Search

Abstract Aims This study aimed to analyse the global prevalence and disability trends of heart failure (HF) from 1990 to 2019, considering both sexes and country‐specific economic strata. Methods This study conducted a secondary analysis employing data from the Global Burden of Disease (GBD) study. The analysis is stratified by sex and Socio‐demographic Index (SDI) levels. Through age‐period‐cohort and Joinpoint regression analyses, we investigated the temporal trends in HF prevalence and years lived with disability (YLDs) during this period. Results Between 1990 and 2019, the global prevalence of HF surged by 106.3% (95% uncertainty interval: 99.3% to 114.3%), reaching 56.2 million cases in 2019. While all‐age prevalence and YLDs increased over the 30 year span, age‐standardized rates decreased by 2019. Countries with higher SDI experienced a more pronounced percentage decrease compared with those with lower SDI. Longitudinal analysis revealed an overall improvement in both prevalence and YLDs for HF, albeit with notable disparities between SDI quintiles and sexes. Ischaemic heart disease and hypertensive heart disease emerged as the most rapidly increasing and primarily contributing causes of HF, albeit with variations observed across different countries. The average annual percentage change for prevalence and YLDs over the period was −0.26% and −0.25%, respectively. Conclusions This study offers valuable insights into the global burden of HF, considering factors such as population aging, regional disparities, sex differences and aetiological variations. The findings hold significant implications for healthcare planning and resource allocation. Continued assessment of these trends and innovative strategies for HF prevention and management are crucial for addressing this pressing global health concern.

Abstract Intestinal fibrosis is the primary cause of disability in patients with Crohn’s disease (CD), yet effective therapeutic strategies are currently lacking. Here, we report a multiomics analysis of gut microbiota and fecal/blood metabolites of 278 CD patients and 28 healthy controls, identifying characteristic alterations in gut microbiota (e.g., Lachnospiraceae, Ruminococcaceae, Muribaculaceae, Saccharimonadales) and metabolites (e.g., L-aspartic acid, glutamine, ethylmethylacetic acid) in moderate-severe intestinal fibrosis. By integrating multiomics data with magnetic resonance enterography features, putative links between microbial metabolites and intestinal fibrosis-associated morphological alterations were established. These potential associations were mediated by specific combinations of amino acids (e.g., L-aspartic acid), primary bile acids, and glutamine. Finally, we provided causal evidence that L-aspartic acid aggravated intestinal fibrosis both in vitro and in vivo. Overall, we offer a biologically plausible explanation for the hypothesis that gut microbiota and its metabolites promote intestinal fibrosis in CD while also identifying potential targets for therapeutic trials.

BackgroundBroad T cell phenotypic alterations and potential dysfunctions were prominent in COVID-19. There are few and inconclusive data about the role of immune checkpoints for T cell exhaustion/activation during SARS-CoV-2 infection in multiple myeloma (MM) patients.MethodsWe tested T cell subsets and immune checkpoints in 177 MM patients with COVID-19, as well as in 32 healthy infected controls and 42 uninfected MM patients. The percentage of CD4+ and CD8+ subpopulation and immune checkpoints (PD-1, TIGIT, TIM-3, LAG-3, CTLA-4, OX40, and 4-1BB) were evaluated by flow cytometry.ResultsWe have found that pronounced lymphopenia and inverted CD4/CD8 ratio in severe COVID-19 patients were especially developed within the first month after infection. And T cell subset dysregulation was persistent in severe patients recovering from SARS-CoV-2 infection. Immune checkpoints on CD4+ T cells were variable and uncorrelated with the level of adaptive immunity, while the proportion of CD4+ T cells was positively correlated with humoral immune response. PD-1 and TIGIT on CD8+ T cells were significantly elevated in severe patients and sustained for more than 2 months, which was associated with impaired cellular immune function. Moreover, exhausted molecules PD-1 and TIGIT on T cells were reduced in immunotherapy patients.ConclusionThe prolonged T cell dysregulation after severe SARS-CoV-2 infection highlights the close surveillance from reinfection in MM patients even during convalescence. PD-1 and TIGIT on CD8+ T cells could be important prognostic factors to stratify prognosis in MM patients with COVID-19. Moreover, immunotherapy may downregulate the expression of exhausted checkpoints PD-1 and TIGIT, leading to T cell overactivation and severe COVID-19.

Abstract Background Myc rearrangement (Myc‐R) is a controversial factor linked to adverse outcomes in newly diagnosed multiple myeloma (NDMM). Aims This study aimed to evaluate the impact of Myc‐R on the prognosis of NDMM patients and its role in risk stratification compared with traditional high‐risk cytogenetic abnormalities (HRCAs). Materials & Methods A total of 417 NDMM patients enrolled from May 2009 to September 2022 were included. Fluorescence in situ hybridization (FISH) was used to detect Myc‐R and other Myc abnormalities (Myc‐OA). Median progression‐free survival (PFS) and overall survival (OS) were analyzed using Kaplan–Meier methods and log‐rank tests. Multivariate Cox regression analysis was used to identify independent risk factors. Results Myc‐R was identified in 13.7% of patients, while 14.6% had Myc‐OA. Patients with Myc‐R had significantly shorter median PFS (15.9 months) and OS (25.1 months) compared with those with Myc‐OA (24.5 months PFS; 29.8 months OS) and Myc‐negative (Myc‐N) status (29.8 months PFS, 29.8 months OS). Myc‐R was independently associated with worse PFS and OS compared to Myc‐OA. Patients with Myc‐R alone had inferior median PFS (15.9 months vs. 28.1 months, p = 0.032) and OS (25.1 months vs. 61.2 months, p = 0.04) compared to those with traditional single HRCA. Discussion The study suggests that traditional single HRCA may not significantly impact survival in NDMM patients. However, incorporating Myc rearrangement or traditional double/triple‐hit HRCAs into the risk stratification model improves its predictive value, highlighting the importance of Myc rearrangement in risk assessment. Conclusion Myc rearrangement is an independent adverse prognostic factor in NDMM. The incorporation of Myc rearrangement or multiple HRCAs into risk stratification models improves their prognostic value, providing a novel perspective on high‐risk factors in NDMM.

