FLT3-selective PROTAC: Enhanced safety and increased synergy with Venetoclax in FLT3-ITD mutated acute myeloid leukemia.

Acute myeloid leukemia (AML) patients carrying Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations often face a poor prognosis. While some FLT3 inhibitors have been used clinically, challenges such as short efficacy and poor specificity persist. Proteolytic targeting chimera (PROTAC), with its lower ligand affinity requirement for target proteins, offers higher and rapid targeting capability. Gilteritinib, used as the ligand for the target protein, was connected with different E3 ligase ligands to synthesize several series of PROTAC targeting FLT3-ITD. Through screening and structural optimization, the optimal lead compound PROTAC Z29 showed better specificity than Gilteritinib. Z29 induced FLT3 degradation through the proteasome pathway and inhibited tumor growth in subcutaneous xenograft mice. We verified Z29's minimal impact on platelets in a patient-derived xenografts (PDX) model compared to Gilteritinib. The combination of Z29 and Venetoclax showed better anti-tumor effects, lower platelet toxicity, and lower hepatic toxicity in FLT3-ITD+ models. The FLT3-selective PROTAC can mitigate the platelet toxicity of small molecule inhibitors, ensuring safety and efficacy in monotherapy and combination therapy with Venetoclax. It is a promising strategy for FLT3-ITD+ patients, especially those with platelet deficiency or liver damage.

Application value of metagenomic next-generation sequencing in hematological patients with high-risk febrile neutropenia.

Background: Metagenomic next-generation sequencing (mNGS) is a novel non-invasive and comprehensive technique for etiological diagnosis of infectious diseases. However, its practical significance has been seldom reported in the context of hematological patients with high-risk febrile neutropenia, a unique patient group characterized by neutropenia and compromised immune responses. Methods: This retrospective study evaluated the results of plasma cfDNA sequencing in 164 hematological patients with high-risk febrile neutropenia. We assessed the diagnostic efficacy and clinical impact of mNGS, comparing it with conventional microbiological tests. Results: mNGS identified 68 different pathogens in 111 patients, whereas conventional methods detected only 17 pathogen types in 36 patients. mNGS exhibited a significantly higher positive detection rate than conventional methods (67.7% vs. 22.0%, P < 0.001). This improvement was consistent across bacterial (30.5% vs. 9.1%), fungal (19.5% vs. 4.3%), and viral (37.2% vs. 9.1%) infections (P < 0.001 for all comparisons). The anti-infective treatment strategies were adjusted for 51.2% (84/164) of the patients based on the mNGS results. Conclusions: mNGS of plasma cfDNA offers substantial promise for the early detection of pathogens and the timely optimization of anti-infective therapies in hematological patients with high-risk febrile neutropenia.

XA21-mediated resistance to Xanthomonas oryzae pv. oryzae is dose dependent.

The rice receptor kinase XA21 confers broad-spectrum resistance to Xanthomonas oryzae pv. oryzae (Xoo), the causal agent of rice bacterial blight disease. To investigate the relationship between the expression level of XA21 and resulting resistance, we generated independent HA-XA21 transgenic rice lines accumulating the XA21 immune receptor fused with an HA epitope tag. Whole-genome sequence analysis identified the T-DNA insertion sites in sixteen independent T0 events. Through quantification of the HA-XA21 protein and assessment of the resistance to Xoo strain PXO99 in six independent transgenic lines, we observed that XA21-mediated resistance is dose dependent. In contrast, based on the four agronomic traits quantified in these experiments, yield is unlikely to be affected by the expression level of HA-XA21. These findings extend our knowledge of XA21-mediated defense and contribute to the growing number of well-defined genomic landing pads in the rice genome that can be targeted for gene insertion without compromising yield.

Extracellular histones promote TWIK2-dependent potassium efflux and associated NLRP3 activation in alveolar macrophages during sepsis-induced lung injury.

