scDecouple: decoupling cellular response from infected proportion bias in scCRISPR-seq.

Single-cell clustered regularly interspaced short palindromic repeats-sequencing (scCRISPR-seq) is an emerging high-throughput CRISPR screening technology where the true cellular response to perturbation is coupled with infected proportion bias of guide RNAs (gRNAs) across different cell clusters. The mixing of these effects introduces noise into scCRISPR-seq data analysis and thus obstacles to relevant studies. We developed scDecouple to decouple true cellular response of perturbation from the influence of infected proportion bias. scDecouple first models the distribution of gene expression profiles in perturbed cells and then iteratively finds the maximum likelihood of cell cluster proportions as well as the cellular response for each gRNA. We demonstrated its performance in a series of simulation experiments. By applying scDecouple to real scCRISPR-seq data, we found that scDecouple enhances the identification of biologically perturbation-related genes. scDecouple can benefit scCRISPR-seq data analysis, especially in the case of heterogeneous samples or complex gRNA libraries.

Magnetosome-inspired synthesis of soft ferrimagnetic nanoparticles for magnetic tumor targeting.

Magnetic targeting is one of the most promising approaches for improving the targeting efficiency by which magnetic drug carriers are directed using external magnetic fields to reach their targets. As a natural magnetic nanoparticle (MNP) of biological origin, the magnetosome is a special "organelle" formed by biomineralization in magnetotactic bacteria (MTB) and is essential for MTB magnetic navigation to respond to geomagnetic fields. The magnetic targeting of magnetosomes, however, can be hindered by the aggregation and precipitation of magnetosomes in water and biological fluid environments due to the strong magnetic attraction between particles. In this study, we constructed a magnetosome-like nanoreactor by introducing MTB Mms6 protein into a reverse micelle system. MNPs synthesized by thermal decomposition exhibit the same crystal morphology and magnetism (high saturation magnetization and low coercivity) as natural magnetosomes but have a smaller particle size. The DSPE-mPEG-coated magnetosome-like MNPs exhibit good monodispersion, penetrating the lesion area of a tumor mouse model to achieve magnetic enrichment by an order of magnitude more than in the control groups, demonstrating great prospects for biomedical magnetic targeting applications.

Hierarchical-Bioinspired MOFs Enhanced Electromagnetic Wave Absorption.

Proteins exhibit complex and diverse multi-dimensional structures, along with a wide range of functional groups capable of binding metal ions. By harnessing the unique characteristics of proteins, it is possible to enhance the synthesis of metal-organic frameworks (MOFs) and modify their morphology. Here, the utilization of biomineralized bovine serum albumin (BSA) protein as a template for synthesizing Mil-100 with superior microwave absorption (MA) properties is investigated. The multi-dimensional structure and abundant functional groups of biomineralized BSA protein make it an ideal candidate for guiding the synthesis of Mil-100 with intricate network structures. The BSA@Mil-100 synthesized using this method exhibits exceptional uniformity and monodispersity of nanocrystals. The findings suggest that the BSA protein template significantly influences the regulation of nanocrystal and microstructure formation of Mil-100, resulting in a highly uniform and monodisperse structure. Notably, the synthesized 2-BSA@Mil-100 demonstrates a high reflection loss value of -58 dB at 8.85 GHz, along with a maximum effective absorption bandwidth value of 6.79 GHz, spanning from 6.01 to 12.8 GHz. Overall, this study highlights the potential of utilizing BSA protein as a template for MOF synthesis, offering an effective strategy for the design and development of high-performance MA materials.

Spectral CT assists differentiation of osteoblastic bone metastasis from bone island in newly diagnosed cancer patients.