Freely engineering the operation frequency of frequency comb sources is crucial for various applications, e.g., high-precision spectroscopy, ranging, communications, and so on. Here, by employing band structure simulations, group velocity dispersion (GVD) analysis, and experimental verifications, we demonstrate that the operation frequency of terahertz (THz) quantum cascade laser frequency combs can be engineered from 4.2 to 4.0 THz. First of all, from the viewpoint of the band structure engineering, we shift the frequency corresponding to the optical transitions in the active region from 4.2 to 4.0 THz by slightly altering the thicknesses of quantum wells. Meanwhile, a GVD analysis is applied to evaluate the potential comb performance. Finally, experimental characterizations, e.g., emission spectra, inter-mode beatnote, dual-comb operation, are performed to validate the exceptional comb operation at 4.0 THz. The advancement in simulations and experimental results present a comprehensive method to customize the desired THz radiative frequency for comb generation, which facilitates the practical development of broadband, high-precision THz comb sources.

Abstract Flexible electronics have demonstrated various strategies to enhance the sensory ability for tactile perception and wearable physiological monitoring. Fibrous microstructures have attracted much interest because of their excellent mechanical properties and fabricability. Herein, a structurally robust fibrous mat was first fabricated by electrospinning, followed by a sequential process of functionalization utilizing ultrasonication treatment and in situ polymerization growth. Electrospun polyurethane (PU) microfibers were anchored with multi-walled carbon nanotubes (MWCNTs) to form conductive paths along each fiber by a scalable ultrasonic cavitation treatment in an MWCNT suspension. After, a layer of poly(3,4-ethylene dioxythiophene) (PEDOT) was grown on the surface of PU fibers decorated with MWCNTs to enhance the conductive conjunctions of MWCNTs. Due to the superior electromechanical behaviors and mechanical reinforcement of PEDOT, the PEDOT/MWCNT@PU mat-based device exhibits a wide working range (0–70 kPa), high sensitivity (1.6 kPa−1), and good mechanical robustness (over 18,000 cycles). The PEDOT/MWCNT@PU mat-based sensor also demonstrates a good linear response to different temperature variations because of the thermoelectricity of the PEDOT/MWCNT composite. This novel strategy for the fabrication of multifunctional fibrous mats provides a promising opportunity for future applications for high-performance wearable devices.

BackgroundAcute lymphoblastic leukemia (ALL) is prone to metastasize to the central nervous system (CNS), which is an important cause of poor treatment outcomes and unfavorable prognosis. However, the pathogenesis of CNS metastasis of ALL cells has not been fully illuminated. Recent reports have shed some light on the correlation between neural mechanisms and ALL CNS metastasis. These progressions prompt us to study the relationship between ALL central nervous system metastasis and neuronal development, exploring potential biomarkers and therapeutic targets of CNS metastasis.Materials and methodsALL central nervous system metastasis- and neuronal development-related differentially expressed genes (DEGs) were identified by analyzing gene expression datasets GSE60926 and GSE13715. Target prediction and network analysis methods were applied to assess protein–protein interaction networks. Gene Ontology (GO) terms and pathway enrichment for DEGs were assessed. Co-expressed differentially expressed genes (co-DEGs) coupled with corresponding predicted microRNAs (miRNAs) were studied as well. Reverse transcription–polymerase chain reaction (RT–PCR) and flow cytometry were employed for the validation of key co-DEGs in primary ALL cells. Furthermore, ALL cells were treated with a vascular endothelial growth factor (VEGF) inhibitor to block neuronal development and assess changes in the co-DEGs.ResultsWe identified 216, 208, and 204 DEGs in ALL CNS metastasis specimens and neuronal development samples (GSE60926 and GSE13715). CD2, CD3G, CD3D, and LCK may be implicated in ALL CNS metastasis. LAMB1, MATN3, IGFBP3, LGALS1, and NEUROD1 may be associated with neuronal development. Specifically, four co-DEGs (LGALS1, TMEM71, SHISA2, and S100A11) may link ALL central nervous system metastasis and neuronal development process. The miRNAs for each co-DEG could be potential biomarkers or therapeutic targets for ALL central nervous system metastasis, especially hsa-miR-22-3p, hsa-miR-548t-5p, and hsa-miR-6134. Additionally, four co-DEGs (LGALS1, TMEM71, SHISA2, and S100A11) were validated in CNS-infiltrated ALL cells. The VEGF inhibitor demonstrated a suppressive effect on mRNA and protein expression of key co-DEGs.ConclusionThe bioinformatic survey and key gene validation suggest a possible correlation between ALL CNS metastasis and the neuronal development process. Simulating the neuronal development process might be a possible strategy for CNS metastasis in ALL. LGALS1, TMEM71, SHISA2, and S100A11 genes are promising and novel biomarkers and targets in ALL CNS metastasis.