BACKGROUND AND AIM: Sepsis-induced acute lung injury (ALI) is a complex and life-threatening condition lacking specific and efficient clinical treatments. Extracellular histones, identified as a novel type of damage-associated molecular patterns, have been implicated in the inflammatory process of ALI. However, further elucidation is needed regarding the precise mechanism through which extracellular histones induce inflammation. The aim of this study was to investigate whether extracellular histones can activate NLRP3 inflammasome-mediated inflammation in alveolar macrophages (AMs) by affecting TWIK2-dependent potassium efflux. METHODS AND RESULTS: We conducted experiments using cecal ligation and puncture (CLP) C57BL/6 mice and extracellular histone-stimulated LPS-primed MH-S cells. The results demonstrated a significant increase in the levels of extracellular histones in the plasma and bronchoalveolar lavage fluid (BALF) of CLP mice. Furthermore, neutralizing extracellular histone mitigated lung injury and inflammation in CLP-induced ALI mice. In vitro studies confirmed that extracellular histones upregulated the expression of NLRP3 inflammasome activation-related proteins in MH-S cells, and this effect was dependent on increased potassium efflux mediated by the TWIK2 channel on the plasma membrane. Moreover, extracellular histones directly triggered a substantial influx of calcium, leading to increased Rab11 activity and facilitating the trafficking and location of TWIK2 to the plasma membrane. CONCLUSION: These findings underscore the critical role of extracellular histone-induced upregulation of TWIK2 expression on the plasma membrane of alveolar macrophages (AMs). This upregulation leads to potassium efflux and subsequent activation of the NLRP3 inflammasome, ultimately exacerbating lung inflammation and injury during sepsis.

The clinical characteristics of cerebral small vessel disease patients with motoric cognitive risk syndrome during single- and dual-task walking.

Objective: We aimed to (1) identify neuroimaging biomarkers of distinguishing motoric cognitive risk syndrome (MCRS) risk among older Chinese adults with cerebral small vessel disease (CSVD) and (2) detect differences in gait parameters and neuroimaging biomarkers between CSVD individual with and without MCRS, especially during dual-task walking (DTW). Methods: We enrolled 126 inpatients with CSVD who were divided into two groups according to MCRS status. Data on basic parameters, variability, asymmetry, and coordination were collected during single-task walking (STW) and DTW. Neuroimaging features (white matter hyperintensities, lacunes, and microbleeds) and total disease burden were calculated. Analysis of variance and logistic regression analyses were applied to assess the role of STW, DTW, and neuroimaging biomarkers in MCRS. Results: In total, 126 consecutive inpatients with CSVD were included (84 and 42 patients were classified as MCRS-negative and MCRS-positive, respectively). The MCRS-positive group showed poorer performance for nearly all gait parameters compared with the MCRS-negative group during cognitive DTW. Meanwhile, all gait parameters except asymmetry were assessed in participants with MCRS for significant deterioration during cognitive DTW compared with that during STW. However, only basic parameters differed between STW and cognitive DTW in participants without MCRS. A significant independent association between total CSVD scores and MCRS was also detected. Conclusions: For CSVD patients, with higher total CSVD burden rather than any single neuroimaging marker, was linked to a greater risk of MCRS. In addition, CSVD individuals with MCRS had higher variability and phase coordination index (PCI), especially in cognitive DTW. Thus, they should concentrate more on their gait variability or coordination and reduce secondary task loads while walking in daily life, especially in cognitive secondary tasks.

Chemical proteomic profiling of protein dopaminylation in colorectal cancer cells.

Histone dopaminylation is a newly identified epigenetic mark that plays a role in the regulation of gene transcription, where an isopeptide bond is formed between the fifth amino acid residue of H3 ( i.e. , glutamine) and dopamine. In our previous studies, we discovered that the dynamics of this post-translational modification (including installation, removal, and replacement) were regulated by a single enzyme, transglutaminase 2 (TGM2), through reversible transamination. Recently, we developed a chemical probe to specifically label and enrich histone dopaminylation via bioorthogonal chemistry. Given this powerful tool, we found that histone H3 glutamine 5 dopaminylation (H3Q5dop) was highly enriched in colorectal tumors, which could be attributed to the high expression level of TGM2 in colon cancer cells. Due to the enzyme promiscuity of TGM2, non-histone proteins have also been identified as targets of dopaminylation on glutamine residues, however, the dopaminylated proteome in cancer cells still remains elusive. Here, we utilized our chemical probe to enrich dopaminylated proteins from colorectal cancer cells in a bioorthogonal manner and performed the chemical proteomics analysis. Therefore, 425 dopaminylated proteins were identified, many of which are involved in nucleic acid metabolism and transcription pathways. More importantly, a number of modification sites of these dopaminylated proteins were identified, attributed to the successful application of our chemical probe. Overall, these findings shed light on the significant association between cellular protein dopaminylation and cancer development, further suggesting that to block the installation of protein dopaminylation may become a promising anti-cancer strategy.