OBJECTIVES: To investigate measurements derived from plain and enhanced spectral CT in differentiating osteoblastic bone metastasis (OBM) from bone island (BI). MATERIALS AND METHODS: From January to November 2020, 73 newly diagnosed cancer patients with 201 bone lesions (OBM = 92, BI = 109) having received spectral CT were retrospectively enrolled. Measurements including CT values of 40-140 keV, slope of the spectral curve, effective atomic number (Zeff), water (calcium) density, calcium (water) density, and Iodine (calcium) density were derived from manually segmented lesions on plain and enhanced spectral CT, and then analyzed using Student t-test and Pearson's correlation. Multivariate analysis was performed to build models (plain spectral model, enhanced spectral CT model, and combined model) for the discrimination of OBM and BI with performance evaluated using receiver operator characteristics curve and DeLong test. RESULTS: All features were significantly different between the BI group and OBM group (all p < 0.05), highly correlated with the corresponding features between plain and enhanced spectral CT both in OBM (r: 0.392-0.763) and BI (r: 0.430-0.544). As for the model performance, the combined model achieved the best performance (AUC = 0.925, 95% CI: 0.879 to 0.957), which significantly outperformed the plain spectral CT model (AUC = 0.815, 95% CI: 0.754 to 0.866, p < 0.001) and enhanced spectral CT model (AUC = 0.901, 95% CI: 0.852 to 0.939, p = 0.024) in differentiating OBM and BI. CONCLUSION: In addition to plain spectral CT measurements, enhanced spectral CT measurements would further significantly benefit the differential diagnosis. CLINICAL RELEVANCE STATEMENT: Measurements derived either from plain or enhanced spectral CT could provide additional valuable information to improve the differential diagnosis between OBM and BI in newly diagnosed cancer patients. KEY POINTS: • We intend to investigate plain and enhanced spectral CT measurements in differentiating OBM from BI. • Both plain and enhanced spectral CT help in discriminating OBM and BI in newly diagnosed cancer patients. • Enhanced spectral CT measurements further improve plain spectral CT measurements-based differential diagnosis.

Acetyl-CoA synthetase 2 promotes diabetic renal tubular injury in mice by rewiring fatty acid metabolism through SIRT1/ChREBP pathway.

Diabetic nephropathy (DN) is characterized by chronic low-grade renal inflammatory responses, which greatly contribute to disease progression. Abnormal glucose metabolism disrupts renal lipid metabolism, leading to lipid accumulation, nephrotoxicity, and subsequent aseptic renal interstitial inflammation. In this study, we investigated the mechanisms underlying the renal inflammation in diabetes, driven by glucose-lipid metabolic rearrangement with a focus on the role of acetyl-CoA synthetase 2 (ACSS2) in lipid accumulation and renal tubular injury. Diabetic models were established in mice by the injection of streptozotocin and in human renal tubular epithelial HK-2 cells cultured under a high glucose (HG, 30 mmol/L) condition. We showed that the expression levels of ACSS2 were significantly increased in renal tubular epithelial cells (RTECs) from the diabetic mice and human diabetic kidney biopsy samples, and ACSS2 was co-localized with the pro-inflammatory cytokine IL-1ß in RTECs. Diabetic ACSS2-deficient mice exhibited reduced renal tubular injury and inflammatory responses. Similarly, ACSS2 knockdown or inhibition of ACSS2 by ACSS2i (10 µmol/L) in HK-2 cells significantly ameliorated HG-induced inflammation, mitochondrial stress, and fatty acid synthesis. Molecular docking revealed that ACSS2 interacted with Sirtuin 1 (SIRT1). In HG-treated HK-2 cells, we demonstrated that ACSS2 suppressed SIRT1 expression and activated fatty acid synthesis by modulating SIRT1-carbohydrate responsive element binding protein (ChREBP) activity, leading to mitochondrial oxidative stress and inflammation. We conclude that ACSS2 promotes mitochondrial oxidative stress and renal tubular inflammation in DN by regulating the SIRT1-ChREBP pathway. This highlights the potential therapeutic value of pharmacological inhibition of ACSS2 for alleviating renal inflammation and dysregulation of fatty acid metabolic homeostasis in DN. Metabolic inflammation in the renal region, driven by lipid metabolism disorder, is a key factor in renal injury in diabetic nephropathy (DN). Acetyl-CoA synthetase 2 (ACSS2) is abundantly expressed in renal tubular epithelial cells (RTECs) and highly upregulated in diabetic kidneys. Deleting ACSS2 reduces renal fatty acid accumulation and markers of renal tubular injury in diabetic mice. We demonstrate that ACSS2 deletion inhibits ChREBP-mediated fatty acid lipogenesis, mitochondrial oxidative stress, and inflammatory response in RTECs, which play a major role in the progression of diabetic renal tubular injury in the kidney. These findings support the potential use of ACSS2 inhibitors in treating patients with DN.

The ratio of neutrophils to lymphocytes effectively predicts clinical outcomes in idiopathic membranous nephropathy.