Abstract Background H9N2 virus is mainly transmitted through the respiratory mucosal pathway, so mucosal immunity is considered to play a good role in controlling avian influenza infection. It is commonly accepted that no adequate mucosal immunity is achieved by inactivated vaccines, which was widely used to prevent and control avian influenza virus infection. Thus, an improved vaccine to induce both mucosal immunity and systemic immunity is urgently required to control H9N2 avian influenza outbreaks in poultry farms. Methods In this study, we constructed a novel Lactococcus lactis (L. lactis) strain expressing a recombinant fusion protein consisting of the HA1 proteins derived from an endemic H9N2 virus strain and chicken IgY Fc fragment. We evaluated the immunogenicity and protective efficacy of this recombinant L. lactis HA1-Fc strain. Results Our data demonstrated that chickens immunized with L. lactis HA1-Fc strain showed significantly increased levels of serum antibodies, mucosal secretory IgA, T cell-mediated immune responses, and lymphocyte proliferation. Furthermore, following challenge with H9N2 avian influenza virus, chickens immunized with L. lactis HA1-Fc strain showed reduced the weight loss, relieved clinical symptoms, and decreased the viral titers and the pathological damage in the lung. Moreover, oropharyngeal and cloacal shedding of the H9N2 influenza virus was detected in chicken immunized with L. lactis HA1-Fc after infection, the results showed the titer was low and reduced quickly to reach undetectable levels at 7 days after infection. Conclusion Our data showed that the recombinant L. lactis HA1-Fc strain could induce protective mucosal and systemic immunity, and this study provides a theoretical basis for improving immune responses to prevent and control H9N2 virus infection.

Abstract. The clinical efficacy of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in reducing major cardiovascular adverse events related to atherosclerotic cardiovascular disease (ASCVD) has been well established in recent large randomized outcome trials. Although the cardiovascular and all-cause mortality benefit of PCSK9i remains inconclusive, current cholesterol management guidelines have been modified toward more aggressive goals for lowering low-density lipoprotein cholesterol (LDL-C). Consequently, the emerging concept of “the lower the better” has become the paradigm of ASCVD prevention. However, there is evidence from observational studies of a U-shaped association between baseline LDL-C levels and all-cause mortality in population-based cohorts. Among East Asian populations, low LDL-C was associated with an increased risk for hemorrhagic stroke in patients not on antithrombotic therapy. Accumulating evidence showed that low LDL-C was associated with an enhanced bleeding risk in patients on dual antiplatelet therapy following percutaneous coronary intervention. Additionally, low LDL-C was associated with a higher risk for incident atrial fibrillation and thereby, a possible increase in the risk for intracranial hemorrhage after initiation of anticoagulation therapy. The mechanism of low-LDL-C-related bleeding risk has not been fully elucidated. This review summarizes recent evidence of low-LDL-C-related bleeding risk in patients on antithrombotic therapy and discusses potential measures for reducing this risk, underscoring the importance of carefully weighing the pros and cons of aggressive LDL-C lowering in patients on antithrombotic therapy.

Abstract Background Lower back pain and stiffness are the typical symptoms of ankylosing spondylitis (AS). In this study, muscle mass was assessed by muscle density, mechanical elasticity, and area. We investigated the characteristics of lumbar paraspinal-muscle (PSM) mass using muscle ultrasound shear-wave elastography (SWE), as well as the validity of this method for identifying patients with AS. Methods We recruited a representative cohort of 30 AS patients, and 27 healthy volunteers who were age- and sex-matched to the patient study group, investigated the Young’s modulus (YM), cross-sectional area (CSA) and thickness of lumbar multifidus (LM) muscle using SWE. This study did not need to be randomized. Data were collected at the department of ultrasonography of Guangdong Provincial Hospital of Chinese Medicine. We analyzed the data using SPSS version 18.0 (IBM Corp, Armonk, NY, USA). Normal distribution was evaluated by the Shapiro–Wilk test and Q–Q plots. Demographic and baseline data will be analyzed with standard descriptive statistics. Data will be presented as the mean ± standard deviation (SD). Non-normally distributed data are presented as medians with interquartile ranges (IQR). Results Young’s modulus (YM) of SWE in AS patients was significantly higher than that in volunteers. Percentage change in lumbar multifidus (LM) muscle cross-sectional area (CSA) and thickness were significantly lower in AS patients than in healthy volunteers on the left side of the body. Correlation analysis showed a positive correlation between percentage change in CSA and thickness in both volunteers and AS patients. In AS patients, YM was negatively correlated with percentage change of CSA and thickness on the right side, while increased disease duration in AS was associated with increased YM on the left. Conclusion AS patients showed reductions in LM muscle mass and function as the disease progressed, SWE could reflect these changes well. Trial registration. Chinese Clinical Trial Registry, ChiCTR2000031476. Registered 02/04/2020. http://www.chictr.org.cn/index.aspx .