Effectiveness of the varicella vaccine in the real world, a matched case-control study.

BACKGROUND: Universal varicella vaccination has been introduced in many countries, but there are a number of important differences in their vaccination strategies. It is essential to establish a vaccination program that can maximize the benefits of varicella vaccine, but there is a lack of comprehensive research on the effectiveness of varicella vaccine in different vaccination status. METHODS: Using data from population-based surveillance platforms we conducted a 1:2 matched case-control study. The cases were clinically diagnosed varicella with onset from 2017 to 2021, 1-14 years old in Chaoyang District, Beijing. The controls were matched according to date of birth (±1 month), sex and residence. The vaccination data of the subjects were obtained from the Childhood Immunization Information Management System in Beijing. Using conditional logistic regression models with or without interaction terms, we evaluated the effectiveness of varicella vaccine in different vaccination status. RESULTS: A total of 2528 cases and 5056 controls were enrolled. This study found that whether the time since last vaccination was adjusted had a substantial effect on the comparing vaccine effectiveness (VE) between subgroups. After adjustment for the time since last vaccination, 1) the incremental VE of 2-dose was 49.6 % (95 % Confidence Interval [CI], 38.8-58.6) compared with 1-dose (93.9 % vs. 88.0 %); 2) Among children who received one dose, the risk of chickenpox in children vaccinated at 18-23 months was 1.382 (95 %CI, 1.084-1.762) times that in children vaccinated at 12-17 months. 3) the VE with less than one, two, and three year intervals is higher than that with six-year-intervals (P < 0.05), respectively. CONCLUSIONS: When comparing VE between subgroups of different vaccination status, the time since last vaccination should be adjusted. The first dose of varicella vaccine should be given as early as the second year of life, and the second dose can improve vaccine effectiveness.

The efficacy of immune checkpoint inhibitors on low PD-L1 cervical cancer: A meta-analysis.

Background and Aims: The effectiveness of immune checkpoint inhibitors (ICIs) in low programmed death ligand 1 (PD-L1) expression in cervical cancer (CC) patients remains unknown. We aimed to evaluate the efficacy of ICIs in low PD-L1 expression CC patients. Methods: The study is an individual patient data (IPD)-based meta-analysis. IPD were compiled through KMSubtraction and IPDfromKM methodologies from high-quality randomized clinical trials and single-arm studies which reported overall survival (OS) or progression-free survival (PFS) stratified by PD-L1 expression. Kaplan-Meier curves and Cox regression analysis were employed to evaluate the survival benefits of ICIs. Results: A total of eight studies and 1110 cases were included in the analysis. Within the low PD-L1 expression subgroup, ICI combination therapy, but not ICI monotherapy, demonstrated significant OS benefits over non-ICI treatment (hazard ratio [HR] = 0.61, 95% confidence interval [CI]: 0.36-1.04, p = 0.06). Concerning PFS, ICI monotherapy was associated with a negative effect compared to non-ICI treatment (HR = 4.59, 95% CI: 2.32-9.07, p < 0.001). Notably, both OS and PFS outcomes were unfavorable for ICI monotherapy compared to both non-ICI and ICI combination therapy in the combined positive score <1 subgroup (OS: HR = 2.60, 95% CI: 1.31-5.16, p = 0.008; PFS: HR = 7.59, 95% CI: 3.53-16.31, p < 0.001). Conclusion: In patients with CC and low PD-L1 expression, ICI monotherapy may not be considered as the optimal treatment strategy when compared to non-ICI treatment or ICI combination therapy. Registration: CRD42023395103.

