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Abstract Background Open fractures are challenging due to susceptibility to Staphylococcus aureus infections. This study examines the impact of Vancomycin-Loaded Calcium Sulfate (VLCS) and negative pressure wound therapy (NPWT) on macrophage behavior in enhancing healing and infection resistance. Both VLCS and NPWT were evaluated individually and in combination to determine their effects on macrophage polarization and infection resistance in open fractures. Methods Through single-cell RNA sequencing, genomic expressions in macrophages from open fracture patients treated with VLCS and NPWT were compared to a control group. The analysis focused on MBD2 gene changes related to macrophage polarization. Results Remarkable modifications in MBD2 expression in the treatment group indicate a shift towards M2 macrophage polarization. Additionally, the combined treatment group exhibited greater improvements in infection resistance and healing compared to the individual treatments. This shift suggests a healing-promoting atmosphere with improved infection resilience. Conclusions VLCS and NPWT demonstrate the ability to alter macrophage behavior toward M2 polarization, which is crucial for infection prevention in open fractures. The synergistic effect of their combined use shows even greater promise in enhancing outcomes in orthopedic trauma care.

ABSTRACT Objective To investigate the clinical value of whole‐exome sequencing (WES) in the diagnosis of foetuses with central nervous system (CNS) abnormalities but having a normal karyotyping and chromosomal microarray result. Method During the period of 2016–2022, there were a total of 149 foetuses with CNS abnormalities but having negative karyotyping and chromosomal microarray analysis results; WES was performed on these foetuses and their parents. Variants were classified according to ACMG guidelines, and the association of pathogenic variants with specific types of CNS abnormalities was explored. Results Among these 149 foetuses, three categories of abnormalities, namely, single CNS abnormality, multiple CNS abnormalities, CNS abnormalities along with other organ system abnormalities were identified, for which the detection rate of P/LP variants is 17.4% (12/69), 28.6% (14/49) and 54.8% (17/31), respectively. Conclusion WES brought about an increase of 28.9% in diagnostic yield in the prenatal evaluation of foetuses with CNS abnormalities but having negative karyotyping and chromosome array results. WES may also be of benefit for the diagnosis of foetuses with isolated CNS abnormalities, as well as for making more informed interpretations of imaging findings and for providing better genetic counselling.

Background: The clinical significance of gastrointestinal (GI) symptoms in patients with severe fever and thrombocytopenia syndrome (SFTS) is poorly characterized. This study aimed to determine the prevalence and effect of GI symptoms on the prognosis of patients with SFTS. Methods: This was a retrospective multi-center cohort study that included hospitalized patients with SFTS from three institutions between October 2010 and August 2022. The risk factors for mortality and intensive care unit (ICU) admission were identified by Cox and logistic regression analyses, respectively. Kaplan-Meier curves were used to analyze the cumulative mortality risk. Results: Among 304 patients, the median age was 62.0 years and 51.0 % of the patients were male. A total of 202 patients (66.4 %) had at least one GI symptom on admission. Diarrhea (69.8 %) and nausea (57.4 %) were the most common symptoms. Patients with GI symptoms had lower male proportion (46.0 % vs. 60.8 %, P = 0.015), higher aspartate aminotransferase (177.5 U/L vs. 118.0 U/L, P = 0.010) and lactic dehydrogenase (771.0 U/L vs. 666.5 U/L, P = 0.017) levels than that of patients without GI symptoms. However, there was no significant difference in mortality rates (23.8 % vs. 21.6 %, P = 0.668) and ICU admission (14.4 % vs. 12.7 %, P = 0.701) between SFTS patients with and without GI symptoms. Multivariate analysis suggested that GI symptoms at admission were not associated with mortality and ICU admission. Conclusions: GI symptoms are common in patients with SFTS. However, the presence of GI symptoms was not an independent risk factor for poor prognosis.

Abstract Background Prenatal exposure to intrauterine inflammation (IUI) is a crucial event in preterm birth (PTB) pathophysiology, increasing the incidence of neurodevelopmental disorders. Gut microbiota and metabolite profile alterations have been reported to be involved in PTB pathophysiology. Method and results In this study, IUI-exposed PTB mouse model was established and verified by PTB rate and other perinatal adverse reactions; LPS-indued IUI significantly increased the rates of PTB, apoptosis and inflammation in placenta tissue samples. LPS-induced IUI caused no significant differences in species richness and evenness but significantly altered the species abundance distribution. Non-targeted metabolomics analysis indicated that the metabolite profile of the preterm mice was altered, and differential metabolites were associated with signaling pathways including pyruvate metabolism. Furthermore, a significant positive correlation between Parasutterella excrementihominis and S4572761 (Nb-p-coumaroyltryptamine) and Mreference-1264 (pyruvic acid), respectively, was observed. Lastly, pyruvic acid treatment partially improved LPS-induced IUI phenotypes and decreased PTB rates and decreased the apoptosis and inflammation in placenta tissue samples. Conclusion This study revealed an association among gut microbiota dysbiosis, metabolite profile alterations, and LPS-induced IUI and PTB in mice models. Our investigation revealed the possible involvement of gut microbiota in the pathophysiology of LPS-induced IUI and PTB, which might be mediated by metabolites such as pyruvic acid. Future studies should be conducted to verify the findings through larger sample-sized animal studies and clinical investigations.

ObjectivesSevere fever with thrombocytopenia syndrome (SFTS) is an epidemic emerging infectious disease with high mortality rate. We investigated the association between liver injury and clinical outcomes in patients with SFTS.MethodsA total of 291 hospitalized SFTS patients were retrospectively included. Cox proportional hazards model was adopted to identify risk factors of fatal outcome and Kaplan-Meier curves were used to estimate cumulative risks.Results60.1% of patients had liver injury at admission, and the median alanine transaminase, aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TBil) levels were 76.4 U/L, 152.3 U/L, 69.8 U/L and 9.9 μmol/L, respectively. Compared to survivors, non-survivors had higher levels of AST (253.0 U/L vs. 131.1 U/L, P < 0.001) and ALP (86.2 U/L vs. 67.9 U/L, P = 0.006), higher proportion of elevated ALP (20.0% vs. 4.4%, P < 0.001) and liver injury (78.5% vs. 54.9%, P = 0.001) at admission. The presence of liver injury (HR 2.049, P = 0.033) at admission was an independent risk factor of fatal outcome.ConclusionsLiver injury was a common complication and was strongly associated with poor prognosis in SFTS patients. Liver function indicators should be closely monitored for SFTS patients.