Abstract Background No consensus has been reached on an optimal blood lactate evaluation system although several approaches have been reported in the literature in recent years. A group-based trajectory modeling (GBTM) method could better stratify patients with acute respiratory distress syndrome (ARDS) complicated with sepsis in the intensive care unit (ICU). Patients and methods 760 patients from the comprehensive ICU of Tianjin Medical University General Hospital with ARDS complicated with sepsis were eligible for analysis. Serial serum lactate levels were measured within 48 h of admission. In addition to the GBTM lactate groups, the initial lactate, peak lactate level, the area under the curve of serial lactate (lactate AUC), and lactate clearance were also considered for comparison. The short- and long-term outcomes were the 30- and 90-day mortality, respectively. Results Three lactate groups were identified based on GBTM, with group 3 exhibiting the worse short- [hazard ratio (HR) for 30-day mortality: 2.96, 95% confidence interval (CI) 1.79–4.87, P

Background Limited data are available for postpartum hypertension prediction after preeclampsia. Methods and Results We examined the association between maternal serum chemerin levels in patients with preeclampsia and blood pressure (BP) levels after delivery in a prospective birth cohort of 15 041 singleton pregnant women. A total of 310 cases among 322 patients with preeclampsia (follow‐up rate, 96.3%) were followed up during a mean 2.8 years after delivery. Compared with matched uncomplicated controls (n=310), serum chemerin measured at ≈35 gestational weeks was significantly increased in preeclampsia (171.8±49.2 versus 140.2±53.5 ng/mL; P

The goal of this paper is to elucidate the effects of sodium restriction on hypertension and left ventricular (LV) hypertrophy in a mouse model with primary aldosteronism (PA). Mice with genetic deletion of TWIK-related acid-sensitive K (TASK)-1 and TASK-3 channels (TASK−/−) were used as the animal model of PA. Parameters of the LV were assessed using echocardiography and histomorphology analysis. Untargeted metabolomics analysis was conducted to reveal the mechanisms underlying the hypertrophic changes in the TASK−/− mice. The TASK−/− adult male mice exhibited the hallmarks of PA, including hypertension, hyperaldosteronism, hypernatremia, hypokalemia, and mild acid-base balance disorders. Two weeks of low sodium intake significantly reduced the 24-h average systolic and diastolic BP in TASK−/− but not TASK+/+ mice. In addition, TASK−/− mice showed increasing LV hypertrophy with age, and 2 weeks of the low-sodium diet significantly reversed the increased BP and LV wall thickness in adult TASK−/− mice. Furthermore, a low-sodium diet beginning at 4 weeks of age protected TASK−/− mice from LV hypertrophy at 8–12 weeks of age. Untargeted metabolomics demonstrated that the disturbances in heart metabolism in the TASK−/− mice (e.g., Glutathione metabolism; biosynthesis of unsaturated fatty acids; amino sugar and nucleotide sugar metabolism; pantothenate and CoA biosynthesis; D-glutamine and D-glutamate metabolism), some of which were reversed after sodium restriction, might be involved in the development of LV hypertrophy. In conclusion, adult male TASK−/− mice exhibit spontaneous hypertension and LV hypertrophy, which are ameliorated by a low-sodium intake.

Abstract Background Acute myeloid leukemia (AML) is the most common type of leukemia in adults. Its therapy has not significantly improved during the past four decades despite intense research efforts. New molecularly targeted therapies are in great need. The proto-oncogene c-Myc (MYC) is an attractive target due to its transactivation role in multiple signaling cascades. Deregulation of the MYC is considered one of a series of oncogenic events required for tumorigenesis. However, limited knowledge is available on which mechanism underlie MYC dysregulation and how long non-coding RNAs (lncRNAs) are involved in MYC dysregulation in AML. Methods AML microarray chips and public datasets were screened to identify novel lncRNA GAS6-AS1 was dysregulated in AML. Gain or loss of functional leukemia cell models were produced, and in vitro and in vivo experiments were applied to demonstrate its leukemogenic phenotypes. Interactive network analyses were performed to define intrinsic mechanism. Results We identified GAS6-AS1 was overexpressed in AML, and its aberrant function lead to more aggressive leukemia phenotypes and poorer survival outcomes. We revealed that GAS6-AS1 directly binds Y-box binding protein 1 (YBX1) to facilitate its interaction with MYC, leading to MYC transactivation and upregulation of IL1R1, RAB27B and other MYC target genes associated with leukemia progression. Further, lentiviral-based GAS6-AS1 silencing inhibited leukemia progression in vivo. Conclusions Our findings revealed a previously unappreciated role of GAS6-AS1 as an oncogenic lncRNA in AML progression and prognostic prediction. Importantly, we demonstrated that therapeutic targeting of the GAS6-AS1/YBX1/MYC axis inhibits AML cellular propagation and disease progression. Our insight in lncRNA associated MYC-driven leukemogenesis may contribute to develop new anti-leukemia treatment strategies.

Menthol is an important flavoring additive that triggers a cooling sensation. Under physiological condition, low to moderate concentrations of menthol activate transient receptor potential cation channel subfamily M member 8 (TRPM8) in the primary nociceptors, such as dorsal root ganglion (DRG) and trigeminal ganglion, generating a cooling sensation, whereas menthol at higher concentration could induce cold allodynia, and cold hyperalgesia mediated by TRPM8 sensitization. In addition, the paradoxical irritating properties of high concentrations of menthol is associated with its activation of transient receptor potential cation channel subfamily A member 1 (TRPA1). Under pathological situation, menthol activates TRPM8 to attenuate mechanical allodynia and thermal hyperalgesia following nerve injury or chemical stimuli. Recent reports have recapitulated the requirement of central group II/III metabotropic glutamate receptors (mGluR) with endogenous κ-opioid signaling pathways for menthol analgesia. Additionally, blockage of sodium channels and calcium influx is a determinant step after menthol exposure, suggesting the possibility of menthol for pain management. In this review, we will also discuss and summarize the advances in menthol-related drugs for pathological pain treatment in clinical trials, especially in neuropathic pain, musculoskeletal pain, cancer pain and postoperative pain, with the aim to find the promising therapeutic candidates for the resolution of pain to better manage patients with pain in clinics.