Acceptance model of new energy vehicles based on PLS-SEM model.

The current energy crisis is worsening worldwide, and in China, urban expansion and per capita vehicle ownership have created a growing energy imbalance and increased pressure to reduce carbon emissions.The popularization of new energy vehicles (NEVs) can provide a step forward to solving energy shortage problems, environmental pollution, and global warming. In 2022, the average penetration rate, which is ratio of new energy vehicle sales to vehicle sales, is just 19.1 %. This paper analysed the reasons for the differences in the penetration rates of new energy vehicles in China's 269 prefecture-level cities, using a Geo Detector approach, and the results showed that the level of economic development, the average annual temperature difference, the density of charging piles, the charging price and the number of population all had significant effects(q＞0.12) on the penetration rate. Based on the above studies, a questionnaire was used to investigate the public's acceptance of new energy vehicles in Xinjiang Uygur Autonomous Region, and a PLS-SEM regression analysis was conducted. The results showed that men, young people and people with a certain level of basic education were 5 % more likely to accept new energy vehicles.Unlike previous studies, perceived cost had no significant correlation with the acceptance of new energy vehicles. Perceived risk had a significant negative correlation with the acceptance of new energy vehicles,the path coefficient is -0.1.The acceptance of new energy vehicles was significantly and positively correlated with vehicle quality and service, the public's understanding of new energy vehicles, and subjective norms, their average path coefficients are above 0.1. We argues that the government should maintain a certain level of promotion of new energy vehicles and accelerate the construction of charging piles, based on the aforementioned results.

Carbon nanotubes integrated photonic barcodes in Herringbone Microfluidics for Multiplex Biomarker Quantification.

Early monitoring of cardiovascular disease (CVD) is crucial for its treatment and prognosis. Hence, highly specific and sensitive detection method is urgently needed. In this study, we propose a novel herringbone microfluid chip with aptamer functionalized core-shell photonic crystal (PhC) barcode integration for high throughput multiplex CVD detection. Based on the PhC derived from co-assembled carboxylated single-wall carbon nanotubes and silicon dioxide nanoparticles, we obtain core-shell PhC barcodes by hydrogel replicating and partially etching. These core-shell PhC barcodes not only retain the original structural colors coding element, but also fully expose a large number of carboxyl elements in the ore for the probe immobilization. We further combine the functionalized barcodes with herringbone groove microfluidic chip to elucidate its acceptability in testing clinical sample. It is demonstrated that the special design of microfluidic chip can significantly enhance fluid vortex resistance and contact frequency, improving the sample capture efficiency and detection sensitivity. These features indicate that our core-shell PhC barcodes-integrated herringbone microfluidic system possesses great potential for multiplex biomarker detection in clinical application.

First Report of Pseudopestalotiopsis ixorae Causing Leaf Spot of Photinia × fraseri in China.