IntroductionSevere fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by a novel bunyavirus infection with a high lethality rate. The purpose of this study was to investigate the changes in coagulation parameters in patients with SFTS, aiming to provide clinical evidence for early diagnosis, treatment, and disease analysis.MethodsA total of 40 patients with SFTS attended from April 1, 2020 to May 21, 2022 in Nanjing Drum Tower Hospital were selected and grouped according to the duration of the disease, mild and severe disease, cure and death, with 50 healthy physical examiners as controls, and the risk of severe and death disease was predicted using ROC curves.ResultsComparison between the healthy, mild and severe groups revealed that PT, INR, APTT, TT, D-D and vWF levels were higher than those in the healthy control group, and FII, FIX, FX, FXI, FXII, PC and PS levels were lower than those in the healthy control group, the differences were statistically significant (p < 0.05). Comparing the results of SFTS patients with different course times, the results of Fib, FV, FVII, FVIII, FIX, FX, FXI were statistically significant (p < 0.05). Among the survived and deceased patients, the PT, INR, DD and PS results of the deceased patients were higher than those of the survived patients, and the FVIII, FIX, FXI, FXII and PC were lower than those of the survived patients. The area under the ROC curve showed that D-D had higher predictive ability for the risk of severe disease (AUROC 0.93, sensitivity and specificity at a Cut-off value of 1.50 mg/L were 90.0 and 86.5%, respectively) and the risk of death occurring (AUROC 0.84, sensitivity and specificity at a Cut-off value of 3.39 mg/L were 87.5 and 80.0%, respectively).DiscussionThe monitoring of the coagulation parameters in patients with SFTS is great significance for identifying the severity and death of the patient’s condition, and it is of great clinical value to provide early attention, timely intervention and maximum reduction of the mortality rate for patients at risk of severe disease.

Cytokinin (CK) is an important hormone that regulates cell differentiation. The CK content in plants is regulated by cytokinin oxidase (CKX), an important enzyme that participates in hormone-regulated pathways. Additionally, CKXs comprise a large family of enzymes, but little information exists on the CKXs in potato (Solanum tuberosum). In this study, nine CKXs were identified in the potato genome and named StCKX01-09, according to their order on the linkage groups (LGs). They belong to six subfamilies, and the members within the respective subfamilies had similar motifs, a similar gene structure, and similar cis-acting elements. Additionally, the CKXs from four other species, including Arabidopsis, rice (Oryza sativa), soybean (Glycine max), and maize (Zea mays), were also divided into six subfamilies, while members within each subfamily had similar types of motifs. Moreover, the potato StCKXs were shown to influence plant hormones and stress-related factors. StCKXs were collinear, with one CKX in Arabidopsis and five CKXs in Glycine max. Quantitative real-time PCR (qRT-PCR) revealed tissue-specific expression patterns in the potato seedlings and changes in the expression levels in response to stress. Furthermore, the cytokinin content and CKX enzyme activity were shown to be regulated by StCKXs. This study provides detailed information that can help future endeavors in the molecular breeding of potato (Solanum tuberosum).

Abstract Reversible protein S-nitrosylation regulates a wide range of biological functions and physiological activities in plants. However, it is challenging to quantitively determine the S-nitrosylation targets and dynamics in vivo. In this study, we develop a highly sensitive and efficient fluorous affinity tag-switch (FAT-switch) chemical proteomics approach for S-nitrosylation peptide enrichment and detection. We quantitatively compare the global S-nitrosylation profiles in wild-type Arabidopsis and gsnor1/hot5/par2 mutant using this approach, and identify 2,121 S-nitrosylation peptides in 1,595 protein groups, including many previously unrevealed S-nitrosylated proteins. These are 408 S-nitrosylated sites in 360 protein groups showing an accumulation in hot5-4 mutant when compared to wild type. Biochemical and genetic validation reveal that S-nitrosylation at Cys337 in ER OXIDOREDUCTASE 1 (ERO1) causes the rearrangement of disulfide, resulting in enhanced ERO1 activity. This study offers a powerful and applicable tool for S-nitrosylation research, which provides valuable resources for studies on S-nitrosylation-regulated ER functions in plants.

A 49-year-old female with multiple myeloma complicated by renal failure had dysuria. The urine culture revealed multidrug-resistant aeromonas caviae during her hospital stay. Her symptoms and signs significantly improved after receiving a seven-day course of piperacillin-tazobactam treatment. She had no history of urinary tract infections(UTIs). On follow-up, she felt clinically well. Aeromonas caviae is a rare cause of UTI. We review previous cases of aeromonas caviae UTIs. The purpose of this case report is to assist in the diagnosis and management of aeromonas caviae cystitis.

Chronic hepatitis B virus (HBV) infection remains one of the major global public health concerns, and it develop into liver fibrosis, cirrhosis, and hepatocellular carcinoma. Recent evidence suggests that endosomal and autophagic vesicles are beneficial for HBV replication. However, it has not been well elucidated how HBV exploits such intracellular vesicle systems for its replication. RAB5A, a member of small GTPase family, plays crucial roles in early endosome biogenesis and autophagy initiation. We observed that RAB5A mRNA and protein levels were significantly increased in HBV-expressing hepatoma cell lines as well as in liver tissue samples from chronic HBV-infected patients. Moreover, RAB5A silencing inhibited HBV replication and subviral particle (SVP) expression significantly in HBV-transfected and -infected hepatoma cells, whereas RAB5A overexpression increased them. Mechanistically, RAB5A increases HBV replication through enhancement of early endosome (EE) – late endosome (LE) activation by interacting with EEA1, as well as enhancing autophagy induction by interacting with VPS34. Additionally, HBV infection enhances RAB5A-mediated dual activation of EE-LE system and autophagy. Collectively, our findings highlight that HBV utilizes RAB5A-mediated dual activation of endosomal and autophagic vesicle pathways for its own replication and persistence. Therefore, RAB5A is a potential target for chronic HBV infection treatment.