Broadband dual‐comb spectroscopy has attracted increasing interests due to its unique advantages in high spectral resolution, fast detection, and so on. Although the dual‐comb technique is relatively mature in the infrared wavelengths, it is, currently, not commercially capable of practical applications in the terahertz regime due to the lack of high‐performance broadband terahertz dual‐comb sources. In the terahertz frequency range, the electrically pumped quantum cascade laser (QCL) is a suitable candidate for the dual‐comb operation. Although the resonant microwave injection locking is widely used to broaden the emission spectra of terahertz QCLs, it is challenging to be employed to obtain broadband dual‐comb sources that can fully exploit the laser gain bandwidth due to the large phase noise induced by the resonant injection and nonideal microwave circuits. Herein, an off‐resonant microwave injection to significantly broaden the dual‐comb bandwidth of a terahertz QCL dual‐comb source is used. The measured optical dual‐comb bandwidth is broadened from 147 GHz in free running to >450 GHz under the off‐resonant injection. By performing a numerical analysis based on a rate equation model, the broadband dual‐comb operation under the off‐resonant microwave injection can result from a wider lasing bandwidth and a higher degree of phase matching.

Background: While the grading of intestinal fibrosis is closely related to the therapeutic strategy of patients with Crohn’s disease (CD), it has not yet been well resolved. Mesenteric abnormalities are inextricably linked to intestinal fibrosis. Objectives: We aimed to establish an optimal model for assessing intestinal fibrosis using computed tomography enterography (CTE) and clinical markers. Design: A total of 174 patients with CD between January 2014 and June 2020 were included in this retrospective multicentre study. Methods: All patients underwent CTE within 3 months prior to surgery. Intestinal fibrosis was pathologically scored as non-mild or moderate-to-severe. Selected imaging of the intestinal walls and mesentery and/or clinical factors were used to develop the diagnostic models. The area under the receiver operating characteristic curve (AUC) analysis was used to evaluate the discrimination performance of the models. A decision curve analysis was performed to evaluate the clinical usefulness of the models. Results: One-, two-, and three-variable models were identified as possible diagnostic models. Model 1 [mesenteric creeping fat index (MCFI)], Model 2 (mesenteric oedema and MCFI), and Model 3 (mesenteric oedema, MCFI, and disease duration) were established. The AUCs of Model 1 in training and test cohorts 1 and 2 were 0.799, 0.859, and 0.693, respectively; Model 2 was 0.851, 0.833, and 0.757, respectively; and Model 3 was 0.832, 0.821, and 0.850, respectively. We did not observe any significant difference in diagnostic performance between the training and total test cohorts in any model (all p > 0.05). The decision curves showed that Model 3 had the highest net clinical benefit in test cohort 2. The nomogram of this optimal model was constructed by considering the favourable and robust performance of Model 3. Conclusion: A nomogram integrating mesenteric abnormalities on CTE with a clinical marker was optimal for differentiating between non-mild and moderate-to-severe fibrosis in patients with CD.

Abstract Background Ankylosing spondylitis (AS) is a high-incidence disease in young men that interferes with patients’ physical and mental wellbeing and overall quality of life (QoL). It is often accompanied by arthralgia, stiffness, and limited lumbar flexibility. Acupuncture is safe and effective for reducing the symptoms of AS, but the underlying mechanisms by which it does so are not fully understood. Therefore, to objectively assess acupuncture efficacy, which is critical for patients making informed decisions about appropriate treatments, we will use shear-wave elastography (SWE) and superb microvascular imaging (SMI) ultrasound techniques to evaluate elasticity of lumbar paraspinal muscles and blood flow to the sacroiliac joint (SIJ) in AS. Methods We will recruit a total of 60 participants diagnosed with AS and 30 healthy subjects. Participants will be randomly allocated 1:1 to either an acupuncture group or a sham control acupuncture group. Primary-outcome measures will be musculoskeletal ultrasound, Ankylosing Spondylitis Quality of Life Scale (ASQoL), Bath Ankylosing Spondylitis Metrology Index (BASMI), and the Visual Analogue Scale (VAS) for pain. Secondary outcome measures will be the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Function Index (BASFI), and Fatigue Scale-14 (FS-14). We will monitor the effect of acupuncture or sham acupuncture on blood flow and SIJ inflammation using SMI, lumbar-muscle stiffness using SWE and the lumbar paraspinal-muscle cross-sectional area (CSA) using a two-dimensional (2D) grayscale imaging. QoL, physical function, and fatigue will be assessed using an evaluation scale or questionnaire developed for this study, with outcomes measured by the ASQoL, BASMI, BASDAI, BASFI, and FS-14. Healthy subjects will not receive acupuncture but undergo only musculoskeletal ultrasound at baseline. Acupuncture and sham control acupuncture interventions will be conducted for 30 min, 2–3 times/week for 12 weeks. Musculoskeletal ultrasound will be conducted at baseline and post-intervention, while other outcomes will be measured at baseline, 6 weeks, and post-intervention. The statistician, outcome assessor, and participants will be blinded to treatment allocation. Discussion The results of this single-blinded, randomized trial with sham controls could help demonstrate the efficacy of acupuncture and clarify whether musculoskeletal ultrasound could be used to evaluate AS. Trial registration ClinicalTrials.gov ChiCTR2000031476 . Registered 3 April 2020.

