Discovery of natural-product-derived sequanamycins as potent oral anti-tuberculosis agents.

The emergence of drug-resistant tuberculosis has created an urgent need for new anti-tubercular agents. Here, we report the discovery of a series of macrolides called sequanamycins with outstanding in vitro and in vivo activity against Mycobacterium tuberculosis (Mtb). Sequanamycins are bacterial ribosome inhibitors that interact with the ribosome in a similar manner to classic macrolides like erythromycin and clarithromycin, but with binding characteristics that allow them to overcome the inherent macrolide resistance of Mtb. Structures of the ribosome with bound inhibitors were used to optimize sequanamycin to produce the advanced lead compound SEQ-9. SEQ-9 was efficacious in mouse models of acute and chronic TB as a single agent, and it demonstrated bactericidal activity in a murine TB infection model in combination with other TB drugs. These results support further investigation of this series as TB clinical candidates, with the potential for use in new regimens against drug-susceptible and drug-resistant TB.

Deregulation and epigenetic modification of BCL2-family genes cause resistance to venetoclax in hematologic malignancies.

The BCL2 inhibitor venetoclax has been approved to treat different hematological malignancies. Because there is no common genetic alteration causing resistance to venetoclax in chronic lymphocytic leukemia (CLL) and B-cell lymphoma, we asked if epigenetic events might be involved in venetoclax resistance. Therefore, we employed whole-exome sequencing, methylated DNA immunoprecipitation sequencing, and genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 screening to investigate venetoclax resistance in aggressive lymphoma and high-risk CLL patients. We identified a regulatory CpG island within the PUMA promoter that is methylated upon venetoclax treatment, mediating PUMA downregulation on transcript and protein level. PUMA expression and sensitivity toward venetoclax can be restored by inhibition of methyltransferases. We can demonstrate that loss of PUMA results in metabolic reprogramming with higher oxidative phosphorylation and adenosine triphosphate production, resembling the metabolic phenotype that is seen upon venetoclax resistance. Although PUMA loss is specific for acquired venetoclax resistance but not for acquired MCL1 resistance and is not seen in CLL patients after chemotherapy-resistance, BAX is essential for sensitivity toward both venetoclax and MCL1 inhibition. As we found loss of BAX in Richter's syndrome patients after venetoclax failure, we defined BAX-mediated apoptosis to be critical for drug resistance but not for disease progression of CLL into aggressive diffuse large B-cell lymphoma in vivo. A compound screen revealed TRAIL-mediated apoptosis as a target to overcome BAX deficiency. Furthermore, antibody or CAR T cells eliminated venetoclax resistant lymphoma cells, paving a clinically applicable way to overcome venetoclax resistance.

Head-to-head comparison of prostate-specific membrane antigen positron emission tomography/computed tomography and multiparametric magnetic resonance imaging in the detection of biochemical recurrence of prostate cancer: a systematic review and meta-analysis.

AIM: Our main goal of this meta-analytical analysis was to evaluate the diagnostic effectiveness of prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) against multiparametric magnetic resonance imaging (mpMRI) in the context of identifying biochemical recurrence in patients with prostate cancer (PCa). MATERIALS AND METHODS: A thorough search covering articles published until March 2023 was carried out across major databases such as PubMed, Embase, and Web of Science. Studies examining the direct comparison of PSMA PET/CT and mpMRI in patients with PCa suffering biochemical recurrence were included in the inclusion criteria. Using the renowned Quality Assessment of Diagnostic Performance Studies-2 technique, each study's methodological rigor was assessed. RESULTS: We analyzed data from six eligible studies involving 290 patients in total. The combined data showed that for PSMA PET/CT and mpMRI, respectively, the pooled overall detection rates for recurrent PCa after definitive treatment were 0.69 (95% confidence interval [CI]: 0.45-0.89) and 0.70 (95% CI: 0.44-0.91). The detection rates for local recurrence were specifically 0.52 (95% CI: 0.39-0.65) and 0.62 (95% CI: 0.31-0.89), while they were 0.50 (95% CI: 0.26-0.74) and 0.32 (95% CI: 0.18-0.48) for lymph node metastasis. Notably, there was no discernible difference between the two imaging modalities in terms of the overall detection rate (P = 0.95). The detection rates for local recurrence and lymph node metastasis did not differ statistically significantly (P = 0.55, 0.23). CONCLUSION: The performance of PSMA PET/CT and mpMRI in identifying biochemical recurrence in PCa appears to be comparable. However, the meta-analysis' findings came from research with modest sample sizes. In this context, more extensive research should be conducted in the future.

