of the other CBE variants (BE4max, YE1-BE4max, evoAPOBEC1-BE4max and SpRY-CBE4max, up to 8.32-fold). Meanwhile, combined application of BE3 and Ricolinostat led to >3-fold higher efficiency of correcting a pathogenic mutation in ABCA4 gene related to Stargardt disease in human cells. Moreover, we demonstrated that our strategy could be applied for efficient generation of mouse models through direct zygote injection and base editing in primary human T cells. Our study provides a new strategy to improve the activity and specificity of CBE in human cells. Ricolinostat and Nexturastat A augment the effectiveness and applicability of CBE.

AIM To examine the impact of the sodium-glucose co-transporter-2 inhibitor, empagliflozin, on plasma and urine metabolites in participants with type 1 diabetes. MATERIAL AND METHODS Participants (n = 40, 50% male, mean age 24.3 years) with type 1 diabetes and without overt evidence of diabetic kidney disease had baseline assessments performed under clamped euglycaemia and hyperglycaemia, on two consecutive days. Participants then proceeded to an 8-week, open-label treatment period with empagliflozin 25 mg/day, followed by repeat assessments under clamped euglycaemia and hyperglycaemia. Plasma and urine metabolites were first grouped into metabolic pathways using MetaboAnalyst software. Principal component analysis was performed to create a representative value for each sufficiently represented metabolic group (false discovery rate ≤ 0.1) for further analysis. RESULTS Of the plasma metabolite groups, tricarboxylic acid (TCA) cycle (P

People evaluated their own voices as sounding more attractive than others rated their voices (i.e., self-enhancement effect from the perspective of the rater, termed "SE_rater"), and people also rated their own voices as more attractive than the voices of others (i.e., self-enhancement effect from the perspective of the voice, termed "SE_voice"). The aim of the present study is to explore whether the gender context (i.e., same-sex and opposite-sex rating context) could influence the SE effect of voice attractiveness evaluation. Male and female participants were asked to rate the attractiveness of their own voices and other participants' voices, either in a same-sex session or an opposite-sex session. The results demonstrated both the SE_rater and SE_voice effect in the same-sex and opposite-sex contexts, for both male and female. More importantly, we found that the SE_rater for the male voices was significantly greater than that for the female voices in the same-sex context whereas no such difference was found in the opposite-sex context. In addition, the SE_voice effect in men was larger in the same-sex context than that in the opposite-sex context whereas the SE_voice in women was smaller in the same-sex context than that in the opposite-sex context. These findings indicated that the self-enhancement effect of vocal attractiveness was modulated by the gender context.

To determine the differences in outcomes between mild and moderate isolated ventriculomegaly (IVM).We conducted a prospective cohort study on 94 fetuses with IVM and evaluated the neurodevelopmental outcomes at 12 months of age using the ASQ-3 and BSID-I neurodevelopmental assessment tools. Progression of VM was defined as an increase in the width of the ventricular by at least 3 mm during sequential ultrasound monitoring. The population was divided into two groups according to ventricular width: mild (10-12 mm) and moderate (12.1-15 mm), which were further evaluated for VM progression in utero separately.Neurodevelopmental assessments at 12 months were the main form of evaluations. Neurodevelopmental impairment (NDI) was defined as a mental development index (MDI) or psychomotor development index (PDI)85. There were no significant differences in NDI values between the mild and moderate groups (There were likely no differences in neurodevelopmental outcomes between mild and moderate IVM. In fetuses with mild to moderate VM, intrauterine progression may be a poor prognostic factor for neurodevelopmental outcomes.

OBJECTIVES: Event debriefing has established benefit, but its adoption is poorly characterized among pediatric ward providers. To improve patient safety, our hospital restructured its debriefing process for ward deterioration events culminating in ICU transfer. The aim of this study was to describe this process’ implementation. METHODS: In the restructured process, multidisciplinary ward providers are expected to debrief all ICU transfers. We conducted a multimethod analysis using facilitative guides completed by debriefing participants. Monthly debriefing completion served as an adoption metric. RESULTS: Between March 2019 and February 2020, providers across 9 wards performed debriefing for 134 of 312 PICU transfers (43%). Bedside nurses participated most frequently (117 debriefings [87%]). There was no significant difference in debriefing by unit, acuity, season, or nurse staffing. Compared with units fully staffed by rotational frontline clinicians (FLCs; eg, resident physicians), units with dedicated FLCs whose responsibilities are primarily limited to that unit (eg, oncology hospitalists) completed significantly more monthly debriefings (average [SD] 57% [30%] vs 33% [28%] of PICU transfers; P = .004). FLC participation was also higher on these units (50% of debriefings [37%] vs 24% [37%]; P = .014). Through qualitative analysis, we identified distinct debriefing themes, with teaming activities such as communication cited most often. CONCLUSIONS: Implementation of a multidisciplinary debriefing process for ward deterioration events culminating in ICU transfer was associated with differential adoption across providers and FLC staffing models but not acuity or nurse staffing. Teaming activities were a debriefing priority. Future study will assess patient safety outcomes.