BACKGROUND: Systemic inflammatory indicators are important in the prognoses of various diseases. Such indicators, including the neutrophil-to-lymphocyte ratio (NLR), can be meaningful in predicting the clinical outcome in patients diagnosed with idiopathic membranous nephropathy (IMN). MATERIALS AND METHODS: 112 IMN patients diagnosed by renal biopsy were recruited retrospectively. The endpoint was defined as a combination of partial and complete remission. Statistical analysis determined the independent factors associated with clinical remission and the predictive utility of NLR. RESULTS: Within the 12-month follow-up period, 72 patients achieved clinical remission after treatment. Univariate analysis identified significant differences in serum albumin, estimated glomerular filtration rate (eGFR), proteinuria, neutrophil count, and NLR between the remission group and the non-remission group (all p < 0.05). Cox proportional hazards indicated that elevated eGFR (HR 1.022, 95% CI (1.009 - 1.035), p = 0.001), lower NLR (HR 0.345, 95% CI (0.237 - 0.501), p = 0.0001), and decreased proteinuria (HR 0.826, 95% CI (0.693 - 0.984), p = 0.032) were protective elements for remission. With an optimal cut-off value of 2.61, the pre-treatment NLR had an excellent ability to identify the remission (area under the curve (AUC), 0.785). Participants were separated into low- and high-NLR groups by using 2.61. Kaplan-Meier survival curves revealed significantly higher remission rates in the lower group (p < 0.0001). CONCLUSION: The NLR is an effective indicator for predicting clinical remission in patients with IMN.

Roxadustat Versus Erythropoietin: The Comparison of Efficacy in Reversing Ventricular Remodeling in Dialysis Patients with Anaemia.

Background: Renal anaemia and left ventricular hypertrophy are the main complications of chronic kidney disease and are shared among dialysis patients. This retrospective study aimed to compare the efficacies of the hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat and recombinant human erythropoietin in reversing ventricular remodeling in dialysis patients with renal anaemia. Methods: A total of 204 participants underwent baseline examinations, including echocardiograms and laboratory tests, before being administered either treatment for at least 24 weeks from January 2018 to October 2021, after which follow-up examinations were conducted at 6 months. Propensity score matching based on key variables included age, gender, cardiovascular diseases, cardiovascular medications, dialysis course and the vascular access at baseline was performed to include populations with similar characteristics between groups. Results: In total, 136 patients were included with roxadustat or recombinant human erythropoietin. The left ventricular mass index after treatment with roxadustat and recombinant human erythropoietin both significantly decreased after 6 months, but there was no significant difference in the change in left ventricular mass index between the two groups. In addition, the left ventricular end-diastolic diameters and left ventricular wall thickness, systolic blood pressure, and diastolic blood pressure significantly decreased in the roxadustat group. Roxadustat and recombinant human erythropoietin also increased haemoglobin significantly, but there was no significant difference in the change in haemoglobin between the two groups. The results of multiple linear regression showed that the change in haemoglobin was independent factor affecting the improvement of left ventricular mass index. Conclusions: The increase of haemoglobin was associated with improving left ventricular hypertrophy in dialysis patients. However, the beneficial effects between roxadustat and recombinant human erythropoietin on left ventricular mass index did not show clear superiority or inferiority in six months.

ITGAM-mediated macrophages contribute to basement membrane damage in diabetic nephropathy and atherosclerosis.

BACKGROUND: Diabetic nephropathy (DN) and atherosclerosis (AS) are prevalent and severe complications associated with diabetes, exhibiting lesions in the basement membrane, an essential component found within the glomerulus, tubules, and arteries. These lesions contribute significantly to the progression of both diseases, however, the precise underlying mechanisms, as well as any potential shared pathogenic processes between them, remain elusive. METHODS: Our study analyzed transcriptomic profiles from DN and AS patients, sourced from the Gene Expression Omnibus database. A combination of integrated bioinformatics approaches and machine learning models were deployed to identify crucial genes connected to basement membrane lesions in both conditions. The role of integrin subunit alpha M (ITGAM) was further explored using immune infiltration analysis and genetic correlation studies. Single-cell sequencing analysis was employed to delineate the expression of ITGAM across different cell types within DN and AS tissues. RESULTS: Our analyses identified ITGAM as a key gene involved in basement membrane alterations and revealed its primary expression within macrophages in both DN and AS. ITGAM was significantly correlated with tissue immune infiltration within these diseases. Furthermore, the expression of genes encoding core components of the basement membrane was influenced by the expression level of ITGAM. CONCLUSION: Our findings suggest that macrophages may contribute to basement membrane lesions in DN and AS through the action of ITGAM. Moreover, therapeutic strategies that target ITGAM may offer potential avenues to mitigate basement membrane lesions in these two diabetes-related complications.

miRTarBase update 2022: an informative resource for experimentally validated miRNA-target interactions.