Summary: Secondary infection in patients with sepsis triggers a new wave of inflammatory response, which aggravates organ injury and increases mortality. Trained immunity boosts a potent and nonspecific response to the secondary challenge and has been considered beneficial for the host. Here, using a murine model of polymicrobial infection, we find that the primary infection reprograms granulocytes to boost enhanced inflammatory responses to the secondary infection, including the excessive production of inflammatory cytokines, respiratory burst, and augmented phagocytosis capacity. However, these reprogramed granulocytes exhibit “non-classic” characteristics of innate immune memory. Two mechanisms are independently involved in the innate immune memory of granulocytes: a metabolic shift in favor of glycolysis and fatty acid synthesis and chromatin remodeling leading to the transcriptional inactivity of genes encoding inhibitors of TLR4-initiated signaling pathways. Counteracting the deleterious effects of stressed granulocytes on anti-infection immunity might provide a strategy to fight secondary infections during sepsis.

Chemo-photothermal/photodynamic synergistic therapy is a new effective cancer treatment method to overcome the limitations of single chemotherapy. However, the limited low photothermal conversion efficiency, the hypoxic tumor microenvironment, and premature leakage of the drug constrain their clinical applications. To address these challenges, an all-in-one biodegradable polydopamine-coated UiO-66 framework nanomedicine (DUPM) was developed to co-deliver the drug doxorubicin hydrochloride (DOX) and the excellent photothermal material MoOx nanoparticles (NPs). The results showed that DUPM exhibited good physicochemical stability and efficiently accumulated tumor tissues under pH-, glutathione-, and NIR-triggered drug release behaviour. Of note, the synthesized MoOx NPs endowed DUPM with self-supporting oxygen production and generated more reactive oxygen species (1O2 and·OH), besides, it induces Mo-mediated redox reaction to deplete excessive glutathione thus relieving tumor hypoxia to enhance PDT, further improving synergistic therapy. Meanwhile, DUPM showed strong absorption in the near-infrared range and high photothermal conversion efficiency at 808 nm (51.50%) to realize photoacoustic imaging-guided diagnosis and treatment of cancer. Compared with monotherapy, the in vivo anti-tumor efficacy results showed that DUMP exerted satisfactory tumor growth inhibition effects (94.43%) with good biocompatibility. This study provides a facile strategy to develop intelligent multifunctional nanoparticles with tumor hypoxia relief for improving synergistic therapy and diagnosis against breast cancer.

Nano-targeted delivery systems have been widely used for breast tumor drug delivery. Estrogen receptors are considered to be significant drug delivery target receptors due to their overexpression in a variety of tumor cells. However, targeted ligands have a significant impact on the safety and effectiveness of active delivery systems, limiting the clinical transformation of nanoparticles. Phytoestrogens have shown good biosafety characteristics and some affinity with the estrogen receptor. In the present study, molecular docking was used to select tanshinone IIA (Tan IIA) among phytoestrogens as a target ligand to be used in nanodelivery systems with some modifications. Modified Tan IIA (Tan-NH2) showed a good biosafety profile and demonstrated tumor-targeting, anti-tumor and anti-tumor metastasis effects. Moreover, the ligand was utilized with the anti-tumor drug Dox-loaded mesoporous silica nanoparticles via chemical modification to generate a nanocomposite Tan-Dox-MSN. Tan-Dox-MSN had a uniform particle size, good dispersibility and high drug loading capacity. Validation experiments in vivo and in vitro showed that it also had a better targeting ability, anti-tumor effect and lower toxicity in normal organs. These results supported the idea that phytoestrogens with high affinity for the estrogen receptor could improve the therapeutic efficacy of nano-targeted delivery systems in breast tumors.

Acute myeloid leukemia (AML) is a devastating blood cancer with poor prognosis. Novel effective treatment is an urgent unmet need. Immunotherapy targeting T cell exhaustion by blocking inhibitory pathways, such as PD-1, is promising in cancer treatment. However, results from clinical studies applying PD-1 blockade to AML patients are largely disappointing. AML is highly heterogeneous. Identification of additional immune regulatory pathways and defining predictive biomarkers for treatment response are crucial to optimize the strategy. CD26 is a marker of T cell activation and involved in multiple immune processes. Here, we performed comprehensive phenotypic and functional analyses on the blood samples collected from AML patients and discovered that CD26lowPD-1+ CD8 T cells were associated with AML progression. Specifically, the percentage of this cell fraction was significantly higher in patients with newly diagnosed AML compared to that in patients achieved completed remission or healthy controls. Our subsequent studies on CD26lowPD-1+ CD8 T cells from AML patients at initial diagnosis demonstrated that this cell population highly expressed inhibitory receptors and displayed impaired cytokine production, indicating an exhaustion status. Importantly, CD26lowPD-1+ CD8 T cells carried features of terminal exhaustion, manifested by higher frequency of TEMRA differentiation, increased expression of transcription factors that are observed in terminally exhausted T cells, and high level of intracellular expression of granzyme B and perforin. Our findings suggest a prognostic and predictive value of CD26 in AML, providing pivotal information to optimize the immunotherapy for this devastating cancer.

Abstract Objective Since 2011, noninvasive prenatal testing (NIPT) has undergone rapid expansion, with both utilization and coverage. However, conclusive data regarding the clinical validity and utility of this testing tool are lacking. Thus, there is a continued need to educate clinicians and patients about the current benefits and limitations in order to inform pre- and post-test counseling, pre/perinatal decision making, and medical risk assessment/management. Methods This retrospective study included women referred for invasive prenatal diagnosis to confirm positive NIPT results between January 2017 and December 2020. Prenatal diagnosis testing, including karyotyping, chromosomal microarray analysis (CMA) were performed. Positive predictive values (PPVs) were calculated. Results In total, 468 women were recruited. The PPVs for trisomies 21, 18, and 13 were 86.1%, 57.8%, and 25.0%, respectively. The PPVs for rare chromosomal abnormalities (RCAs) and copy number variants (CNVs) were 17.0% and 40.4%, respectively. The detection of sex chromosomal aneuploidies (SCAs) had a PPV of 20% for monosomy X, 23.5% for 47,XXX, 68.8% for 47,XXY, and 62.5% for 47,XYY. The high-risk groups had a significant increase in the number of true positive cases compared to the low- and moderate-risk groups. Conclusions T13, monosomy X, and RCA were associated with lower PPVs. The improvement of cell-free fetal DNA screening technology and continued monitoring of its performance are important.