Background Tricalcium silicate-based sealers have been usually indicated for the single-cone technique and result in more residual filling materials in root canal retreatment. Passive ultrasonic irrigation and photon-initiated photoacoustic streaming have been reported to improve the removal efficacy of root canal filling materials. However, the abilities of both techniques combined with NiTi re-instrumentation to remove residual tricalcium silicate-based sealer and gutta-percha have not been compared. The aim of this study was to evaluate the efficacy of laser-activated and ultrasonic-activated techniques in vitro for the removal of the tricalcium silicate-based sealer iRoot SP and gutta-percha after standard canal retreatment procedures with the use of nickel-titanium (NiTi) rotary instruments.

New findings What is the central question of this study? It is reported that SFTPB polymorphisms are associated with COPD. The function and its mechanism of SFTPB in COPD are still unknown. We indicate the function and underlying mechanism in controls and COPD patients, A549 cells induced by 10% CSE and a mouse model of COPD. Furthermore, we have indicated the mechanism of SFTPB in COPD by regulating the expression of SFTPB in A549 cells. What is the main finding and its importance? Under the stimulation of the risk factors of COPD, SFTPB expression is decreased, which may be involved in the formation of COPD. The progress of COPD induces an inflammatory response and reduces SFTPB expression. Otherwise, levels of PTGS2 and inflammatory responses are changed by SFTPB, which indicates that SFTPB promotes the progression of COPD by PTGS2 and inflammation. Abstract Pulmonary surfactant-associated protein B (SFTPB) is a critical protein for lung homeostasis, and its polymorphisms are associated with COPD. However, few studies have so far confirmed the functional involvement of SFTPB in COPD. Serum SFTPB and inflammatory cytokines levels were measured in 54 patients with acute exacerbation of COPD and 29 healthy controls. A549 cells were induced using 10% cigarette smoke extract (CSE) and treated with dexamethasone to investigate the effect of inflammation on SFTPB expression, and the effect of SFTPB overexpression and silencing on inflammatory cytokines was measured using real-time PCR and ELISA. Lastly, SFTPB expression was assessed in mouse lung tissues using immunofluorescence. Serum levels of SFTPB were significantly lower in COPD patients than in controls (p = 0.009). Conversely, levels of IL-6 and prostaglandin-endoperoxide synthase-2 (PTGS2) were increased in COPD patients (IL-6: p = 0.006, PTGS2: p = 0.043). After CSE treatment, SFTPB mRNA and protein levels were significantly decreased compared to controls (mRNA: p = 0.002; protein: p = 0.011), while IL-6, IL-8 and PTGS2 were elevated. Dexamethasone treatment increased SFTPB levels. Following SFTPB overexpression in A549 cells, mRNA and protein levels of IL-6, IL-8 and PTGS2 were significantly reduced, while silencing induced the opposite effect. SFTPB levels were significantly reduced in the lung tissue of a mouse model of COPD compared to controls. Reduced SFTPB levels may induce PTGS2 and inflammatory responses in COPD and could be a key protein for evaluation of COPD progression. This article is protected by copyright. All rights reserved.

Cyclodextrins (CDs), as pharmaceutical excipients with excellent biocompatibility, non-immunogenicity, and low toxicity in vivo, are widely used to carry drugs by forming inclusion complexes for improving the solubility and stability of drugs. However, the limited space of CDs' lipophilic central cavity affects the loading of many drugs, especially with larger molecules. In this study, β-CDs were modified by acetonization to improve the affinity for the chemotherapy drug doxorubicin (DOX), and doxorubicin-adsorbing acetalated β-CDs (Ac-CD:DOX) self-assembled to nanoparticles, followed by coating with the amphiphilic zinc phthalocyanine photosensitizer ZnPc-(PEG)5 for antitumor therapy. The final product ZnPc-(PEG)5:Ac-CD:DOX was demonstrated to have excellent stability and pH-sensitive drug release characteristics. The cell viability and apoptosis assay showed synergistic cytotoxic effects of chemotherapy and phototherapy. The mechanism of cytotoxicity was analyzed in terms of intracellular reactive oxygen species, mitochondrial membrane potential, and subcellular localization. More importantly, in vivo experiments indicated that ZnPc-(PEG)5:Ac-CD:DOX possessed significant tumor targeting, prominent antitumor activity, and less side effects. Our strategy expands the application of CDs as drug carriers and provides new insights into the development of CD chemistry.

Chromobox 4 (CBX4) is a core component of polycomb-repressive complex 1 with important roles in cancer biology and tissue homeostasis. Aberrant expression of CBX4 has been implicated in several human malignancies. However, its role and underlying mechanisms in the tumorigenesis of lung adenocarcinoma (LUAD) have not been defined in vivo. Here, we found that expression of CBX4 was frequently up-regulated in human LUAD samples and correlated with poor patient survival. Importantly, genetic ablation of CBX4 greatly dampened lung tumor formation and improved survival in the KrasG12D/P53L/L (KP) autochthonous mouse model of LUAD. In addition, CBX4 depletion significantly inhibited proliferation and anchorage-independent growth of KP mouse embryonic fibroblasts. Moreover, ectopic CBX4 expression clearly promoted proliferation and anchorage-independent growth in both human and mouse LUAD cells, whereas silencing of CBX4 exerted opposite effects. Mechanistically, CBX4 promoted growth of LUAD cells through activation of the Wnt/β-catenin pathway. Furthermore, expression levels of CBX4 were positively correlated with β-catenin in human LUAD samples. In conclusion, our data suggest that CBX4 plays an oncogenic role via the Wnt/β-catenin pathway and could serve as a potential therapeutic target in LUAD.