MicroRNAs (miRNAs) are noncoding RNAs with 18-26 nucleotides; they pair with target mRNAs to regulate gene expression and produce significant changes in various physiological and pathological processes. In recent years, the interaction between miRNAs and their target genes has become one of the mainstream directions for drug development. As a large-scale biological database that mainly provides miRNA-target interactions (MTIs) verified by biological experiments, miRTarBase has undergone five revisions and enhancements. The database has accumulated >2 200 449 verified MTIs from 13 389 manually curated articles and CLIP-seq data. An optimized scoring system is adopted to enhance this update's critical recognition of MTI-related articles and corresponding disease information. In addition, single-nucleotide polymorphisms and disease-related variants related to the binding efficiency of miRNA and target were characterized in miRNAs and gene 3' untranslated regions. miRNA expression profiles across extracellular vesicles, blood and different tissues, including exosomal miRNAs and tissue-specific miRNAs, were integrated to explore miRNA functions and biomarkers. For the user interface, we have classified attributes, including RNA expression, specific interaction, protein expression and biological function, for various validation experiments related to the role of miRNA. We also used seed sequence information to evaluate the binding sites of miRNA. In summary, these enhancements render miRTarBase as one of the most research-amicable MTI databases that contain comprehensive and experimentally verified annotations. The newly updated version of miRTarBase is now available at https://miRTarBase.cuhk.edu.cn/.

Enhancing diagnostic performance and image quality in coronary CT angiography: Impact of SnapShot Freeze 2 algorithm across varied heart rates in stent patients.

PURPOSE: To investigate the enhancement of image quality achieved through the utilization of SnapShot Freeze 2 (SSF2), a comparison was made against the results obtained from the original SnapShot Freeze algorithm (SSF) and standard motion correction (STND) in stent patients undergoing coronary CT angiography (CCTA) across the entire range of heart rates. MATERIALS AND METHODS: A total of 118 patients who underwent CCTA, were retrospectively included in this study. Images of these patients were reconstructed using three different algorithms: SSF2, SSF, and STND. Objective assessments include signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), diameters of stents and artifact index (AI). The image quality was subjectively evaluated by two readers. RESULTS: Compared with SSF and STND, SSF2 had similar or even higher quality in the parameters (AI, SNR, CNR, inner diameters) of coronary artery, stent, myocardium, MV (mitral valve), TV (tricuspid valve), AV (aorta valve), and PV (pulmonary valve), and aortic root (AO). Besides the above structures, SSF2 also demonstrated comparable or even higher subjective scores in atrial septum (AS), ventricular septum (VS), and pulmonary artery root (PA). Furthermore, the enhancement in image quality with SSF2 was significantly greater in the high heart rate group compared to the low heart rate group. Moreover, the improvement in both high and low heart rate groups was better in the SSF2 group compared to the SSF and STND group. Besides, when using the three algorithms, an effect of heart rate variability on stent image quality was not detected. CONCLUSION: Compared to SSF and STND, SSF2 can enhance the image quality of whole-heart structures and mitigate artifacts of coronary stents. Furthermore, SSF2 has demonstrated a significant improvement in the image quality for patients with a heart rate equal to or higher than 85 bpm.

Surgical treatment of coronal shear fractures of the distal humerus with an intact lateral epicondyle by the lateral combined approach.