Treponema pallidum protein Tp47 induced prostaglandin E2 to inhibit the phagocytosis in human macrophages.

BACKGROUND: During Treponema pallidum (T. pallidum) infection, the host's immune system actively engages in pursuit and elimination of T. pallidum, while T. pallidum skillfully employs various mechanisms to evade immune recognition. Macrophages exhibit incomplete clearance of T. pallidum in vitro and the underlying mechanism of how T. pallidum resists the attack of macrophage remains unclear. OBJECTIVES: To investigate the effect of T. pallidum membrane protein Tp47 on the phagocytosis of macrophages. METHODS: THP-1-derived macrophages were used to investigate the role of Tp47 in the secretion of Prostaglandin E2 (PGE2) in macrophages and the mechanism by which Tp47 induced the production of PGE2, as well as the impact of PGE2 on the macrophage's phagocytosis. RESULTS: Tp47 (1-10 µg/mL) significantly inhibited the phagocytosis of latex beads and T. pallidum in macrophages (p ≤ 0.05). PGE2 production by macrophages could be induced by Tp47, and the phagocytic function of macrophages could be restored using PGE2 antibody. Tp47 produced PGE2 by activating the PERK/NF-κB/COX-2 pathway in macrophages. Inhibitors targeting PERK, NF-κB and COX-2, respectively, reduced the level of PGE2 and restored the phagocytic function of macrophages. CONCLUSION: Tp47-induced PGE2 production via the PERK/NF-κB/COX-2 pathway contributed to macrophage phagocytosis inhibition, which potentially contributes to immune evasion during the T. pallidum infection.

Treponema pallidum-induced prostaglandin E2 secretion in skin fibroblasts leads to neuronal hyperpolarization: A cause of painless ulcers.

BACKGROUND: Primary syphilis is characterized by painless ulcerative lesions in the genitalia, the aetiology of painless remains elusive. OBJECTIVES: To investigate the role of Treponema pallidum in painless ulcer of primary syphilis, and the mechanisms underlying painless ulcers caused by T. pallidum. METHODS: An experimental rabbit model of primary syphilis was established to investigate its effects on peripheral nerve tissues. Human skin fibroblasts were used to examine the role of T. pallidum in modulating neurotransmitters associated with pain and to explore the signalling pathways related to neurotransmitter secretion by T. pallidum in vitro. RESULTS: Treponema pallidum infection did not directly lead to neuronal damage or interfere with the neuronal resting potential. Instead, it facilitated the secretion of prostaglandin E2 (PGE2) through endoplasmic reticulum stress in both rabbit and human skin fibroblasts, and upregulation of PGE2 induced the hyperpolarization of neurones. Moreover, the IRE1α/COX-2 signalling pathway was identified as the underlying mechanism by which T. pallidum induced the production of PGE2 in human skin fibroblasts. CONCLUSION: Treponema pallidum promotes PGE2 secretion in skin fibroblasts, leading to the excitation of neuronal hyperpolarization and potentially contributing to the pathogenesis of painless ulcers in syphilis.

Association of blood heavy metal concentrations with hearing loss: a systematic review and meta-analysis.