ObjectivesThere is paucity of studies to investigate the association between combined and long-term exposure to air pollution and the risk of incident chronic kidney disease (CKD) in older adults.MethodsA prospective cohort of 90,032 older adults who did not have CKD at baseline were followed up from January 1, 2017, to December 31, 2019. Various pollutant data, including particulate matter with diameters ≤ 2.5 mm (PM2.5), ≤ 10 mm (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2), Ozone (O3), and carbon monoxide (CO), from all monitoring stations in Binhai New Area, Tianjin were considered in calculating the mean exposure concentration of each pollutant over 2 years. By summing each pollutant concentration weighted by the regression coefficients, we developed an air pollution score that assesses the combined exposure of these air pollutants. Due to the strong correlation between air pollutants, Principal Component Analysis (PCA) score was also developed. The association between air pollutants and incident CKD in the elderly was analyzed.ResultsA total of 90,032 subjects participated in this study with a median follow-up of 545 days. Among them, 22,336 (24.8%) developed CKD. The HR (95% CI) for air pollution score and incidence of CKD was 1.062 (1.060-1.063) and p p for trend p for trend ConclusionCombined air pollution score, AQI, and PCA score were associated with an increased risk of CKD in an exposure-response relationship. Our current results might also provide evidence for developing environmental protection policies.

Contrast-enhanced computed tomography (CE-CT) is the gold standard for diagnosing aortic dissection (AD). However, contrast agents can cause allergic reactions or renal failure in some patients. Moreover, AD diagnosis by radiologists using non-contrast-enhanced CT (NCE-CT) images has poor sensitivity. To address this issue, we propose a novel cascaded multi-task generative framework for AD detection using NCE-CT volumes. The framework includes a 3D nnU-Net and a 3D multi-task generative architecture (3D MTGA). Specifically, the 3D nnU-Net was employed to segment aortas from NCE-CT volumes. The 3D MTGA was then employed to simultaneously synthesize CE-CT volumes, segment truefalse lumen, and classify the patient as AD or non-AD. A theoretical formulation demonstrated that the 3D MTGA could increase the Jensen-Shannon Divergence (JSD) between AD and non-AD for each NCE-CT volume, thus indirectly improving the AD detection performance. Experiments also showed that the proposed framework could achieve an average accuracy of 0.831, a sensitivity of 0.938, and an F1-score of 0.847 in comparison with seven state-of-the-art classification models used by three radiologists with junior, intermediate, and senior experiences, respectively. The experimental results indicate that the proposed framework obtains superior performance to state-of-the-art models in AD detection. Thus, it has great potential to reduce the misdiagnosis of AD using NCE-CT in clinical practice. The source codes and supplementary materials for our framework are available at https://github.com/yXiangXiong/CMTGF.

Ribosomally synthesized and post-translationally modified peptide (RiPP) represents one of the largest yet largely underexplored natural product families in bacteria. Although varied precursors and maturases lead to remarkable structural diversity, genetically-encoded nature of RiPP results in a residue-defined modification landscape of macrocyclic peptides, which simplifies the prediction and prioritization of their biosynthetic gene clusters (BGCs). Here, we report a small peptide and enzyme co-occurrence analysis workflow (SPECO), which enabled us to perform a large-scale analysis of radical S-adenosylmethionine (rSAM) enzyme-catalyzed RiPPs BGCs and disclosed uncharted enzyme sequence space for unprecedented post-translational modification of macrocyclic peptides. Applying this approach to 161,954 bacterial genomes, we identified 32,220 BGCs of rSAM-catalyzed RiPPs and prioritized 25 new families with unseen biosynthetic architectures or precursor peptide patterns. We further discovered three new enzymes for macrocyclic peptides construction, which catalyzed crosslinks between cysteine to glycine, histidine to aliphatic side-chain, and tyrosine/histidine to arginine, respectively. Together, these results demonstrate the strength of our SPECO approach in discovering new RiPP BGCs and diverse enzymes for macrocyclic peptides biosynthesis.

Serum agglutination test plus exposure history were used to diagnose most cases of human brucellosis in 2 China provinces. After appropriate treatment, 13.3% of acute brucellosis cases progressed to chronic disease; arthritis was an early predictor. Seropositivity can persist after symptoms disappear, which might cause physicians to subjectively extend therapeutic regimens.

To analyze the genomic variation characteristics of fetal with abnormal serological screening, and to further explore the value of copy number variation (CNV) detection technology in prenatal diagnosis of fetal with abnormal serological screening.7617 singleton pregnant women who underwent amniocentesis for prenatal diagnosis solely due to abnormal Down's serological screening were selected. According to the results of serological screening, the patients were divided into high risk group, borderline risk group and single abnormal multiple of median (MOM) group. CMA and CNV-Seq were used to detect the copy number variation of amniotic fluid cell genomic DNA and combined with amniotic fluid cell karyotype analysis for prenatal diagnosis. Outpatient revisit combined with telephone inquiry was used for postnatal follow-up.Among 7617 amniotic fluid samples, aneuploidy was detected in 138cases (1.81%) by CMA and CNV-Seq, 9 cases of aneuploid chimerism were detected by amniotic fluid cell karyotype analysis, and 203 cases of fetus carrying pathogenic and likely pathogenic CNV (P/LP CNV) were detected, the variant of uncertain significance (VUS) was detected in 437 cases (5.7%), the overall abnormal detection rate was 10.33%. The detection rate of aneuploidy by CMA and CNV-Seq in three group were 123 cases (2.9%), 13 cases (1.3%) and 2 cases (0.4%), respectively,and showing no significant difference (χCompared with the traditional chromosome karyotype, CMA and CNV-Seq can improve the detection rate of pathogenic and likely pathogenic CNV. CMA and CNV-seq can be used for first tier diagnosis of pregnant women in the general population with abnormal Down's serological screening.