Abstract Long noncoding RNAs (lncRNAs) are known to play a key role in chronic myelocytic leukemia (CML) development, and we aimed to identify the involvement of the lncRNA HOX antisense intergenic RNA (HOTAIR) in CML via binding to DNA methyltransferase 1 (DNMT1) to accelerate methylation of the phosphatase and tensin homolog (PTEN) gene promoter. Bone marrow samples from CML patients and normal bone marrow samples from healthy controls were collected. HOTAIR, DNMT1, DNMT3A, DNMT3B, and PTEN expression was detected. The biological characteristics of CML cells were detected. The relationship among HOTAIR, DNMT1, and PTEN was verified. Tumor volume and weight in mice injected with CML cells were tested. We found that HOTAIR and DNMT1 expression was increased and PTEN expression was decreased in CML. We also investigated whether downregulated HOTAIR or DNMT1 reduced proliferation, colony formation, invasion, and migration and increased the apoptosis rate of CML cells. Moreover, we tested whether low expression of HOTAIR or DNMT1 reduced the volume and weight of tumors in mice with CML. Collectively, the results of this studied showed that depleted HOTAIR demonstrated reduced binding to DNMT1 to suppress CML progression, which may be related to methylation of the PTEN promoter.

Chronic pain is a common, complex and unpleasant sensation following nerve injury, tissue trauma, inflammatory diseases, infection and cancer. It affects up to 25% of adults and is increasingly recognized as the leading cause of distress, disability and disease burden globally. Chronic pain is often refractory to most current analgesics, thus emphasizing the requirement for improved therapeutic medications. It is of great importance to elucidate the specific pathogenesis of chronic pain with different etiologies. Recent progress has advanced our understanding in the contribution of neuroinflammation and glial cells (microglia and astrocyte) activation in the plasticity of excitatory nociceptive synapses and the development of chronic pain phenotypes. Oxidative stress-associated neuronal apoptosis is also identified to be a pivotal step for central pain sensitization. The family of cysteine aspartate specific proteases (Caspases) has been well known to be key signaling molecules for inflammation and apoptosis in several neurological conditions. Recent studies have highlighted the unconventional and emerging role of caspases in microgliosis, astrocytes morphogenesis, chemokines release, cytokines secretion and neuronal apoptosis in initiating and maintaining synaptogenesis, synaptic strength and signal transduction in persistent pain hypersensitivity, suggesting the possibility of targeting caspases pathway for prevention and treatment of chronic pain. In this review, we will discuss and summarize the advances in the distinctive properties of caspases family in the pathophysiology of chronic pain, especially in neuropathic pain, inflammatory pain, cancer pain and musculoskeletal pain, with the aim to find the promising therapeutic candidates for the resolution of chronic pain to better manage patients undergoing chronic pain in clinics.

Through the advancements in recent decades, childhood acute lymphoblastic leukemia (ALL) is gradually becoming a highly curable disease. However, the truth is there remaining relapse in ∼15% of ALL cases with dismal outcomes. RAS mutations, in particular NRAS mutations, were predominant mutations affecting relapse susceptibility. KRAS mutations targeting has been successfully exploited, while NRAS mutation targeting remains to be explored due to its complicated and compensatory mechanisms. Using targeted sequencing, we profiled RAS mutations in 333 primary and 18 relapsed ALL patients and examined their impact on ALL leukemogenesis, therapeutic potential, and treatment outcome. Cumulative analysis showed that RAS mutations were associated with a higher relapse incidence in children with ALL. In vitro cellular assays revealed that about one-third of the NRAS mutations significantly transformed Ba/F3 cells as measured by IL3-independent growth. Meanwhile, we applied a high-throughput drug screening method to characterize variable mutation-related candidate targeted agents and uncovered that leukemogenic-NRAS mutations might respond to MEK, autophagy, Akt, EGFR signaling, Polo−like Kinase, Src signaling, and TGF−β receptor inhibition depending on the mutation profile.

Fibrostenosis is a serious complication of Crohn’s disease (CD), affecting approximately one-half of all patients. Surgical resection is the typical clinical end due to ineffective antifibrotic therapy mainly through anti-inflammatory treatment and fibrosis can be reverted only at early stages. Mover, human fibrotic disorders is known to be associated with aging process. Thus, accurate monitoring of the progression of fibrosis is crucial for CD management as well as can be benefit to aging related fibrosis. The excessive deposition of type I collagen (ColI) is the core point in major complications of fibrosis, including that in patients with CD and aging related fibrosis. Therefore, a MR imaging probe (EP-3533) targeted ColI was employed to stage bowel fibrosis in CD using a rat model and to compare its efficiency with the common MR imaging contrast medium gadopentetatedimeglumine (Gd-DTPA). The bowel fibrotic rat model was established with different degrees of bowel fibrosis, were scanned using a 3.0-T MRI scanner with a specialized animal coil. MRI sequence including T1 mapping and T1-weighed imaging were performed before and after injecting the MRI probe (EP-3533 or Gd-DTPA). The T1 relaxation time (T1 value) and change in the contrast-to-noise ratio (ΔCNR) were measured to evaluate bowel fibrosis. Masson’s trichrome staining was performed to determine the severity of fibrosis. EP-3533 offered a better longitudinal relaxivity (r1) with 67.537 L/mmol·s, which was approximately 13 times that of Gd-DTPA. The T1 value on bowel segments was reduced in the images from EP-3533 compared to that from Gd-DTPA (F = 16.478; p < 0.001). Additionally, a better correlation between ΔCNR calculated from EP-3533 imaging and bowel fibrosis (AUC = 0.846) was determined 10 min after enhanced media administration than with Gd-DTPA (AUC = 0.532). The 10th-minute ΔCNR performed using the ColI probe showed the best correlation with the severity of bowel fibrosis (r = 0.538; p = 0.021). Our results demonstrates that targeted MRI probe (EP-3533) supplies a better enhanced effect compared to Gd-DTPA and could be a promising method to evaluate the progression and monitor the therapeutic response of bowel fibrosis.