OBJECTIVES: This study aimed to assess the associations between blood heavy metal concentrations and hearing loss. STUDY DESIGN: This was a systematic review and meta-analysis. METHODS: A comprehensive literature search was performed using Embase, PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Chinese Biomedical Literature, Wanfang and Weipu databases. Ten studies were included, and a random or fixed-effects model was used for the meta-analysis. Review Manager 5.4 software was used for data synthesis, and Stata 15.1 software was used for the publication bias and sensitivity analyses. RESULTS: Blood lead concentrations were significantly and substantially associated with hearing loss (mean difference (MD) = 1.14; 95% confidence interval [CI] = 0.03, 2.26; P = 0.04; I2 = 81%), and iron deficiency was significantly related to hearing loss (MD = -0.42; 95% CI = -0.66, -0.18; P = 0.12; I2 = 60%). CONCLUSIONS: These results suggest an association between blood heavy metal concentrations and hearing loss. However, there were limitations: confounding factors, lack of description for the specific methods of blinding and independent verification of case definition, limited sample size, Chinese publications comprising half of the primary data and the lack of assessment of the relationship between different blood heavy metal concentrations and the severity of hearing loss. Therefore, larger and well-designed prospective cohort studies are required for further exploration.

[Reconsideration of the indications for unicompartmental knee arthroplasty].

Unicompartmental knee arthroplasty (UKA), a procedure that has gradually emerged in recent years, is considered an effective treatment for resolving knee pain and restoring good function due to its significant clinical advantages. In the 1980s, Kozinn and Scott proposed the classic indications as selection criteria to identify ideal candidates for UKA. However, as treatment concepts, surgical instruments, surgical techniques, and prosthesis designs for this disease have improved, these indications proposed more than 30 years ago appear too limited, leading to some limitations in the widespread use of UKA. Specifically, surgeons have offered new perspectives on issues related to obesity, age, patellofemoral arthritis, severe varus deformity of the knee, anterior cruciate ligament deficiency, flexion contracture, failed high tibial osteotomy and post-traumatic arthritis. For this reason, this article will briefly discuss modern perspectives involving the indications for UKA based on current evidence with the aim of providing a reference for the reader.

[Proactively embracing the challenges of multimorbidity].

With rapid socio-economic development and the acceleration of population aging, the average life span of human beings has increased significantly. Individuals suffering from the co-existence of multiple diseases (multimorbidity) have become a new normal in public health and posed severe challenge to human health. Multimorbidity significantly reduces the quality of life, increases disability and mortality risks, complicates disease treatment and care and increases burden of the healthcare system with higher costs. This commentary discusses the definition of multimorbidity and common public misconceptions, then assesses its profound impact on overall public health, socio-economic development and healthcare system. We also proposes the potential strategies to meet the challenges posed by multimorbidity. The main aim is to raise awareness of multimorbidity, advocate proactive responses to improve public health and build a healthy society through the development of prevention and treatment systems and promote precision prevention and treatment for multimorbidity.

[The innovation and challenge of artificial intelligence in the whole process management of fundus disease].

Artificial intelligence (AI) has demonstrated revolutionary potential and wide-ranging applications in the comprehensive management of fundus diseases, yet it faces challenges in clinical translation, data quality, algorithm interpretability, and cross-cultural adaptability. AI has proven effective in the efficient screening, accurate diagnosis, personalized treatment recommendations, and prognosis prediction for conditions such as diabetic retinopathy, age-related macular degeneration, and other fundus diseases. However, there is a significant gap between the need for large-scale, high-quality, and diverse datasets and the limitations of current research data. Additionally, the black-box nature of AI algorithms, the acceptance by clinicians and patients, and the generalizability of these algorithms pose barriers to their widespread clinical adoption. Researchers are addressing these challenges through approaches such as federated learning, standardized data collection, and prospective trials to enhance the robustness, interpretability, and practicality of AI systems. Despite these obstacles, the benefits of AI in fundus disease management are substantial. These include improved screening efficiency, support for personalized treatment, the discovery of novel disease characteristics, and the development of precise treatment strategies. Moreover, AI facilitates the advancement of telemedicine through 5G and the Internet of Things. Future research should continue to tackle existing issues, fully leverage the potential of AI in the prevention and treatment of fundus diseases, and advance intelligent, precise, and remote ophthalmic services to meet global eye health needs.

[Utilization of outpatient service of pneumoconiosis patients in Chongqing and its influencing factors].