Currently available evidence favors the combination of chemotherapy with concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma (LANPC). However, the optimal timing for additional chemotherapy is unclear. This study was conducted to compare the efficacy and toxicity of induction chemotherapy plus concurrent chemoradiotherapy (IC+CCRT) versus concurrent chemoradiotherapy plus adjuvant chemotherapy (CCRT+AC).Two medical centers in China enrolled patients with LANPC (stage III-IVB) between January 2009 and May 2020. Through the use of propensity score matching (PSM), baseline characteristics were balanced. The primary endpoint was overall survival (OS), which was evaluated by the Kaplan-Meier method and log-rank test. Potential independent prognostic factors were identified using univariate and multivariate Cox proportional hazard analyses. Based on the chi-squared test, we compared the adverse events associated with treatment between the groups.After the implementation of PSM, 159 patients treated with IC+CCRT and 72 patients treated with CCRT+AC were eventually enrolled in this study. There was no significant difference between patients treated with IC+CCRT and CCRT+AC in terms of 3-year OS (94.7% versus 90.9%, p=0.816), progression-free survival (PFS) (91.2% versus 83.1%, p=0.588), locoregional recurrence-free survival (LRFS) (92.5% versus 81.8%, p=0.478), or distant metastasis-free survival (DMFS) (93.4% versus 88.2%, p=0.783). There was no prognostic significance of the treatment for OS, PFS, LRFS, or DMFS (all pgt; 0.05) in the univariate and multivariate analyses. Patients treated with CCRT+AC had a higher incidence of grade 3 to 4 leucopenia (p=0.001) and neutropenia (p=0.001) than those treated with IC+CCRT.IC plus CCRT achieved comparable survival outcomes to CCRT plus AC and had a lower incidence of toxicity.

Colorectal carcinoma (CRC) recurrence is often accompanied by metastasis. Most metastasis undergo through epithelial‐mesenchymal transition (EMT). Studies showed that retinol X receptor alpha (RXRα) and 20(S)‐Protopanaxadiol (PPD) have anti‐tumour effects. However, the anti‐metastasis effect of 20(S)‐PPD and the effect of RXRα on EMT‐induced metastasis are few studies on. Therefore, the role of RXRα and 20(S)‐PPD in CRC cell metastasis remains to be fully elucidated. RXRα with clinicopathological characteristics and EMT‐related expression in clinical samples were examined. Then, RXRα and EMT level in SW480 and SW620 cells, overexpressed and silenced RXRα in SW620 cells and SW480 cells, respectively, were evaluated. Finally, 20(S)‐PPD effect on SW620 and SW480 cells was evaluated. The results showed that a lower RXRα expression in cancer tissues, and a moderate negative correlation between RXRα and N stage, and tended to higher level of EMT. SW480 and SW620 cells had the highest and lowest RXRα expression among four CRC cell lines. SW480 had lower EMT level than SW620. Furthermore, 20(S)‐PPD increased RXRα and inhibited EMT level in SW620 cell. Finally, 20(S)‐PPD cannot restore SW480 cells EMT level to normal when RXRα silencing. These findings suggest that 20(S)‐PPD may inhibit EMT process in CRC cells by regulating RXRα expression.

Background Constipation is frequently encountered in patients undergoing brain tumor resection. Constipation has negative effects on daily living, well-being, and individuals' quality of life. We examined the impact of acupuncture and electroacupuncture (EA) stimulation on postoperative constipation for patients undergoing brain tumor resection. Methods Patients undergoing brain tumor resection (n = 150) were randomly divided into a nontreatment group, an acupuncture group, and an EA group. Rome III Diagnostic Criteria, Cleveland Clinic Constipation Score, symptom assessment, Patient Assessment of Constipation Quality of Life questionnaire, Self-Rating Anxiety Scale, and a Self-Rating Depression Scale were collected. Results Acupuncture and EA were effective in relieving postoperative constipation. Electroacupuncture decreased constipation and improved quality of life scores. Conclusion Acupuncture and EA are novel adjuvant therapies to treat constipation.

Highlights • Liver injury is not very severe in pregnant COVID-19 patients. • Pregnant COVID-19 patients with liver injury had higher inflammation. • Newborns of COVID-19 patients with liver injury were negative for SARS-CoV-2., Liver injury is not very severe in pregnant COVID-19 patients. Pregnant COVID-19 patients with liver injury had higher inflammation than those without liver injury. All newborns delivered by pregnant COVID-19 patients with liver injury were negative for SARS-CoV-2.