BACKGROUND: Coronal shear fractures of the distal humerus are not only rare and prone to misdiagnosis, but their surgical treatment can be challenging. We aimed to investigate the feasibility of exposing distal humeral coronal shear fractures with a combined lateral approach that preserves the extensors and lateral ulnar collateral ligament (LUCL) and to analyze the clinical efficacy of open reduction and internal fixation (ORIF) in the treatment of these injuries. METHODS: We included 45 patients who sustained coronal shear fractures of the distal humerus with the lateral epicondyle intact and were treated with ORIF from January 2013 to August 2020. The fractures were exposed by the lateral combined approach in which the tendons involving the common extensor, the extensor carpi ulnaris (ECU), and the LUCL were preserved. Two observation windows were formed anterior to and posterior to these tendons and the LUCL was used to achieve fracture reduction. Countersunk screws, with or without a plate placed on the posterior lateral condyle, were used to fix the fragments. The functional outcomes of these patients were reviewed and assessed with physical and radiographic examinations, range of motion (ROM) measurements, and self-evaluation Mayo Elbow Performance Index (MEPI) and Disabilities of the Arm, Shoulder, and Hand (DASH) scores. RESULTS: In total, 40 patients were followed up with for over 1 year and were included in the final analysis. The mean follow-up duration was 42±30 months (range, 12-107 months). The patients' mean age was 42 years (range, 14-74 years). According to the Dubberley Classification, there were 15 type I, 17 type II, and 8 type III fractures. At the final follow-up, the mean flexion-extension arc was 131° (range, 65-150) and mean pronation and supination was 73° (range, 45-80) and 71° (range, 40-80), respectively. The mean MEPI score was 88 (range, 61-97) points; the results were excellent in 21, good in 13, fair in 4, and poor in 2 patients. The mean DASH score was 11 (range, 0-42) points. Neither functional score nor range of movement was associated with age, sex, fracture type, injury type, or surgical timing. CONCLUSION: Reduction and stable fixation with internal fixation for coronal shear fractures of the distal humerus can be achieved by the lateral combined approach. Early functional mobilization allows for satisfactory restoration of elbow function.

The Mechanism of Short-Circuit Oscillations in Automotive-Grade Multi-Chip Parallel Power Modules and an Effective Mitigation Approach.

This paper presents an in-depth analysis of the oscillation phenomenon occurring in multi-chip parallel automotive-grade power modules under short-circuit conditions and investigates three suppression methods. We tested and analyzed two commercial automotive-grade power modules, one containing two chips and the other containing a single chip, and found that short-circuit gate oscillations were more likely to occur in multi-chip parallel packaged modules than in single-chip packaged modules. Through experimental and simulation analyses, we observed that gate oscillations were mainly caused by the interaction between internal parasitic parameters of the module and the external drive circuit, and we found that high drive resistance and low common emitter inductance between parallel chips could effectively suppress gate voltage oscillations. We also analyzed the two mainstream suppression schemes, increasing the drive gate resistance and placing the drive capacitors in parallel. Unfortunately, we found that these suppression schemes were not ideal solutions because both schemes changed the switching characteristics of the power module. As an alternative, we propose a simple and effective solution that involves adding parallel connections between the parallel chips. Simulation calculations showed that this optimized method reduced the emitter inductance between parallel chips in the upper bridge arm by about 30% and in the lower bridge arm by 35%. Through short-circuit experiments conducted at different DC bus voltages, it has been verified that the new optimized solution effectively resolves gate oscillation issues without affecting the switching characteristics of the power module.

[Newborn screening, clinical features and genetic analysis for Citrin deficiency in Henan province].

OBJECTIVE: To explore the prevalence, clinical features, genetic characteristics and prognosis of Citrin deficiency in Henan province of China. METHODS: A total of 986 565 neonates screened by tandem mass spectrometry at the Third Affiliated Hospital of Zhengzhou University from January 2013 to December 2021 were retrospectively analyzed. Analysis of SLC25A13 gene variants and parental verification were carried out for neonates suspected for Citrin deficiency by next-generation sequencing. The clinical, biochemical and genetic characteristics of Citrin deficiency patients were integrated to guide the diet treatment and follow up the growth and development. Paired-t test was used to compare the amino acid levels in the peripheral blood samples before and after the treatment. RESULTS: Nine cases of Citrin deficiency were diagnosed among the 986 565 neonates. Specific elevation of citrulline was observed in all of the 9 cases. Six variants were detected by genetic sequencing, among which c.852_855delTATG, c.615+5G>A, c.550C>T and IVS16ins3kb were known pathogenic variants, whilst c.1111_1112delAT and c.837T>A were unreported previously. The detection rate for c. 852_855delTATG was the highest (61.6%, 11/18), followed by IVS16ins3kb (16.7%, 3/18). The clinical symptoms of all patients were relieved after the treatment, and the blood amino acid profile and biochemical parameters were significantly improved by gradually falling within the normal range. By June 2022, all patients had shown a good prognosis. CONCLUSION: The prevalence of Citrin deficiency among neonates from Henan Province by tandem mass spectrometry is 1/109 618, and the carrier rate for the pathogenic variants of the SLC25A13 gene was 1/166. The c.852_855delTATG may be a hot spot variant among the patients. Discovery of the novel variants has enriched the mutational spectrum of the SLC25A13 gene. Above results have provided a basis for the early diagnosis, treatment, prognosis and genetic counseling for the affected families.