Ge2Sb2Te5 (GST) is the typical phase change material (PCM) that can reversibly transform between the amorphous (a) and crystalline (c) states. Because the optical properties are phase-dependent, GST has been widely used in various photonic applications, such as optical switches and non-volatile memories. Currently, the photonic applications of the GST PCM have been demonstrated by employing lasers in visible and infrared wavelengths. Extending the photonic applications into other wavelengths is much demanded. Here, we investigate the phase change of the GST material illuminated by using a terahertz quantum cascade laser emitting around 2.5 THz. A finite-element simulation is employed to study the temperature and transmission changes induced by terahertz irradiation. It reveals that the phase change can be achieved and the transmission is reduced by 30% when the GST material is irradiated by the 2.5 THz laser light. Furthermore, a z-scan technique experimentally presents the phase change behaviors of GST illuminated by the terahertz light, which is visually proved by transmission electron microscopy. Our work paves a way for the applications of GST materials in the terahertz optical components, e.g., modulators and switches.

Abstract Background Medical education in China is in a transitional period, from passive learning models to experiential education. We modified an experiential education method for radiology education. The aim of this study is to evaluate the effect of this method on undergraduate radiology education. Method With the help of the picture archiving and communication system (PACS) and RadiAnt DICOM Viewer, we modified an experiential education method that simulates similar working conditions for undergraduate medical students to formulate radiology diagnosis similar to clinical radiologists. A total of 101 students were allocated into either the experiential education group or the control group. The final examination scores and a 5-point Likert scale self-assessment questionnaire of radiologic skills were collected from all the students as an objective assessment and a subjective assessment respectively. A questionnaire was also used to assess the satisfaction with the experiential model in the experiential education group. Mann-Whitney U test was used to compare the ranked data, and t-tests were used to compare the numeric data. Results The experiential education group demonstrated significantly higher scores (7.4 ± 1.3) compared to the control group (6.7 ± 1.5, p

Designing high performance THz pixelless imaging devices is nowadays challenging due to the inability to obtain normal incidence excitation using a grating coupler. Here, the authors report a broadband GaAs HIWIP-LED THz-NIR up-conversion imaging device avoiding the use of any grating coupler.

Treatment outcomes in children with acute lymphoblastic leukemia (ALL) have been improved substantially, with a cure rate exceeding 80% using conventional therapy. However, the outcome for patients with relapsed/refractory ALL remains unsatisfactory, despite the fact that these patients generally receive more intense therapy. Glucocorticoid (GC) resistance is a leading cause of treatment failure and relapse in ALL. Abnormal NR3C1 transcription and/or translation is strongly associated with GC resistance, but the underlying molecular mechanism and the clinical value of NR3C1 alterations with GC resistance in ALL treatment remain unclear. This study applied panel sequencing to 333 newly diagnosed and 18 relapsed ALL samples to characterize the link between NR3C1 and ALL further. We identified NR3C1 mutations in three patients with newly diagnosed ALL (0.9%) and two patients with relapsed ALL (11.1%). Functional analyses revealed that four of these five NR3C1 mutations (p. R477H, p. Y478C, p. P530fs, and p. H726P) were loss-of-function (LoF) mutations. A drug sensitivity test further showed that LoF NR3C1 mutations influence GC resistance. Saturated mutagenesis of hotspot R477 demonstrated the importance of this residue for NR3C1 function. The dominant-negative effect of p. R477C and p. R477S and the non-dominant negative effect of p. R477H and p. Y478C suggests multiple mechanisms underlying GC resistance. Thus, primary or acquired genomic lesions in NR3C1 may play a critical role in GC resistance and contribute to ALL treatment failure and/or relapse.

Background: Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, with an overall prevalence of 4/100,000, accounting for 25–30% of all childhood cancers. With advances in childhood ALL treatment, the cure rate for childhood ALL has exceeded 80% in most countries. However, refractory/relapsed ALL remains a leading cause of treatment failure and subsequent death. Forkhead box O1 (FOXO1) belongs to the forkhead family of transcription factors, but its role in B-cell ALL (B-ALL) has not been determined yet.Procedures: RNA sequencing was applied to an ALL case with induction failure (IF) to identify the possible genetic events. A cytokine-dependent growth assay in Ba/F3 cells was used to test the leukemic transformation capacity of MEIS1–FOXO1. The propidium iodide (PI) staining method was used to evaluate the effect of MEIS1–FOXO1 on cycle distribution. FOXO1 transactivity was examined using a luciferase reporter assay. FOXO1 mRNA expression levels were examined using real-time quantitative PCR among 40 children with B-ALL treated with the CCCG-ALL-2015 protocol. Association analysis was performed to test the correlation of FOXO1 transcription with childhood B-ALL prognosis and relapse in a series of GEO datasets. An MTT assay was performed to test the drug sensitivity.Results: In this ALL case with IF, we identified a novel MEIS1–FOXO1 fusion gene. The transactivity of MEIS1–FOXO1 was significantly lower than that of wild-type FOXO1. MEIS1–FOXO1 potentiated leukemia transformation and promoted Ba/F3 cell cycle S-phase entry. Low FOXO1 transcription levels were found to be strongly associated with unfavorable ALL subtype, minimal residual disease (MRD) positivity, and relapse. Lower FOXO1 expression was associated with prednisone and cyclophosphamide resistance.Conclusions: Low FOXO1 transcription was associated with high-risk stratification and relapse in children with B-ALL, probably due to multi-drug resistance.