Channel catfish (Ictalurus punctatus) are one of the most important commercial freshwater fish in the world. China has been the major producer and consumer of channel catfish following the rapid development in the past three decades. In the present study, a novel orthologous myostatin gene, IpMSTNa, of channel catfish was identified based on homology cloning and genome locating. Multiple sequence alignments and gene structure analyses showed that the IpMSTNa gene and its deduced protein presented similar architectures to other known vertebrates. Phylogenetic and synteny analyses indicated that IpMSTNa belongs to MSTN1 orthologues. Pro-IpMSTNa protein is a typical disulphide-linked homodimer, with each chain containing an N-terminal pro-domain and a C-terminal unmatured GF domain, while pro-IpMSTNa present some significant differences in secondary structure and three-dimensional substances with pro-IpMSTNb. Relative expression level of the IpMSTNa gene upregulated rapidly and decreased dramatically during the embryonic and larval developmental stages, respectively. In addition, IpMSTNa displayed remarkably higher expression at most developmental stages compared to IpMSTNb. Tissue distribution analysis indicated that the IpMSTNa gene had a significantly higher level of expression than IpMSTNb in all selected tissues, with abundantly greater expression in the liver, muscle, gill and spleen, and moderately greater expression in the kidney, intestine, and head kidney. ISH analysis demonstrated that the expression signals of IpMSTNa and IpMSTNb at the selected developmental stages are consistent to qRT-PCR tests. Our study suggested that the IpMSTNa gene may have more biological functions, which have yet to be determined compared to the IpMSTNb gene.

The aim of the present study was to determine whether the self-enhancement effect of voice attractiveness evaluation is due to general self-positivity bias and/or the familiarity effect. The participants were asked to rate the attractiveness of their own voice, a friend's voice and strangers' voices. In addition, a self-reference valence (SR-valence) task was adopted in the experiment. Significant self-enhancement effects in voice attractiveness ratings were demonstrated, regardless of whether the participants recognized their self-voice or not. However, the friend-enhancement effect was found in only those participants who successfully recognized their friend's voice. Moreover, a significant correlation was found between self-positivity bias in the SR-valence task and the self-enhancement effect (but not the friend-enhancement effect). Our findings suggest that both the familiarity effect and self-positivity bias account for the vocal self-enhancement effect, and the influence of self-positivity bias could be implicit. The present study thus provides empirical evidence to clarify the potential explanations for the self-enhancement of voice attractiveness assessment.

Clear cell renal cell carcinoma (ccRCC) is the most common RCC subtype with high metastasis, poor prognosis and conventional chemotherapy resistance. Prostate cancer associated transcript 1 (PCAT1) is an important lncRNA that was reported to be involved in cell proliferation, migration and invasion of several types of cancer cells. However, its role in ccRCC is still undetermined. This study found that PCAT1 levels were elevated in ccRCC tumors as well as several ccRCC cells, and knockdown of PCAT1 with siRNA (si-PCAT1) alleviated cell proliferation, migration and invasion of Caki-2 and ACHN cells. With bioinformatics analysis, dual-luciferase reported assay, RNA pull-down assay and Spearman’s correlation analysis, we demonstrated that PCAT1 acted as a sponge for miR-656 and miR-539. Moreover, we found dual competitive interaction of miR-656/539 with PCAT1 and yes-associated protein (YAP), resulting in the identification of PCAT1-miR-656/539-YAP axis in Caki-2 and ACHN cells. With CCK-8 assay and transwell assay, miR-656/539 inhibitor or YAP overexpression could alleviate the effects of si-PCAT1 on the proliferation, migration and invasion of Caki-2 and ACHN cells. Our data indicated that PCAT1 promotes proliferation, migration and invasion of ccRCC cells by upregulating YAP via sponging miR-656 and miR-539. Taken together, this study provided a novel therapeutic target for ccRCC treatment.

The present study aimed to explore the influence of sexual dimorphism on the evaluation of the attractiveness of one’s own face. In the experiment, a masculinized and a feminized version of the self-faces of the participants were obtained by transferring the original faces toward the average male or female face. The participants were required to rate the attractiveness of three types (original, masculine, feminine) of their own faces and the other participants’ faces in same-sex and opposite-sex contexts. The results revealed that the participants rated their own faces as more attractive than other participants rated them regardless of the sexually dimorphic type (original, masculine, feminine) or the evaluation context. More importantly, the male and female participants showed different preferences for the three types of self-faces. Specifically, in the same-sex context, the female participants rated their own original faces as significantly more attractive than the masculine and feminine faces, and the male participants rated their own masculine faces as significantly more attractive than the feminine faces; while in the opposite-sex context, no significant difference among the attractiveness scores of the three types of self-faces was found in both the male and female participants. The present study provides empirical evidence of the influence of sexual dimorphism on the evaluation of the attractiveness of self-faces.

Artificial intelligence (AI) is playing an important role in radiation oncology. One of the most important applications is in radiotherapy physics. In this field, it has improved the automation of radiotherapy plan design and quality control (QC), thereby promoting and ensuring individualized precision treatment. This article reviews the applications and research on AI in the physics of radiotherapy and projects the prospects of AI in the following aspects: radiotherapy plan design, radiotherapy quality assurance, and QC, organs at risk contouring, dose prediction, etc.