A major threat to rice production is the disease epidemics caused by insect-borne viruses that emerge and re-emerge with undefined origins. It is well known that some human viruses have zoonotic origins from wild animals. However, it remains unknown whether native plants host uncharacterized endemic viruses with spillover potential to rice (Oryza sativa) as emerging pathogens. Here, we discovered rice tiller inhibition virus (RTIV), a novel RNA virus species, from colonies of Asian wild rice (O. rufipogon) in a genetic reserve by metagenomic sequencing. We identified the specific aphid vector that is able to transmit RTIV and found that RTIV would cause low-tillering disease in rice cultivar after transmission. We further demonstrated that an infectious molecular clone of RTIV initiated systemic infection and causes low-tillering disease in an elite rice variety after Agrobacterium-mediated inoculation or stable plant transformation, and RTIV can also be transmitted from transgenic rice plant through its aphid vector to cause disease. Finally, global transcriptome analysis indicated that RTIV may disturb defense and tillering pathway to cause low tillering disease in rice cultivar. Thus, our results show that new rice viral pathogens can emerge from native habitats, and RTIV, a rare aphid-transmitted rice viral pathogen from native wild rice, can threaten the production of rice cultivar after spillover.

Abstract Despite the increased usage of post-transplant cyclophosphamide (PTCy) in allogeneic hematopoietic stem cell transplantation (allo-HSCT), our knowledge of immune reconstitution post-allo-HSCT in the setting of PTCy is limited. Adequate immune reconstitution is the key to a successful transplant. In this study, we aim to investigate the effect of PTCy on the reconstitution of each immune component; more focus was placed on the immunophenotype and functions of T cells. Using blood samples from patients who underwent allo-HSCT under regimens containing PTCy (n = 23) versus those who received no PTCy (n = 14), we examined the impact of PTCy on the post-transplant immune response. We demonstrated a distinct T cell immune signature between PTCy versus non-PTCy group. PTCy significantly delayed T cell reconstitution and affected the T cell subsets by increasing regulatory T cells (Treg) while reducing naïve T cells. In addition, we observed remarkable enhancement of multiple inhibitory receptors (TIGIT, PD-1, TIM-3, CD38, CD39) on both CD4+ and CD8+ T cells on day 30 post-transplantation in patients who received PTCy. Importantly, upregulation of PD-1 on CD8 T cells was persistent through day 180 and these T cells were less functional, manifested by reduced cytokine production upon anti-CD3/CD28 stimulation. Furthermore, we found a significant correlation of T cell immune phenotypes to clinical outcome (disease relapse and GVHD) in patients who received PTCy. Our novel findings provide critical information to understand the mechanism of how PTCy impacts immune reconstitution in allo-HSCT and may subsequently lead to optimization of our clinical practice using this treatment.

Abstract. We describe a case of infective endocarditis (IE) caused by Granulicatella adiacens in a patient who had fever for 4 months before admission. He had a complex medical history of active hyperthyroidism and schizophrenia, which might have misled the clinician in ignoring the existence of a serious infection like IE. A history of splenectomy and the likelihood of congenital cardiac valve deficiency were the possible underlying risk factors. His persistent leukocytosis perplexed our judgement in terms of resolution of infection and treatment efficacy, which was probably due to his splenectomy. C-reactive protein was the alternative laboratory indicator. Clinical and Laboratory Standards Institute criteria have not been established for the fastidious G. adiacens. Therefore, we referred to the viridans group streptococci and literature to evaluate antimicrobial susceptibility testing. We suggest that teicoplanin combined with ceftriaxone could serve as an effective therapy for IE caused by G. adiacens.

Abstract Introduction As an emerging infectious disease, coronavirus disease 2019 (COVID‐19) has rapidly spread throughout worldwide. Health care workers (HCWs) on frontline directly participated in the diagnosis, treatment, and care of COVID‐19 patients are at high risk of getting infected with the highly infectious severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the novel coronavirus that causes COVID‐19. In Nanjing Drum Tower Hospital, a total of 222 medical staff went to Wuhan city for support. In this study, we aimed to determine any nosocomial infection among our cohort of HCWs who worked in Wuhan. Methods Throat swab samples were obtained for RNA testing on day 1 and 14 of their quarantine upon their return to Nanjing. Radiological assessments were performed by chest computed tomography (CT) on day 14 of their quarantine. The blood was collected from 191 HCWs between May 12 and May 15. Anti‐SARS‐CoV‐2 immunoglobulin M (IgM) and IgG antibody responses were determined by a chemiluminescence immunoassay. Results All the throat swab specimens were found negative for SARS‐CoV‐2. The radiological analysis revealed that there was no typical chest CT scan of COVID‐19 among 222 HCWs. Consistently, anti‐SARS‐CoV‐2 IgM or IgG was also found to be negative among 191 HCWs. Conclusions There was no nosocomial infection of SARS‐CoV‐2 among our cohort of the frontline HCWs, suggesting that zero occupational infection is an achievable goal with appropriate training, strict compliance, and psychological support for the frontline HCWs.

Integration of the unique advantages of the fields of drug discovery and drug delivery is invaluable for the advancement of drug development. Here, the authors generate single-drug nanoparticles by hybridising lysomotropic detergents and the bisaminoquinoline-based autophagy inhibitor, and show their therapeutic potential as autophagy-inhibition based combination therapy.