In this study, we investigated the utility of native T1 mapping in differentiating between various grades of fibrosis and compared its diagnostic accuracy to magnetization transfer imaging (MTI) in a rat model of CD. Bowel specimens (64) from 46 CD model rats undergoing native T1 mapping and MTI were enrolled. The longitudinal relaxation time (T1 value) and normalized magnetization transfer ratio (MTR) were compared between none-to-mild and moderate-to-severe fibrotic bowel walls confirmed by pathological assessments. The results showed that the correlation between the T1 value and fibrosis (r = 0.438, p < 0.001) was lower than that between the normalized MTR and fibrosis (r = 0.623, p < 0.001). Overall, the T1 values (t = −3.066, p = 0.004) and normalized MTRs (z = 0.081, p < 0.001) in none-to-mild fibrotic bowel walls were lower than those in moderate-to-severe fibrotic bowel walls. The area under the curve (AUC) of the T1 value (AUC = 0.716, p = 0.004) was significantly lower than that of the normalized MTR (AUC = 0.881, p < 0.001) in differentiating moderate-to-severe fibrosis from none-to-mild fibrosis (z = −2.037, p = 0.042). Our results support the view that the T1 value could be a promising imaging biomarker in grading the fibrosis severity of CD. However, the diagnostic performance of native T1 mapping was not superior to MTI.

Abstract Optical frequency combs, consisting of well‐controlled equidistant frequency lines, have been widely used in precision spectroscopy and metrology. Terahertz combs have been realized in quantum cascade lasers (QCLs) by employing either an active mode‐locking or phase seeding technique, or a dispersion compensator mirror. However, it remains a challenge to achieve the passive comb formation in terahertz semiconductor lasers due to the insufficient nonlinearities of conventional saturable absorbers. Here, a passive terahertz frequency comb is demonstrated by coupling a multilayer graphene sample into a QCL compound cavity. The terahertz modes are self‐stabilized with intermode beat note linewidths down to a record of 700 Hz and the comb operation of graphene‐coupled QCLs is validated by on‐chip dual‐comb measurements. Furthermore, the optical pulse emitted from the graphene‐coupled QCL is directly measured employing a terahertz pump–probe technique. The enhanced passive frequency comb operation is attributed to the saturable absorption behavior of the graphene‐integrated saturable absorber mirror, as well as the dispersion compensation introduced by the graphene sample. The results provide a conceptually different graphene‐based approach for passive comb formation in terahertz QCLs, opening up intriguing opportunities for fast and high‐precision terahertz spectroscopy and nonlinear photonics.

Limited data exists in China on the comparative cost of gadolinium ethoxybenzyl diethylenetriamine magnetic resonance imaging (Gd-EOB-DTPA-MRI) with other imaging techniques. This study compared the total cost of Gd-EOB-DTPA-MRI with multidetector computed tomography (MDCT) and extracellular contrast media-enhanced MRI (ECCM-MRI) as initial imaging procedures in patients with suspected hepatocellular carcinoma (HCC). We developed a decision-tree model on the basis of the Chinese clinical guidelines for HCC, which was validated by clinical experts from China. The model compared the diagnostic accuracy and costs of alternative initial imaging procedures. Compared with MDCT and ECCM-MRI, Gd-EOB-DTPA-MRI imaging was associated with higher rates of diagnostic accuracy, i.e. higher proportions of true positives (TP) and true negatives (TN) with lower false positives (FP). Total diagnosis and treatment cost per patient after the initial Gd-EOB-DTPA-MRI evaluation was similar to MDCT (¥30,360 vs. ¥30,803) and lower than that reported with ECCM-MRI (¥30,360 vs. ¥31,465). Lower treatment cost after initial Gd-EOB-DTPA-MRI was driven by reduced utilization of confirmatory diagnostic procedures and unnecessary treatments. The findings reported that Gd-EOB-DTPA-MRI offered higher diagnostic accuracy compared with MDCT and ECCM-MRI at a comparable cost, which indicates Gd-EOB-DTPA-MRI could be the preferred initial imaging procedure for the diagnosis of HCC in China.

Objective. This study aims to establish a model to analyze clinical experience of TCM veteran doctors. We propose an ensemble learning based framework to analyze clinical records with ICD-10 labels information for effective diagnosis and acupoints recommendation. Methods. We propose an ensemble learning framework for the analysis task. A set of base learners composed of decision tree (DT) and support vector machine (SVM) are trained by bootstrapping the training dataset. The base learners are sorted by accuracy and diversity through nondominated sort (NDS) algorithm and combined through a deep ensemble learning strategy. Results. We evaluate the proposed method with comparison to two currently successful methods on a clinical diagnosis dataset with manually labeled ICD-10 information. ICD-10 label annotation and acupoints recommendation are evaluated for three methods. The proposed method achieves an accuracy rate of 88.2% ± 2.8% measured by zero-one loss for the first evaluation session and 79.6% ± 3.6% measured by Hamming loss, which are superior to the other two methods. Conclusion. The proposed ensemble model can effectively model the implied knowledge and experience in historic clinical data records. The computational cost of training a set of base learners is relatively low.