The aim of this review is to summarize existing research investigating the use of sodium glucose cotransporter-2 (SGLT2) inhibitors in patients with type 1 diabetes mellitus (T1DM) while highlighting potential strategies to mitigate the risk of diabetic ketoacidosis (DKA).SGLT2 inhibitors have been studied in patients with T1DM in phase 3 clinical trials such as the inTandem, DEPICT, and EASE trials, which demonstrated consistent reductions in HbA1c. Secondary analyses of these trials have also reported potential kidney protective effects that are independent of improved glycemic control. However, trials in patients with type 2 diabetes mellitus (T2DM) have found an increased risk of DKA with SGLT2 inhibitors, a serious concern in patients with T1DM. SGLT2 inhibitors provide cardiovascular benefits and kidney protection in patients with T2DM and are a promising therapeutic option for patients with T1DM due to overlapping pathophysiological mechanisms. However, SGLT2 inhibitors increase the risk of DKA, and there is currently a lack of research investigating the beneficial effects of SGLT2 inhibitors in patients with T1DM. Preventative measure for DKA would have to be implemented and the risks would need to be carefully balanced with the benefits offered by SGLT2 inhibitors. Additional research will also be required to determine the kidney protective effects of SGLT2 inhibitors in patients with T1DM and diabetic kidney disease and to quantify the risk of DKA after the implementation of preventative measures, proper patient education, and ketone monitoring.

Chimeric antigen receptor T-cell (CAR-T) therapy is an exciting development in the field of cancer immunology and has received a lot of interest in recent years. Many time-to-event (TTE) endpoints related to relapse, disease progression, and remission are analyzed in CAR-T studies to assess treatment efficacy. Definitions of these TTE endpoints are not always consistent, even for the same outcomes (e.g., progression-free survival), which often stems from analysis choices regarding which events to consider as part of the composite endpoint, censoring or competing risk in the analysis. Subsequent therapies such as hematopoietic stem cell transplantation are common but are not treated the same in different studies. Standard survival analysis methods are commonly applied to TTE analyses but often without full consideration of the assumptions inherent in the chosen analysis. We highlight two important issues of TTE analysis that arise in CAR-T studies, as well as in other settings in oncology: the handling of competing risks and assessing the association between a time-varying (post-infusion) exposure and the TTE outcome. We review existing analytical methods, including the cumulative incidence function and regression models for analysis of competing risks, and landmark and time-varying covariate analysis for analysis of post-infusion exposures. We clarify the scientific questions that the different analytical approaches address and illustrate how the application of an inappropriate method could lead to different results using data from multiple published CAR-T studies. Codes for implementing these methods in standard statistical software are provided.

To determine the relationship between renal hemodynamic function and neuropathy in adults with ≥50-years of type 1 diabetes (T1D) compared to nondiabetic controls.Glomerular filtration rate (GFR, inulin), effective renal plasma flow (ERPF, p-aminohippurate), modified Toronto Clinical Neuropathy Score (mTCNS), corneal confocal microscopy, nerve conduction, and heart rate variability (autonomic function) were measured; afferent (RHigher mTCNS associated with lower renal blood flow (β ± SE:-9.29 ± 4.20, p = 0.03) and greater RAlthough neurological dysfunction in the presence of diabetes may contribute to impaired renal blood flow resulting in ischemic injury in patients with T1D, early autonomic dysfunction does not appear to be associated with kidney function changes.

Nanomedicine has emerged as a promising platform for disease treatment and much progress has been achieved in the clinical translation for cancer treatment. Several types of nanomedicines have been approved for therapeutic application. However, many nanoparticles still suffer from challenges in the translation from bench to bedside. Currently, nanoparticle-based delivery systems have been developed to explore their functions in targeted gene silencing and cancer therapy. This review describes the research progress of different nano-carriers in targeted gene editing, and the recent progress in co-delivery of anticancer drugs and small ribonucleic acid. We also summarize the strategies for improving the specificity of carrier systems. Finally, we discuss the functions of targeted nano-carriers in overcoming chemotherapeutic drug resistance in cancer therapy. As research continues to advance, a better understanding of the safety including long-term toxicity, immunogenicity, and body metabolism may impel nanoparticle translation.

Evidence on the associations of prolonged ambient pollutants exposure with chronic non-communicable diseases among middle-aged and elderly residents is still limited. This prospective cohort study intends to investigate the long-term effects of ambient pollution on hypertension and diabetes incidence among relatively older residents in China. Individual particulate matter exposure levels were estimated by satellite-based model. Individual gaseous pollutants exposure levels were estimated by Inverse Distance Weighted model. A Cox regression model was employed to assess the risks of hypertension and diabetes morbidity linked to air pollutants exposures. The cross-product term of ambient pollutants exposure and covariates was further added into the regression model to test whether covariates would modify these air pollution-morbidity associations. During the period from 2014 to 2018, a total of 97,982 subjects completed follow-up. 12,371 incidents of hypertension and 2034 of diabetes occurred. In the multi-covariates model, the hazard ratios (HR) and 95% confidence interval (CI) were 1.49 (1.45-1.52), 1.28 (1.26-1.30), 1.17 (1.15-1.18), 1.21 (1.17-1.25) and 1.33 (1.31-1.35) for hypertension morbidity per 10 μg/m