Photinia × fraseri is a well-known ornamental shrub in southern China. In December 2021, we observed leaf spots that were circular to irregular, gray with dark red margins and violet brown with brownish violet edges on the leaves of Photinia × fraseri shrubs in the scenic area of Shenlongtan (28°46'10″N, 115°42'93″E), Jiangxi Province, China. Almost 15% of the leaves in the 1300 m2 Photinia × fraseri planting area were symptomatic. Thirty symptomatic leaves were randomly collected from different plants, and sectioned into 5-mm2 pieces, which were surface-sterilized using 1% NaOCl for 30 s. After rinsing thrice in sterile distilled water and drying, the pieces were transferred onto potato dextrose agar (PDA) and incubated at 28 ℃ for 5-7 days. A total of sixteen morphologically similar isolates were obtained. After incubation on PDA for 20 days, the fungi had irregular edges, were white to pale brown, and had spare aerial mycelium on the surface with irregularly distributed black, gregarious conidiomata. Conidia were fusoid, subcylindrical, straight to slightly curved, 4-septated, slightly constricted at the septa, and 23 to 36 × 6 to 10 µm (mean: 27.6 × 7.7 µm). The morphological characteristics were consistent with the features of Pseudopestalotiopsis species (Maharachchikumbura et al. 2014). The genomic DNA of two representative isolates (JFRL032 and JFRL033) was extracted for further identification. The internal transcribed spacer (ITS) region, translation elongation factor 1-ɑ (tef1-ɑ) and ß-tubulin (tub2) genes were amplified and sequenced using primers ITS5/ITS4, EF1-526F/EF1-1567R, and Bt2A/Bt2B, respectively (Maharachchikumbura et al. 2012). The sequences of the two representative isolates were 100% identical to each other. These nucleotide sequences were deposited in GenBank with accession numbers, ON342794 and ON342795 (ITS); ON375851 and ON375852 (tef1-ɑ); ON375853 and ON375854 (tub2). BLASTn searches of the obtained sequences revealed 99%-100% to ITS (MG816316, 478/478 nucleotides), tef1-ɑ (MG816336, 924/926 nucleotides), tub2 (MG816326, 441/442 nucleotides) sequences of the ex-type strain of Pseudopestalotiopsis ixorae (NTUCC17-001.1). Phylogenetic analysis was conducted using the concatenation of multiple sequences (ITS, tef1-ɑ and tub2) with the Maximum likelihood statistics in PhyloSuite v1.2.2 (Zhang et al.2020). The phylogenetic tree showed the two isolates clustered with P. ixorae in a clade with 100% bootstrap support. The isolates were identified as P. ixorae based on morphological and molecular data. To confirm pathogenicity, eight healthy leaves of 3-year-old Photinia × fraseri were surface sterilized, scratched with a pair of sterilized tweezers, and ten µl of conidial suspension (106 conidia/ml) was sprayed on the injured leaves and the control was sprayed with sterile distilled water. Then, All plants were potted in a climate chamber at 25℃ and 85% relative humidity. After 3 days, leaf spot symptoms similar to those described above were observed on inoculated leaves, while the non-inoculated leaves remained symptomless. The pathogen was reisolated from the inoculated leaves to fulfill Koch's postulates and confirmed as P. ixorae by morphological and molecular analysis. It has been reported that P. ixorae can infect the Ixora plant (Tsai et al., 2018). To the best of our knowledge, this is the first report of P. ixorae causing leaf spot on Photinia × fraseri in China. The study provides valuable information for identifying and controlling the leaf spot on Photinia × fraseri.

Differential Gene Analysis of Langerhans Cell Histiocytosis and the Significance of MMP1-Targeted Drug Repositioning.

Langerhans cell histiocytosis (LCH) is a rare condition predominantly affecting young children. Activation of the MAPK pathway has offered key new insights into the pathogenesis of LCH; however, the precise mechanisms underlying its occurrence and development are still far from being completely elucidated. There is still a relapse/reactivation rate in patients with multisystem LCH. Therefore, this study aimed to investigate other potential LCH pathophysiologies and prospective therapeutic targets. The gene expression omnibus (GEO) database was used to retrieve gene expression profiles of LCH (GSE16395). Three distinct types of analyses were performed after identifying the common differentially expressed genes (DEGs) in LCH: hub gene identification, functional annotation, module construction, drug repositioning, and expression analysis via immunohistochemistry (IHC). We identified 417 common DEGs and 50 central hub genes. This functional study highlighted the significance of keratinization, skin development, and inflammation. In addition, we predicted new drug candidates (RS2 drugs targeting matrix metalloprotease1, MMP1) that could be used for LCH treatment. Finally, gene-miRNA and gene-TF networks and immune cell infiltration were analyzed for MMP1-related genes. MMP1 expression levels in LCH tissues were validated by IHC. Our study identified the central communal genes and novel drug candidates. These shared pathways and hub genes offer new perspectives on future mechanisms of action and therapeutic targets.

Inflammasome-related gene signatures as prognostic biomarkers in osteosarcoma.