Abstract. Background. About 10% of patients get a surgical-site infection (SSI) after radical gastrectomy for gastric cancer, but SSI remains controversial among surgeons. The aim of this study was to explore the risk factors for SSIs after radical gastrectomy in patients with gastric cancer to guide clinical therapies and reduce the incidence of SSI. Methods. The study was a retrospective cohort study in patients who underwent radical gastrectomy for gastric cancer. SSI was defined in accordance with the National Nosocomial Infection Surveillance System. We evaluated patient-related and peri-operative variables that could be risk factors for SSIs. The Chi-squared test and logistic regression analysis were used to assess the association between these risk factors and SSI. Results. Among the 590 patients, 386 were men and 204 were women. The mean age was 56.6 (28–82) years and 14.2% (84/590) of these patients had an SSI. Among them, incisional SSI was observed in 23 patients (3.9%) and organ/space SSI in 61 patients (10.3%). Multivariate logistic regression analysis identified sex (odds ratios [ORs] = 2.548, and 95% confidence interval [CI]: 1.268–5.122, P = 0.009), total gastrectomy (OR = 2.327, 95% CI: 1.352–4.004, P = 0.002), albumin level (day 3 after surgery)

Abstract Background In this study, we sought to evaluate the correlation between TV, GTD, and lymph node metastases in NSCLC patients with tumors of GTD ≤ 3.0 cm. Methods We retrospectively analyzed the characteristics of clinicopathologic variables for lymph node involvement in 285 NSCLC patients with tumors of GTD ≤ 3.0 cm who accepted curative surgical resection. The TVs were semi-automatically measured by a software, and optimal cutoff points were obtained using the X-tile software. The relationship between GTD and TV were described using non-linear regression. The correlation between GTD, TV, and N stages was analyzed using the Pearson correlation coefficient. The one-way ANOVA was used to compare the GTD and TV of different lymph node stage groups. Results The relationship between GTD and TV accorded with the exponential growth model: y = 0.113e1.455x (y = TV, x = GTD). TV for patients with node metastases (4.78 cm3) was significantly greater than those without metastases (3.57 cm3) (P < 0.001). However, there were no obvious GTD differences in cases with or without lymph node metastases (P = 0.054). We divided all cases into three TV groups using the two cutoff values (0.9 cm3 and 3.9 cm3), and there was an obvious difference in the lymphatic involvement rate between the groups (P < 0.001). The tendency to metastasize was greater with higher TV especially when the TV was > 0.9–14.2 cm3 (P = 0.010). Conclusions For NSCLC tumors with GTD ≤ 3.0 cm, TV is a more sensitive marker than GTD in predicting the positive lymph node metastases. The likelihood for metastasis increases with an increasing TV especially when GTD is > 2.0–3.0 cm.

Abstract. Urinary tract infections (UTIs) are among the most frequent causes for antibiotic prescription and; therefore, alternative treatment options for UTIs can potentially reduce antibiotic usage and development of resistance. To evaluate the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDS) for the treatment of uncomplicated lower UTIs in women, this study implemented a meta-analytic approach to evaluate the results of available randomized clinical studies from online databases. A total of four trials involving 1144 patients with uncomplicated lower UTIs were included in the final evaluation. Results showed that symptom resolution at Day 3–4 in the NSAIDs group was significantly lower than that in the antibiotics group [pooled odds ratio (OR) = 0.41, 95% confidence interval (CI): 0.23–0.74, P < 0.05]. However, there was no significant difference between the NSAIDs and antibiotics groups in symptom resolution at Day 7 (pooled OR = 0.43, 95% CI: 0.17–1.06, P = 0.07), secondary antibiotic treatment rate at Day 28–30 (pooled OR = 1.15, 95% CI: 0.16–7.98, P = 0.89) and adverse events rate (pooled OR = 1.09, 95% CI: 0.61–1.96, P = 0.77). Therefore, this meta-analysis suggests that, although inferior to antibiotics in fast symptom resolution, symptomatic treatment with NSAIDs can be considered as an alternative treatment option for uncomplicated lower UTIs in women. However, given the low number of randomized controlled trials that met inclusion criteria in this meta-analysis, efficacy of NSAIDs for treatment of uncomplicated lower UTIs should be further evaluated in more comprehensive clinical studies.

In the field of blasting vibration signal analysis, accurate removal of low-frequency noise in the signal has important practical significance. In view of the shortcomings of the existing methods, such as cumbersome calculation and limited scope of application, a method based on variational mode decomposition (VMD) to remove low-frequency noise was proposed. In this paper, the parameter selection of VMD algorithm to identify low-frequency noise of blasting signal is optimized by simulation experiment. The results show that frequency has little influence on the decomposition effect. When the frequency of low-frequency noise is between 0 and 5 Hz, the influence of frequency on the decomposition effect remains basically unchanged. The amplitude has a significant effect on the decomposition effect. The smaller the amplitude, the worse the decomposition effect of the VMD method. Taking the excavation of the Badaling Great Wall Station as the background, the LSM method, EMD method, and VMD method are used to remove the low-frequency noise of the randomly selected test signals in order. Compared with the LSM method and the EMD method, the signal processed by the VMD method does not have modal mixing and does not have much low-frequency noise residue. It has more extensive applicability in removing low-frequency noise of blasting signal.

The Kagami–Ogata syndrome (KOS) is a rare imprinting disorder with a distinct clinical phenotype. In KOS, polyhydramnios is associated with a small bell-shaped thorax and coat-hanger ribs. The genetic etiology of KOS includes paternal uniparental disomy 14 [upd(14)pat], epimutations, and microdeletions affecting the maternally derived imprinted region of chromosome 14q32.2. More than 77 cases of KOS have been reported; however, only one mosaic upd(14)pat case has been reported. Here we report a second mosaic upd(14)pat case. The prognosis of upd(14)pat patients is poor because of severe respiratory insufficiency. We summarized prenatal ultrasound findings of KOS to raise awareness of this condition for possible diagnosis of KOS prenatally when polyhydramnios combination with a small bell-shaped thorax and other related features are first observed. Prenatal diagnosis using methylation-specific multiplex ligation-dependent probe amplification (MLPA) or a single-nucleotide polymorphism-based microarray analysis is recommended.