Preeclampsia is a major cause of maternal and perinatal morbidity and mortality. Growth discordance is associated with an increased risk of preeclampsia in twin pregnancies. The management of preeclampsia combined with discordant twins is difficult and controversial because of severe maternal conditions and severe growth restriction in 1 twin.A 34-year-old woman with dichorionic diamniotic twin pregnancy complicated by preeclampsia at 29 weeks of gestation, and 1 twin with severe growth restriction and fetal intracranial hemorrhage.The patient developed severe preeclampsia with high blood pressure (160/100 mm Hg) and proteinuria, hydrothorax and leg edema. Ultrasound examination confirmed growth restriction (weight estimation: 915 g,1st percentile) and abnormal umbilical flow in 1 twin (twin B), with a normal co-twin (estimated weight: 1693 g) (twin A). Magnetic resonance imaging revealed intracranial hemorrhage in the germinal matrix of twin B.Selective termination of twin B by intracardiac injection of potassium chloride was performed at 31 weeks and 2 days' gestation.Symptoms of preeclampsia resolved after selective termination, allowing the pregnancy to be prolonged for nearly 4 weeks. A healthy female infant was delivered at 35 weeks of gestation.Delivery of both fetus is not the only choice for the management for twin pregnancy with severe preeclampsia and discordant twins. Selective termination of the fetus with poor prognosis could be a reasonable treatment choice in carefully selected cases.

Background Coronary heart disease (CHD) has become the leading cause of death and one of the most serious epidemic diseases worldwide. CHD is characterized by urgency, danger and severity, and dynamic treatment strategies for CHD patients are needed. We aimed to build and validate an AI model for dynamic treatment recommendations for CHD patients with the goal of improving patient outcomes and learning best practices from clinicians to help clinical decision support for treating CHD patients. Methods We formed the treatment strategy as a sequential decision problem, and applied an AI supervised reinforcement learning-long short-term memory (SRL-LSTM) framework that combined supervised learning (SL) and reinforcement learning (RL) with an LSTM network to track patients’ states to learn a recommendation model that took a patient’s diagnosis and evolving health status as input and provided a treatment recommendation in the form of whether to take specific drugs. The experiments were conducted by leveraging a real-world intensive care unit (ICU) database with 13,762 admitted patients diagnosed with CHD. We compared the performance of the applied SRL-LSTM model and several state-of-the-art SL and RL models in reducing the estimated in-hospital mortality and the Jaccard similarity with clinicians’ decisions. We used a random forest algorithm to calculate the feature importance of both the clinician policy and the AI policy to illustrate the interpretability of the AI model. Results Our experimental study demonstrated that the AI model could help reduce the estimated in-hospital mortality through its RL function and learn the best practice from clinicians through its SL function. The similarity between the clinician policy and the AI policy regarding the surviving patients was high, while for the expired patients, it was much lower. The dynamic treatment strategies made by the AI model were clinically interpretable and relied on sensible clinical features extracted according to monitoring indexes and risk factors for CHD patients. Conclusions We proposed a pipeline for constructing an AI model to learn dynamic treatment strategies for CHD patients that could improve patient outcomes and mimic the best practices of clinicians. And a lot of further studies and efforts are needed to make it practical.

Liver fibrosis is a growing public health concern without effective medical treatment. Recent reports have indicated that inhibitors of apoptosis proteins (IAPs) were potential targets for idiopathic pulmonary fibrosis therapy. However, their roles have not been well identified in liver fibrosis.The expression of IAPs were examined in human liver tissue and experimental mouse models. Liver fibrosis in CClOur study showed that increased expression of cIAP2 was associated with liver fibrosis severity in liver tissues. Deletion of cIAP2 from hepatocytes or degrading cIAPs by APG-1387 ameliorated liver fibrosis induced by CClThese results suggested that cIAPs, especially cIAP2, might play a novel role in the pathogenesis of liver fibrosis, and targeting cIAPs represented a promising therapeutic strategy for liver fibrosis by increasing MMP9 expression induced by CCL5 chemotactic neutrophils.

The non-canonical nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway is an important component of NF-κB transcription complex. Activation of this pathway mediates the development and function of host immune system involved in inflammation and viral infection. During hepatitis B virus (HBV) infection, there is a complex interaction between infected hepatocytes and the immune cells, which can hinder antiviral immune responses and is associated with pathological changes in liver tissue. Consistently, the host immune system is closely related to the severity of liver damage and the level of viral replication. Previous studies indicated that the non-canonical NF-κB signaling pathway was affected by HBV and might play an important regulatory role in the antiviral immunity. Therefore, systematically elucidating the interplay between HBV and non-canonical NF-κB signaling will contribute the discovery of more potential therapeutic targets and novel drugs to treat HBV infection.

Background The gasdermin E gene (GSDME, also known as DFNA5) is mutated in familial aging-related hearing loss. Recent studies have also revealed that the expression of DFNA5 is suppressed in many cancer types; however, little is known about the function of DFNA5 in head and neck squamous cell carcinoma (HNSCC). Accordingly, the aim of the present study was to evaluate the expression of DFNA5 and explore its prognostic value in HNSCC. Result We used a set of bioinformatics tools, including Oncomine, TIMER, TISIDB, cBioPortal, and GEPIA, to analyze the expression of DFNA5 in patients with HNSCC from public databases. Kaplan-Meier plotter was used to evaluate the potential prognostic significance of DFNA5. DFNA5 mRNA levels were significantly higher in HNSCC tissues than in normal tissues, and high DFNA5 expression was correlated with worse survival. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that DFNA5 expression has a strong positive correlation with cell adhesion and the integrin signaling pathway, whereas its expression was negatively correlated with the levels of infiltrating B cells (cor = − 0.223, P = 8.57e-07) and CD8 T cells (cor = − 0.223, P = 2.99e-07). Conclusion This study demonstrates that DFNA5 expression has prognostic value for HNSCC patients. Moreover, these results suggest that regulation of lymphocyte infiltration is the mechanism underlying the function of DFNA5 in HNSCC.