Osteosarcoma, the primary bone cancer in adolescents and young adults, is notorious for its aggressive growth and metastatic potential. Our study delved into the prognostic impact of inflammasome-related gene signatures in osteosarcoma patients, employing comprehensive genetic profiling to uncover signatures linked with patient outcomes. We identified three patient subgroups through consensus clustering, with one showing worse survival rates correlated with high FGFR3 and RARB expressions. Immune profiling revealed significant immune cell infiltration differences among these subgroups, affecting survival. Utilising advanced machine learning, including StepCox and gradient boosting machine algorithms, we developed a prognostic model with a notable c-index of 0.706, highlighting CD36 and MYD88 as key genes. Higher inflammasome risk scores from our model were associated with poorer survival, corroborated across datasets. In vitro experiments validated CD36 and MYD88's roles in promoting osteosarcoma cell proliferation, invasion and migration, emphasising their therapeutic potential. This research offers new insights into inflammasomes' role in osteosarcoma, introducing novel biomarkers for risk assessment and potential therapeutic targets. Our findings suggest a pathway towards personalised treatment strategies, potentially improving patient outcomes in osteosarcoma.

TLR9 promotes monocytic myeloid-derived suppressor cell induction during JEV infection.

Myeloid-derived suppressor cells (MDSCs) are a group of heterologous populations of immature bone marrow cells consisting of progenitor cells of macrophages, dendritic cells and granulocytes. Recent studies have revealed that the accumulation of MDSCs in the mouse spleen plays a pivotal role in suppressing the immune response following JEV infection. However, the mechanisms by which JEV induces MDSCs are poorly understood. Here, it was found that JEV infection induces mitochondrial damage and the release of mitochondrial DNA (mtDNA), which further leads to the activation of TLR9. TLR9 deficiency decreases the M-MDSCs population and their suppressive function both in vitro and in vivo. Moreover, the increase of MHCⅡ expression on antigen-presenting cells and CD28 expression on T cells in TLR9-/- mice was positively correlated with M-MDSCs reduction. Accordingly, the survival rate of TLR9-/- mice dramatically increased after JEV infection. These findings reveal the connections of mitochondrial damage and TLR9 activation to the induction of M-MDSCs during JEV infection.

Prevalence trends of anemia impairment in adolescents and young adults with HIV/AIDS.

BACKGROUND: Anemia is a common complication of HIV/AIDS, particularly in adolescents and young adults across various countries and regions. However, little is known about the changing prevalence trends of anemia impairment in this population over time. METHODS: Data on anemia in adolescents and young adults with HIV/AIDS from 1990 to 2019 were collected from the Global Burden of Disease. Prevalence was calculated by gender, region, and country for individuals aged 10-24, and trends were measured using estimating annual percentage changes (EAPC). RESULTS: Globally, the prevalence of adolescents and young adults with HIV/AIDS increased from 103.95 per 100,000 population in 1990 to 203.78 in 2019. However, anemia impairment has decreased over the past three decades, with a global percentage decreasing from 70.6% in 1990 to 34.7% in 2019, mainly presenting as mild to moderate anemia and significantly higher in females than males. The largest decreases were observed in Central Sub-Saharan Africa, North America, and Eastern Sub-Saharan Africa, with EAPCs of -2.8, -2.34, and -2.17, respectively. Tajikistan (78.76%) and Madagascar (74.65%) had the highest anemia impairment percentage in 2019, while China (16.61%) and Iceland (13.73%) had the lowest. Anemia impairment was closely related to sociodemographic index (SDI) levels, with a high proportion of impairment in low SDI regions but a stable decreasing trend (EAPC = -0.37). CONCLUSION: Continued anemia monitoring and management are crucial for patients with HIV, especially in high-prevalence regions and among females. Public health policies and interventions can improve the quality of life and reduce morbidity and mortality.

Triune Nanomodulator Enables Exhausted Cytotoxic T Lymphocyte Rejuvenation for Cancer Epigenetic Immunotherapy.