Abstract Background Successful treatment for acute myeloid leukemia (AML) remains challenging. Inhibiting immune checkpoint to enhance anti-tumor response is an attractive strategy for effective leukemia therapeutics. CD73 is a recently recognized immune checkpoint mediator that is highly expressed on tumor cells and stromal cells in tumor microenvironment. The ectonucleotidase activity of CD73 catalyzes AMP to adenosine, which subsequently inhibits anti-tumor immune responses. In this study, we aim to explore the effect of CD73 in AML. Methods Peripheral blood samples collected from patients with newly diagnosed AML (n = 27) were used in this study. CD73 expression on each immune cell component was examined by flow cytometry. Phenotypic study of CD73-expressing T cells and analysis of the correlation between CD73 and other immune checkpoints were performed using flow cytometry-based assays. Functional status of CD73+ vs. CD73− T cells was assessed in an in vitro cytokine release assay upon CD3/CD28 antibody stimulation. Results In contrast to the long recognized immune suppressive effect of CD73-adenosine signaling in tumor tissue, we made a striking observation that in AML, CD73 expression on CD8 T cells associates with an increased immune response. CD73+ CD8 T cells are more functional, whereas CD73− CD8 T cells exhibit features of exhaustion manifested by high expression of inhibitory receptors such as PD-1 and TIGIT, increased intracellular expression of Eomes, reduced capacity of cytokine production, and high susceptibility to apoptosis. Conclusions Our data highlight the potential of CD73 as a double-edged sword in anti-leukemia immunity and argue strongly for the combinational treatment by adding immune checkpoint inhibitors to the CD73-targeting approaches.

Blasting excavation is extensively used in tunnel construction, and the adverse effect of ground vibration induced by blasting on surrounding structures and inhabitants is a critical problem. This study aims to investigate the tunnel hollow effect on triaxial peak particle velocities (PPV) and dominant frequencies induced by electronic detonator. Field experiments were conducted in a shallow tunnel construction site and the ground vibration waveforms were recorded. Variational mode decomposition (VMD) was applied to denoise and correct the zero-drift phenomenon, and the proposed method of selecting the optimal parameter was verified. A series of statistical analyses and tests were performed to evaluate the differences of peak particle velocity and dominant frequency among various monitoring points. The results showed that the hollow effect on Z-axis PPV is significant, and triaxial PPV is also affected when the horizontal distance exceeds 30 m. The hollow effect on dominant frequency could not be identified since the hollow of tunnel is a free face, and the dominant frequency of reflected wave remains unchanged. An augmented factor of 1.229 is determined carefully as the hollow effect factor on PPV. Therefore, blasting vibration induced by electronic detonator of the excavated zone should be attached with greater importance, and hollow effect on PPV should be considered in the blasting design of tunnel excavation.

Background: This study aimed to evaluate T staging system for non-small cell lung cancer (NSCLC) using tumor volume (TV) and other prognostic factors. Methods: This study included 1309 cases. The TV and greatest tumor diameter (GTD) were semi-automatically measured. The receiver operating characteristic (ROC) curves of TV and GTD were used to predict survival. The regression analysis was used to describe the correlation between GTD and TV. Overall survival (OS) was analyzed using the Kaplan-Meier method. Cox’s proportional hazards regression model was applied for multivariate analysis. Results: Using the OS in pN0M0 patients (997 cases), we obtained 4 optimal cutoff values and divided all cases into 5 TV groups (V1: TV ≤ 2.80 cm 3 ; V2: TV > 2.80–6.40 cm 3 ; V3: TV > 6.40–12.9 cm 3 ; V4: TV > 12.9–55.01 cm 3 ; V5: TV > 55.01 cm 3 ) with significant OS ( P < 0.001). Multivariate analysis showed that age, visceral pleural invasion (VPI), and all TV cutoff points were independent factors of OS ( P < 0.05). For V3 and V4 groups, the OS in patients without VPI was better than that in patients with VPI. Using the values of TV, VPI, and N stages, we classified all cases into 5 stages from I to V depending on the OS. The OS in I, II, III, IV, and V stages were 71.3%, 65.5%, 59.8%, 47.7%, and 35.1% respectively ( P < 0.001). Conclusions: We proposed a new T staging system using TV as the main prognostic descriptor in NSCLC patients, which may provide a better comprehensive clinical value than GTD in clinical applications.

Brucellosis, a bacterial zoonosis, is transmitted directly or indirectly from infected animals (mainly domesticated ruminants and pigs) to humans. People are generally susceptible to brucella, which is mainly transmitted by direct contact, digestive tract and respiratory tract. Since brucella can be discharged from various secretions and feces after human infection, sexual transmission has become a potential mode of transmission. We report a case of highly suspected sexually transmitted brucellosis infection patient, which was discharged after treatment with etimicin + minocycline.

Size and charge can significantly affect delivery of therapeutic agents to tumours. Here, the authors report on nanoparticles optimised for delivery to the tumour which release smaller particles and change charge in the tumour microenvironment to optimise tumour penetration and cellular uptake.

Here we describe the sequencing and assembly of the pathogenic fungus Lomentospora prolificans using a combination of short, highly accurate Illumina reads and additional coverage in very long Oxford Nanopore reads. The resulting assembly is highly contiguous, containing a total of 37,627,092 bp with over 98% of the sequence in just 26 scaffolds. Annotation identified 8896 protein-coding genes. Pulsed-field gel analysis suggests that this organism contains at least 7 and possibly 11 chromosomes, the two longest of which have sizes corresponding closely to the sizes of the longest scaffolds, at 6.6 and 5.7 Mb.

Abstract The gamma-glutamyl transpeptidase to platelet ratio (GPR) is a novel index to estimate liver fibrosis in chronic hepatitis B (CHB). Few studies compared diagnostic accuracy of GPR with other non-invasive fibrosis tests based on blood parameters. We analyzed diagnostic values of GPR for detecting liver fibrosis and compared diagnostic performances of GPR with APRI (aspartate aminotransferase-to-platelet ratio index), FIB-4 (fibrosis index based on the four factors), NLR (neutrophil-to-lymphocyte ratio), AAR (aspartate aminotransferase/alanine aminotransferase ratio) and RPR (red cell distribution width-to-platelet ratio) in HBeAg positive CHB and HBeAg negative CHB. We found AUROCs of GPR in predicting significant liver fibrosis, advanced liver fibrosis and liver cirrhosis were 0.732 (95% CI 0.663 to 0.801), 0.788 (95% CI 0.729 to 0.847) and 0.753 (95% CI 0.692 to 0.814), respectively. Further comparisons showed the diagnostic performance of GPR was not significantly different with APRI, FIB-4 and RPR in identifying significant fibrosis, advanced fibrosis and cirrhosis, but it was significantly superior to AAR and NLR in both HBeAg positive CHB and HBeAg negative CHB. In conclusion, GPR does not show advantages than APRI, FIB-4 and RPR in identifying significant liver fibrosis, advanced liver fibrosis and liver cirrhosis in both HBeAg positive CHB and HBeAg negative CHB in China.