Patients with type 2 diabetes are at high risk of developing renal and cardiovascular complications. Sodium–glucose cotransporter 2 (SGLT2) inhibitors have garnered interest due to their glucose-independent cardiorenal protective effects, as reported in trials including participants with and without diabetes, such as Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) (1,2). These trials have demonstrated that SGLT2 inhibitors reduce cardiovascular disease (CVD) risk, especially hospitalization for heart failure (1,2). Despite these clinical benefits, the underlying physiological mechanisms of SGLT2 inhibitors are incompletely understood, particularly in patients with chronic kidney disease (CKD). Accordingly, this analysis examined the impact of treatment with an SGLT2 inhibitor, ertugliflozin, on markers of plasma volume contraction and myocardial strain in participants with type 2 diabetes and moderate CKD. We performed a post hoc exploratory analysis in a subset of 231 participants from the eValuation of ERTugliflozin efficacy and Safety (VERTIS) RENAL trial (clinical trial reg. no. NCT01986855, ClinicalTrials.gov) with type 2 diabetes and stage 3 CKD (estimated glomerular filtration rate [eGFR] 30–59 mL/min/1.73 m2) who were randomized to SGLT2 inhibitor therapy with ertugliflozin (5 mg or 15 mg daily; pooled herein) or placebo (3). Clinical and biomarker measurements were obtained at baseline and 26 weeks and 52 weeks postrandomization. Biomarkers were quantified with Luminex xMAP (cardiac troponin, renin, and N-terminal pro B-type natriuretic peptide [NT-proBNP]) or ELISA (atrial natriuretic peptide [ANP], human erythropoietin [EPO], ACE, and ACE2). Aldosterone was quantified by DiaSorin LIAISON XL Analyzer based on competitive chemiluminescent immunoassay. Differences in longitudinal changes in biomarkers among participants receiving either …

Multidrug combination therapy based on drug delivery systems (DDSs) has great potential for cancer treatment. Stimuli-sensitive DDSs further enhance therapeutic efficacy by providing controllable drug delivery. Herein, the phospholipid compound DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine) was used to construct thermosensitive liposomes to load the photosensitizer ZnPc(PEG)4 (zinc phthalocyanine substituted by tetraethylene glycol) for molecular imaging, and photodynamic and photothermal therapy, together with doxorubicin (DOX) for chemotherapy. Interestingly, ZnPc(PEG)4 as an amphipathic molecule was found to be important in the construction of the liposomes, and it provided liposomes with improved stability. The thus-obtained liposomes ZnPc(PEG)4:DOX@LiPOs were demonstrated to have enhanced ROS production capacity, heat generation properties and a photo-triggered doxorubicin release effect, and, in cellular experiments, increased cytotoxicity and apoptotic cell proportions, compared to ZnPc(PEG)4@LiPOs and DOX@LiPOs. ZnPc(PEG)4 loaded in lipid bilayers showed stronger intracellular ROS production ability compared to free ZnPc(PEG)4. In vivo studies indicated that ZnPc(PEG)4:DOX@LiPOs exhibited enhanced tumor accumulation, increased anti-cancer effects and reduced liver retention. These photo-triggered liposomes constructed by the photosensitizer ZnPc(PEG)4 can also be used to package other cargo for combined target tumor therapy and molecular imaging.

OBJECTIVE To analyze the predictors of both distant metastasis and survival in patients with adenoid cystic carcinoma of the external auditory canal. STUDY DESIGN Retrospective patient review. SETTING A single university hospital. PATIENTS Eighty-two cases with adenoid cystic carcinoma of the external auditory canal were referred to our institution between 2004 and 2016. MAIN OUTCOME MEASURES Distant metastasis was detected by lung computed tomography, proton emission tomography computed tomography, or histopathologic examination of tissue samples. Distant metastasis predictors were analyzed using Student's t tests and χ tests. The log-rank tests of Kaplan-Meier survival curves were used to evaluate survival differences. RESULTS During a median follow-up of 36 months (range, 6-162 mo), distant metastasis developed in 25 patients. The occurrence of distant metastasis was significantly associated with histopathologic subtype, T classification, and local recurrence (p

OBJECTIVE To assess depressive symptom outcomes in a pooled sample of epilepsy self-management randomized controlled trials (RCTs) from the Managing Epilepsy Well (MEW) Network integrated research database (MEW DB). METHODS Five prospective RCTs involving 453 adults with epilepsy compared self-management intervention (n = 232) versus treatment as usual or wait-list control outcomes (n = 221). Depression was assessed with the nine-item Patient Health Questionnaire. Other variables included age, gender, race, ethnicity, education, income, marital status, seizure frequency, and quality of life. Follow-up assessments were collapsed into a visit 2 and a visit 3; these were conducted postbaseline. RESULTS Mean age was 43.5 years (SD = 12.6), nearly two-thirds were women, and nearly one-third were African American. Baseline sample characteristics were mostly similar in the self-management intervention group versus controls. At follow-up, the self-management group had a significantly greater reduction in depression compared to controls at visit 2 (P