Oncogene activation and epigenome dysregulation drive tumor initiation and progression, contributing to tumor immune evasion and compromising the clinical response to immunotherapy. Epigenetic immunotherapy represents a promising paradigm in conquering cancer immunosuppression, whereas few relevant drug combination and delivery strategies emerge in the clinic. This study presents a well-designed triune nanomodulator, termed ROCA, which demonstrates robust capabilities in tumor epigenetic modulation and immune microenvironment reprogramming for cancer epigenetic immunotherapy. The nanomodulator is engineered from a nanoscale framework with epigenetic modulation and cascaded catalytic activity, which self-assembles into a nanoaggregate with tumor targeting polypeptide decoration that enables loading of the immunogenic cell death (ICD)-inducing agent. The nanomodulator releases active factors specifically triggered in the tumor microenvironment, represses oncogene expression, and initiates the type 1 T helper (TH1) cell chemokine axis by reversing DNA hypermethylation. This process, together with ICD induction, fundamentally reprograms the tumor microenvironment and significantly enhances the rejuvenation of exhausted cytotoxic T lymphocytes (CTLs, CD8+ T cells), which synergizes with the anti-PD-L1 immune checkpoint blockade and results in a boosted antitumor immune response. Furthermore, this strategy establishes long-term immune memory and effectively prevents orthotopic colon cancer relapse. Therefore, the nanomodulator holds promise as a standalone epigenetic immunotherapy agent or as part of a combination therapy with immune checkpoint inhibitors in preclinical cancer models, broadening the array of combinatorial strategies in cancer immunotherapy.

Incremental Prognostic Value of Left Atrial Strain in Patients With Suspected Myocarditis and Preserved Left Ventricular Ejection Fraction.

BACKGROUND: Analysis of left atrial (LA) strain and left atrioventricular coupling index (LACI) have prognostic value in cardiovascular diseases. However, the prognostic value of LA strain and LACI in patients with suspected myocarditis and preserved left ventricular ejection fraction (LVEF) is unclear. PURPOSE: To investigate the prognostic value of LA strain and LACI in patients with suspected myocarditis and preserved LVEF in comparison with conventional MRI outcome predictors. STUDY TYPE: Retrospective. POPULATION: One hundred sixty-five patients with clinically suspected myocarditis and preserved LVEF with available follow-up data. FIELD STRENGTH/SEQUENCE: Steady-state free precession cine and phase-sensitive inversion recovery segmented gradient echo late gadolinium enhancement sequences at 3.0 T. ASSESSMENT: Left ventricular (LV) and LA strain were evaluated using feature tracking. LACI was calculated as the ratio of LA and LV volumes at LV end-diastole. Patients were followed-up with the primary endpoint being major adverse cardiovascular events (MACE). STATISTICAL TESTS: Independent-samples t-test and Mann-Whitney U test to compare patients with and without MACE, receiver operating characteristic (ROC) curve analysis to define high/low risk groups, Kaplan-Meier survival analysis and Cox proportional hazards regression to assess prognosis. A P value of <0.05 was considered statistically significant. RESULTS: The associations of LV strain parameters (including global radial, circumferential, and longitudinal strain) and LACI with MACE were not significant (P = 0.511, 0.108, 0.148, and 0.847, respectively). An optimal LA conduit strain (Ԑe) cutoff value of 10.4% was identified to best classify patients into low- and high-risk groups. Only Ԑe was significantly associated with MACE in both univariable (hazards ratio [HR] 0.936, 95% confidence interval [CI] 0.884-0.991) and multivariable Cox survival analyses (HR 0.937, 95% CI 0.884-0.994). DATA CONCLUSION: LA conduit strain has prognostic value in patients with suspected myocarditis and preserved LVEF, incremental to conventional MRI outcome predictors, whereas LACI was not associated with MACE occurrence. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

A stacked transmembrane electro-chemisorption system connected by hydrophobic gas permeable membranes for on-site utilization of authigenic acid and base to enhance ammonia recovery from wastewater.