[Clinical study of Bushen Culuan Formula in treatment of ovulatory disorder infertility caused by hyperprolactinemia].

This paper aims to study the therapeutic effect and safety of Bushen Culuan Formula in the treatment of patients with infertility caused by hyperprolactinemia. Sixty patients with infertility caused by hyperprolactinemia of kidney deficiency and blood stasis were divided into the treatment group(Bushen Culuan Formula + Bromocriptine Mesylate Tablets placebo) and the control group(Bromocriptine Mesylate Tablets + Bushen Culuan Formula placebo), and ovulation rate, pregnancy rate, serum sex hormones, basal body temperature(BBT), and traditional Chinese medicine(TCM) symptom scores were observed. The results showed the clinical effective rate was 90.00% in the treatment group and 80.00% in the control group. The treatment group was able to significantly reduce the PRL level and increase the pregnancy rate, and it was superior to the control group in increasing the BBT biphasic ratio, improving the TCM symptom scores, and enhancing the ovulation rate. The results show that Bushen Culuan Formula is safe and reliable in treating ovulatory disorder infertility caused by hyperprolactinemia, with remarkable effects.

[Study on mechanism of regulation of sex hormones in treatment of hyperprolactinemia-induced ovulatory disorder infertility with Bushen Culuan Formula].

Transcriptomics was used to investigate the mechanism of action of Bushen Culuan Formula in the treatment of infertility caused by hyperprolactinemia(HPRL), and animal experiments were carried out to verify the results. After establishing an animal model of HPRL-induced infertility, the mice were divided into normal group, model group, Bushen Culuan Formula groups with high-, medium-, and low-doses, and bromocriptine group, and they were observed in terms of the estrous cycle, gonadal index, serum sex hormones, morphology of ovary and mammary gland, follicle count, and fertility. The results showed that the Bushen Culuan Formula could effectively restore the estrous cycle, down-regulate the levels of prolactin(PRL), follicle-stimulating hormone(FSH), and luteinizing hormone(LH), up-regulate the level of estradiol(E_2), increase the number of primordial follicles and sinus follicles, and improve the ovulation rate and fertility of mice. Through RNA sequencing combined with biosignature analysis, Bushen Culuan Formula may regulate the metabolism of lipids, antioxidant enzymes, and other substances in the cells of the ovary and pituitary gland through the signaling pathways of cAMP-PKA, Kiss-1/GPR54, and Hippo and exert therapeutic effects. The results of animal experiments showed that Bushen Culuan Formula could up-regulate serum dopamine(DA) level and pituitary DRD2 expression, down-regulate hypothalamus and ovary cAMP levels, as well as protein expressions of the pituitary gland and ovary PKA, CREB, and p-CREB, and treat HPRL-induced infertility by regulating the cAMP-PKA signaling pathway.

[Network Meta-analysis of Chinese patent medicines combined with antibiotics in treatment of pelvic inflammatory diseases].

To evaluate the efficacy and safety of different Chinese patent medicines in the treatment of pelvic inflammatory disease(PID) using network Meta-analysis. The databases of CNKI, Wanfang, VIP, SinoMed, PubMed, Cochrane Library, EMbase, and Web of Science were searched, and from the time of database construction to July 16, 2023, the randomized controlled trial(RCT) of Chinese patent medicines combined with antibiotics in the treatment of PID included in these databases was collected. The quality of the included literature was evaluated using the Cochrane risk of bias tool, and data was analyzed using RevMan 5.4 and Stata 16 software. Forty-six RCTs were finally included, including Kangfu Xiaoyan Suppositories, Fuke Qianjin Tablets/Capsules, Kangfuyan Capsules, Fuyanxiao Capsules, Huahong Tablets/Capsules, Fuyanshu Capsules, Fuyue Tablets, Jingangteng Capsules, and Fuyan Kangfu Capsules. Network Meta-analysis showed that,(1) in terms of clinical effective rate, the optimal intervention was Kangfu Xiaoyan Suppositories combined with antibiotics.(2) In terms of lowering hypersensitive C-reactive protein(hs-CRP), the optimal intervention was Huahong Tablets/Capsules combined with antibiotics.(3) In terms of lowering tumor necrosis factor-α(TNF-α), the optimal intervention was Fuyue Tablets combined with antibiotics.(4) In terms of lowering recurrence rate, the optimal intervention was Fuyanshu Capsules combined with antibiotics.(5) In terms of safety, the intervention with the least adverse reactions was Kangfuyan Capsules combined with antibiotics. The results show that Chinese patent medicines combined with antibiotics in the treatment of PID can improve the comprehensive efficacy, reduce the patient's hs-CRP and TNF-α, and have a low recurrence rate, as well as safe and reliable efficacy. In clinical treatment, Kangfu Xiaoyan Suppositories or Kangfuyan Capsules combined with antibiotics can be preferred. Due to the limitations of the sample size and the quality of the literature, more large-sample and high-quality studies are needed to validate the conclusions.