Abstract Background T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) and programmed cell death protein 1 (PD-1) are important inhibitory receptors that associate with T cell exhaustion in acute myeloid leukemia (AML). In this study, we aimed to determine the underlying transcriptional mechanisms regulating these inhibitory pathways. Specifically, we investigated the role of transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1) in T cell response and transcriptional regulation of TIGIT and PD-1 in AML. Methods Peripheral blood samples collected from patients with AML were used in this study. Blimp-1 expression was examined by flow cytometry. The correlation of Blimp-1 expression to clinical characteristics of AML patients was analyzed. Phenotypic and functional studies of Blimp-1-expressing T cells were performed using flow cytometry-based assays. Luciferase reporter assays and ChIP assays were applied to assess direct binding and transcription activity of Blimp-1. Using siRNA to silence Blimp-1, we further elucidated the regulatory role of Blimp-1 in the TIGIT and PD-1 expression and T cell immune response. Results Blimp-1 expression is elevated in T cells from AML patients. Consistent with exhaustion, Blimp-1+ T cells upregulate multiple inhibitory receptors including PD-1 and TIGIT. In addition, they are functionally impaired manifested by low cytokine production and decreased cytotoxicity capacity. Importantly, the functional defect is reversed by inhibition of Blimp-1 via siRNA knockdown. Furthermore, Blimp-1 binds to the promoters of PD-1 and TIGIT and positively regulates their expression. Conclusions Our study demonstrates an important inhibitory effect of Blimp-1 on T cell response in AML; thus, targeting Blimp-1 and its regulated molecules to improve the immune response may provide effective leukemia therapeutics.

This paper concerns constructing topological sigma models governing maps from semirigid super Riemann surfaces to general target supermanifolds. We define both the A model and B model in this general setup by defining suitable BRST operators and physical observables. Using supersymmetric localization, we express correlation functions in these theories as integrals over suitable supermanifolds. In the case of the A model, we obtain an integral over the supermoduli space of “superinstantons”. The language of supergeometry is used extensively throughout this paper.

Exposure to intrauterine inflammation (IUI) is associated with short- and long-term adverse perinatal outcomes. However, little data exist on utilizing placenta to prognosticate fetal injury in this scenario. Our study aimed to utilize imaging modalities to evaluate mechanisms contributing to placental injury following IUI exposure and correlated it to concomitant fetal brain injury. CD1 pregnant dams underwent laparotomies and received intrauterine injections of either lipopolysaccharide (LPS; a model of IUI) or phosphate-buffered saline (PBS). In utero ultrasound Doppler velocimetry of uterine and umbilical arteries and magnetic resonance imaging (MRI) of placental volumes with confirmatory immunohistochemical (vimentin) and histochemistry (fibrin) analyses were performed. ELISA for thrombosis markers, fibrinogen and fibrin was performed to analyze thrombi in placenta. Fetal brain immunohistochemistry was performed to detect microglial activation (ionized calcium-binding adaptor molecule 1, Iba1). On ultrasound, LPS group demonstrated elevated resistance indices, pulsatility indices and a greater occurrence of absent end-diastolic flow in the umbilical and uterine arteries. In the fetus, there was an increased cardiac Tei indices in the LPS group. MRI revealed decreased volume of placenta in the LPS group associated with placental thinning and placental endothelial damage on immunohistochemistry. Decreased fibrinogen content and more thrombi staining in placenta exposed to maternal LPS indicated the hypercoagulability. Furthermore, the expression of Iba1was significantly associated with placental thickness (r = -0.7890, Pearson correlation coefficient). Our data indicate that IUI can trigger events leading to maternal placental malperfusion and fetal vessel resistance, as well as predispose the developing fetus to cardiac dysfunction and brain damage. Furthermore, our data suggest that prenatal ultrasound can be a real-time clinical tool for assessing fetal risk for adverse neurologic outcomes following the potential IUI exposure.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-22419-2

Treatment of acute myeloid leukemia (AML) remains challenging. Enhancement of anti-tumor responses by blocking negative immune regulators is a promising strategy for novel effective leukemia therapeutics. V-domain Ig suppressor of T-cell activation (VISTA) is a recently defined negative regulator mediating immune evasion in cancer. To investigate the effect of VISTA on anti-leukemia immune response in AML, we initiated a study using clinical samples collected from AML patients. Here we report that VISTA is highly expressed on myeloid-derived suppressor cells (MDSCs) in the peripheral blood of AML patients. Both the frequency and intensity of VISTA expression on MDSCs are significantly higher in newly diagnosed AML than in healthy controls. Importantly knockdown of VISTA by specific siRNA potently reduced the MDSCs-mediated inhibition of CD8 T cell activity in AML, suggesting a suppressive effect of VISTA on anti-leukemia T cell response. Furthermore, we observed a strong positive association between MDSC expression of VISTA and T cell expression of PD-1 in AML. These results support the strategy of VISTA-targeted treatment for AML and underscore the strong potential for combined blockade of VISTA and PD-1 pathways in effective leukemia control.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging epidemic infectious disease caused by the SFTS bunyavirus (SFTSV) with an estimated high case-fatality rate of 12.7% to 32.6%. Currently, the disease has been reported in mainland China, Japan, Korea, and the United States. At present, there is no specific antiviral therapy for SFTSV infection. Considering the higher mortality rate and rapid clinical progress of SFTS, supporting the appropriate treatment in time to SFTS patients is critical. Therefore, it is very important for clinicians to predict these SFTS cases who are more likely to have a poor prognosis or even more likely to decease. In the present study, we established a simple and feasible model for assessing the severity and predicting the prognosis of SFTS patients with high sensitivity and specificity. This model may aid the physicians to immediately initiate prompt treatment to block the rapid development of the illness and reduce the fatality of SFTS patients.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous subset of cells that expands dramatically in many disease states and can suppress T-cell responses. MDSCs mainly include monocytic and granulocytic subpopulations that can be distinguished in mice by the expression of Ly6G and Ly6C cell surface markers. This identification system has been validated in experimental tumor models, but not in models of inflammation-associated conditions such as sepsis. We challenged growth factor independent 1 transcription repressor green fluorescent protein (Gfi1:GFP) knock-in reporter mice with cecal ligation and puncture surgery and found that CD11b+Ly6GlowLy6Chigh MDSCs in this sepsis model comprised both monocytic and granulocytic MDSCs. The evidence that conventional Ly6G/Ly6C marker analysis may not be suited to study of inflammation-induced MDSCs led to the development of a novel strategy of distinguishing granulocytic MDSCs from monocytic MDSCs in septic mice by expression of CD48. Application of this novel model should help achieve a more accurate understanding of the inflammation-induced MDSC activity.