The ammonia recovery from wastewater via electrochemical technologies represents a promising way for wastewater treatment, resource recovery, and carbon emissions reduction. However, chemicals consumption and reactors scalability of the existing electrochemical systems have become the key challenges for their development and application. In this study, a stacked transmembrane electro-chemisorption (sTMECS) system was developed to utilize authigenic acid and base on site for enhancing ammonia recovery from wastewater. The easily scaled up system was achieved via innovatively connecting the cathode chamber in a unit with the anode chamber in the adjacent unit by a hydrophobic gas permeable membrane (GPM). Thus, authigenic base at cathodes and authigenic acid at anodes could be utilized as stripper and absorbent on site to enhance the transmembrane chemisorption of ammonia. Continuous power supply, reducing the distances of electrodes to GPM and moderate aeration of the catholyte could promote ammonia recovery. Applied to the ammonia recovery from the simulated urine, the sTMECS under the current density 62.5 A/cm2 with a catholyte aeration rate of 3.2 L/(L⋅min) for operation time 4 h showed the transmembrane ammonia flux of 26.00 g N/(m2·h) and the system energy consumption of 10.5 kWh/kg N. Accordingly, the developed sTMECS system with chemicals saving, easy scale-up and excellent performance shows good prospects in recovering ammonia from wastewater.

Obstetrical and neonatal outcomes after vitrified-warmed blastocyst transfer in day 1 rescue intracytoplasmic sperm injection cycles: a retrospective cohort study.

BACKGROUND: Fertilization failure often occurs in conventional IVF cycles, and day 1 rescue ICSI is frequently recommended. In this study, the effect of rescue ICSI on obstetrical and neonatal outcomes after a single blastocyst transfer in vitrified-warmed cycles is evaluated. METHODS: This cohort study was a retrospective analysis of 703 vitrified-warmed single blastocyst transfers and 219 singletons in the r-ICSI group compared with 11,611 vitrified-warmed single blastocyst transfers in the IVF/ICSI and 4472 singletons in the IVF/ICSI group, respectively, and patients just undergoing their first IVF treatments were included in this study. Pregnancy rate (PR), live birth rate (LBR), and singleton birthweight were the primary outcome measures. Multiple linear regression analysis and logistic regression analysis were performed to evaluate the possible relationship between obstetrical and neonatal outcomes and fertilization method (including IVF, ICSI, and r-ICSI) after adjusting for other potential confounding factors. RESULTS: PR and the LBR were lower in the r-ICSI group compared with the IVF/ ICSI group. Singletons from the r-ICSI group had a higher Z-score and the proportion of large for gestational age (LGA) newborns was greater compared with singletons from the IVF/ICSI group. CONCLUSION: The results of the study indicated that a 31% LBR after r-ICSI is acceptable for vitrified-warmed blastocyst transfer, but the safety of transfer is a concern because of the lower PR and LBR compared with IVF/ICSI. The safety of r-ICSI newborns is also a concern because of the significantly higher birthweight and the proportion of LGA in r-ICSI group newborns compared with the IVF/ICSI group.

Genetic Screening of Patients with Sporadic Alzheimer's Disease and Frontotemporal Lobar Degeneration in the Chinese Population.

Background: Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) account for the vast majority of neurodegenerative dementias. AD and FTLD have different clinical phenotypes with a genetic overlap between them and other dementias. Objective: This study aimed to identify the genetic spectrum of sporadic AD and FTLD in the Chinese population. Methods: A total of 74 sporadic AD and 29 sporadic FTLD participants were recruited. All participants underwent whole-exome sequencing (WES) and testing for a hexanucleotide expansion in C9orf72 was additionally performed for participants with negative WES results. Results: Four known pathogenic or likely pathogenic variants, including PSEN1 (p.G206D), MAPT (p.R5H), LRRK2 (p.W1434*), and CFAP43 (p.C934*), were identified in AD participants, and 1 novel pathogenic variant of ANXA11 (p.D40G) and two known likely pathogenic variants of MAPT (p.D177V) and TARDBP (p.I383V) were identified in FTLD participants. Twenty-four variants of uncertain significance as well as rare variants in risk genes for dementia, such as ABCA7, SORL1, TRPM7, NOS3, MPO, and DCTN1, were also found. Interestingly, several variants in participants with semantic variant primary progressive aphasia were detected. However, no participants with C9orf72 gene variants were found in the FTLD cohort. Conclusions: There was a high frequency of genetic variants in Chinese participants with sporadic AD and FTLD and a complex genetic overlap between these two types of dementia and other neurodegenerative diseases.