[Professor MA Kun treats infertility caused by uterine dysplasia with kidney deficiency and blood stasis].

Uterine dysplasia is a common cause of infertility. Traditional Chinese medicine has unique advantages in the treatment of this disease. This paper introduces a case of infertility caused by uterine dysplasia treated by Professor MA Kun who adopted the therapy of tonifying kidney and activating blood, aiming to summarize the theoretical foundation and formula principles of Professor MA Kun in the clinical treatment of this disease. The kidney stores essence and governs reproduction. Kidney deficiency is the root cause of infertility. The deficiencies in kidney Qi, Yin, and Yang can result in blood stasis to obstruct the uterus, leading to insufficient source for essence and aggravating kidney deficiency. Kidney deficiency and blood stasis affect each other and form a vicious cycle, resulting in uterine dysplasia due to insufficient nutrition and difficult pregnancy. Therefore, Professor MA Kun believes that kidney deficiency and blood stasis is the key pathogenesis of infertility caused by uterine dysplasia and proposes the treatment principle of tonifying kidney and activating blood. Sufficient essence and Qi in the kidney can resolve stasis and generate blood, thus harmonizing Yin and Yang, which can reach thoroughfare and conception vessels to nourish the uterus and recover the normal physiological function of the uterus. In that case, normal pregnancy is possible. Professor MA Kun attaches importance to the therapeutic principle of supplementing Qi and nourishing blood. In addition, she advocates conforming to changes in the menstrual cycle to promote the development of the uterus and the implantation of fertilized eggs. She also integrates traditional Chinese medicine and western medicine to treat both symptoms and root causes. Professor MA Kun's experience has demonstrated definite clinical effect on this disease and can be taken as a reference.

[Bushen Culuan Formula in treatment of infertility caused by polycystic ovary syndrome].

This study aims to observe the efficacy and safety of Bushen Culuan Formula in the treatment of infertility caused by polycystic ovary syndrome(PCOS) and to explore the mechanism using metabolomics. Ninety-four patients with infertility caused by PCOS with the syndrome of kidney deficiency and blood stasis were selected and assigned into treatment and control groups(n=47). The basal body temperature(BBT) was measured, and B-ultrasonography was employed to monitor follicles, ovarian volume, endometrium, ovulation, and pregnancy. The serum levels of sex hormones including follicle-stimulating hormone(FSH), luteinizing hormone(LH), prolactin(PRL), estradiol(E_2), progestin(P), testosterone(T), free testosterone(FT), androstenedione(A2), inhibin B(INHB), and anti-Müllerian hormone(AMH) were measured. The coagulation function, traditional Chinese medicine(TCM) symptom scores, blood and urine routine, liver and kidney functions and other safety indicators were determined. Metabolomics was employed to comparatively analyze the serum metabolites of 26 patients(13 patients in each group) in the clinical study. The results showed that the total response rate and pregnancy rate of the treatment group were higher than those of the control group(P<0.001), suggesting that Bushen Culuan Formula regulated the sex hormones and ovarian function. Specifically, it reduced the levels of LH, T, FT, A2, and INHB(P<0.05 or P<0.01) and the LH/FSH ratio(P<0.05), elevated the level of P(P<0.05), promoted ovulation, increased endothelial thickness, and lowered TCM symptom scores without causing adverse reactions. A total of 24 differential metabolites were screened by metabolomics, and there were correlations between sex hormones and differential metabolites in the PCOS-induced infertility patients with kidney deficiency and blood stasis. In conclusion, Bushen Culuan Formula may regulate hormone levels through lipid and amino acid metabolism.