Successful expansion of hematopoietic stem cells would benefit the use of hematopoietic stem cell transplants in the clinic. Several angiopoietin-like proteins, including angiopoietin-like 7, can support the activity of hematopoietic stem cells. However, effects of ANGPTL7 on human hematopoietic stem cells and the downstream signaling cascade activated by ANGPTL7 are poorly understood. Here, we established a human hematopoietic stem and progenitor cell-supportive mouse fetal liver cell line that specifically expressed the Angptl7 protein. Furthermore, we found ANGPTL7 is capable of stimulating human hematopoietic stem and progenitor cell expansion and increasing the repopulation activities of human hematopoietic progenitors in xenografts. RNA-sequencing analysis showed that ANGPTL7 activated the expression of CXCR4, HOXB4 and Wnt downstream targets in human hematopoietic progenitors. In addition, chemical manipulation of Wnt signaling diminished the effects of ANGPTL7 on human hematopoietic stem and progenitor cells in culture. In summary, we identify the secreted growth factor ANGPTL7 as a regulator of both human hematopoietic stem and progenitor cell expansion and regeneration.

Inland surface water is essential to terrestrial ecosystems and human civilization. Accurate mapping of surface water dynamic is vital for both scientific research and policy-driven applications. MODIS provides twice observation per day, making it perfect for monitoring temporal water dynamic. Although MODIS provides two bands at 250 m resolution, accurately deriving water area always depends on observations from the spectral bands with 500 m resolution, which limits its discrimination ability over small lakes and rivers. The paper presents an automated method for downscaling the 500 m MODIS surface reflectance (SR) to 250 m to improve the spatial discrimination of water body extraction. The method has been tested at Co Ngoin and Co Bangkog in Qinghai-Tibet plateau. The downscaled SR and the derived water bodies were compared to SR and water body mapped from Landsat-7 ETM+ images were acquired on the same date. Consistency metrics were calculated to measure their agreement and disagreement. The comparisons indicated that the downscaled MODIS SR showed significant improvement over the original 500 m observations when compared with Landsat-7 ETM+ SR, and both commission and omission errors were reduced in the derived 250 m water bodies.

The microRNA319 (miR319) family is conserved among diverse plant species. In rice (Oryza sativa L.), the miR319 gene family is comprised of two members, Osa-miR319a and Osa-miR319b. We found that overexpressing Osa-miR319b in rice resulted in wider leaf blades and delayed development. Here, we focused on the biological function and potential molecular mechanism of the Osa-miR319b gene in response to cold stress in rice. The expression of Osa-miR319b was down-regulated by cold stress, and the overexpression of Osa-miR319b led to an enhanced tolerance to cold stress, as evidenced by higher survival rates and proline content. Also, the expression of a handful of cold stress responsive genes, such as DREB1A/B/C, DREB2A, TPP1/2, was increased in Osa-miR319b transgenic lines. Furthermore, we demonstrated the nuclear localization of the transcription factors, OsPCF6 and OsTCP21, which may be Osa-miR319b-targeted genes. We also showed that OsPCF6 and OsTCP21 expression was largely induced by cold stress, and the degree of induction was obviously repressed in plants overexpressing Osa-miR319b. As expected, the down-regulation of OsPCF6 and OsTCP21 resulted in enhanced tolerance to cold stress, partially by modifying active oxygen scavenging. Taken together, our findings suggest that Osa-miR319b plays an important role in plant response to cold stress, maybe by targeting OsPCF6 and OsTCP21.

The groundbreaking discovery of induced pluripotent stem cells (iPS cells) provides a new source for cell therapy. However, whether the iPS derived functional lineages from different cell origins have different immunogenicity remains unknown. It had been known that the cells isolated from extra-embryonic tissues, such as umbilical cord mesenchymal cells (UMCs), are less immunogenic than other adult lineages such as skin fibroblasts (SFs). In this report, we differentiated iPS cells from human UMCs and SFs into neural progenitor cells (NPCs) and analyzed their immunogenicity. Through co-culture with allologous peripheral blood mononuclear cells (PBMCs), we showed that UMCs were indeed less immunogenic than skin cells to simulate proliferation of PBMCs. Surprisingly, we found that the NPCs differentiated from UMC-iPS cells retained low immunogenicity as the parental UMCs based on the PBMC proliferation assay. In cytotoxic expression assay, reactions in most kinds of immune effector cells showed more perforin and granzyme B expression with SF-NPCs stimulation than that with UMC-NPCs stimulation in PBMC co-culture system, in T cell co-culture system as well. Furthermore, through whole genome expression microarray analysis, we showed that over 70 immune genes, including all members of HLA-I, were expressed at lower levels in NPCs derived from UMC-iPS cells than that from SF-iPS cells. Our results demonstrated a phenomenon that the low immunogenicity of the less immunogenic cells could be retained after cell reprogramming and further differentiation, thus provide a new concept to generate functional lineages with lower immunogenicity for regenerative medicine.