[Examples of Professor MA Kun's treatment of infertility caused by uterine fibroids using method of tonifying kidney and activating blood].

Uterine fibroids are a prevalent factor that impacts fertility in women of reproductive age. This study discusses the theoretical foundation and formula principles of Professor MA Kun's clinical treatment for infertility caused by uterine fibroids. The kidney stores essence and is responsible for reproduction, while blood serves as a vital material basis for women's physiological functions. Kidney deficiency is the fundamental pathogenesis of infertility, and imbalances in kidney Qi and essence or deficiencies in kidney Yin and Yang can result in blood stasis. Blood stasis plays a significant role throughout this condition by impeding the flow of blood, which is crucial for nourishing Qi. Therefore, both kidney deficiency and blood stasis are key factors contributing to infertility caused by uterine fibroids. Professor MA Kun treats infertility caused by uterine fibroids using an approach that involves tonifying the kidneys and activating blood circulation based on changes in Qi and blood during the menstrual cycle as well as follicular growth processes. By identifying stage-specific evidence, appropriate treatments can be applied accordingly. During menstruation when the uterus opens and menstrual blood flows out, promoting follicular development through nourishing kidney Yin and activating blood circulation becomes essential. In later stages of menstruation, additional measures are taken to remove blood stasis, alleviate symptoms, disperse knots, attack pathogens while simultaneously replenishing vital energy. During intermenstrual periods when Yin holds greater importance than Yang, tonifying the kidneys and activating blood circulation helps facilitate smooth discharge of eggs by promoting transformation between Yin and Yang energies. Premenstrual period to warm kidney Yang to promote pregnant egg implantation, and at the same time to dredge the liver and regulate Qi, Qi elimination stagnation, complementary in the line, with the symptoms of additional subtractions. Clinical effect is remarkable, for the reference of colleagues.

Identification of a tumour immune barrier in the HCC microenvironment that determines the efficacy of immunotherapy.

BACKGROUND & AIMS: The tumour microenvironment (TME) is a crucial mediator of cancer progression and therapeutic outcome. The TME subtype correlates with patient response to immunotherapy in multiple cancers. Most previous studies have focused on the role of different cellular components in the TME associated with immunotherapy efficacy. However, the specific structure of the TME and its role in immunotherapy efficacy remain largely unknown. METHODS: We combined spatial transcriptomics with single-cell RNA-sequencing and multiplexed immunofluorescence to identify the specific spatial structures in the TME that determine the efficacy of immunotherapy in patients with hepatocellular carcinoma (HCC) receiving anti-PD-1 treatment. RESULTS: We identified a tumour immune barrier (TIB) structure, a spatial niche composed of SPP1+ macrophages and cancer-associated fibroblasts (CAFs) located near the tumour boundary, which is associated with the efficacy of immune checkpoint blockade. Furthermore, we dissected ligand‒receptor networks among malignant cells, SPP1+ macrophages, and CAFs; that is, the hypoxic microenvironment promotes SPP1 expression, and SPP1+ macrophages interact with CAFs to stimulate extracellular matrix remodelling and promote TIB structure formation, thereby limiting immune infiltration in the tumour core. Preclinically, the blockade of SPP1 or macrophage-specific deletion of Spp1 in mice led to enhanced efficacy of anti-PD-1 treatment in mouse liver cancer, accompanied by reduced CAF infiltration and increased cytotoxic T-cell infiltration. CONCLUSIONS: We identified that the TIB structure formed by the interaction of SPP1+ macrophages and CAFs is related to immunotherapy efficacy. Therefore, disruption of the TIB structure by blocking SPP1 may be considered a relevant therapeutic approach to enhance the therapeutic effect of immune checkpoint blockade in HCC. IMPACT AND IMPLICATIONS: Only a limited number of patients with hepatocellular carcinoma (HCC) benefit from tumour immunotherapy, which significantly hinders its application. Herein, we used multiomics to identify the spatial structure of the tumour immune barrier (TIB), which is formed by the interaction of SPP1+ macrophages and cancer-associated fibroblasts in the HCC microenvironment. This structure constrains immunotherapy efficacy by limiting immune cell infiltration into malignant regions. Preclinically, we revealed that blocking SPP1 or macrophage-specific deletion of Spp1 in mice could destroy the TIB structure and sensitize HCC cells to immunotherapy. These results provide the first key steps towards finding more effective therapies for HCC and have implications for physicians, scientists, and drug developers in the field of HCC.