Objective: To understand the utilization and characteristics of outpatient services for pneumoconiosis patients within two weeks in Chongqing, and analyze the influencing factors, so as to provide reference for relevant policy making. Methods: From October 2020 to October 2022, 1771 pneumoconiosis patients who met the inclusion criteria were selected by multi-stage stratified random cluster sampling. A questionnaire survey was conducted on their basic situation, utilization of outpatient services within two weeks, treatment for pneumoconiosis-related symptoms, and selection of medical service institutions using χ(2)-test and logistic regression analysis. Results: All the 1771 pneumoconiosis patients were male, with the average age of (56.1±10.19) years old. In the pneumoconiosis patients were treated in outpatient department within 2 weeks.40.0% (204/510) of aged 41~50 years Rural patients accounted for 87.8% (448/510) ; 65.1% (332/510) of silicosis patients, 37.5% (191/510) of stage II patients, 75.1% (383/510) of patients did not continue to engage in dust work after diagnosis of pneumoconiosis, and 57.1% (291/510) of patients never had work-related injury insurance at work. The outpatient rate within two weeks of pneumoconiosis related assistance and subsistence allowance was 17.6% (90/510) and 12.5% (64/510), respectively. The average self-health score of the patients was (52.9±16.2). 28.2% of the patients had purchased work-related injury insurance; Among the 1204 patients who received the treatment within two weeks, 42.2% were in the outpatient department, 20.7% were in the inpatient department, and 36.9% were self-buyers. There was a significant difference between the different treatment methods of the patients (χ(2)=27.53, P<0.05). There was a significant difference in patients from different residence choosing to visit different medical institutions (χ(2)=13.97, P<0.05). The stage of pneumoconiosis, presence of complications, presence of work injury insurance, self-health score, and whether he/she has been hospitalized in the past year are the important factors affecting the outpatient treatment of pneumoconiosis patients. Conclusion: The utilization of outpatient service of pneumoconiosis patients is influenced by demographic sociology, social support and disease characteristics. The quality of occupational disease medical service in primary health institutions should be strengthened so that pneumoconiosis patients can get convenient and effective treatment. Establish a more perfect social security support system to reduce the disease burden of pneumoconiosis patients.

First Constraints on Heavy QCD Axions with a Liquid Argon Time Projection Chamber Using the ArgoNeuT Experiment.

We present the results of a search for heavy QCD axions performed by the ArgoNeuT experiment at Fermilab. We search for heavy axions produced in the NuMI neutrino beam target and absorber decaying into dimuon pairs, which can be identified using the unique capabilities of ArgoNeuT and the MINOS near detector. This decay channel is motivated by a broad class of heavy QCD axion models that address the strong CP and axion quality problems with axion masses above the dimuon threshold. We obtain new constraints at a 95% confidence level for heavy axions in the previously unexplored mass range of 0.2-0.9 GeV, for axion decay constants around tens of TeV.

Breast cancer diagnosis and prognosis using a high b-value non-Gaussian continuous-time random-walk model.

AIM: To compare the diagnostic performance of mono-exponential model-derived apparent diffusion coefficient (ADC), continuous-time random-walk (CTRW) model-derived Dm, α, ß and their combinations in discriminating malignancy of breast lesions, and investigate the association between model-derived parameters and prognosis-related immunohistochemical indices. MATERIALS AND METHODS: A total of 85 patients with breast lesions (51 malignant, 34 benign) were analysed in this retrospective study. Clinical characteristics include oestrogen receptor (ER), progesterone receptor (PR), human epidermal receptor 2 (HER2), and Ki-67. The ADC was fitted using a mono-exponential model (b-values = 0, 800 s/mm2), while Dm, α, and ß were fitted using a CTRW model. Independent Student's t-test and the Mann-Whitney U-test were used for the comparison of parameters. Discrimination performance was accomplished by receiver operating characteristic (ROC) analysis, and Spearman's correlation analysis was used to explore the association between immunohistochemical indices and diffusion parameters, the statistical significance level was p<0.05. RESULTS: Dm and ADC demonstrated similar performance in differentiating malignant and benign lesions (AUC = 0.928 versus 0.930), while the combination of Dm, α, and ß could improve the AUC to 0.969. The combined parameter generated by ADC, Dm, α, and ß was effective in identifying the ER+/ER- and PR+/PR- patients. Temporal heterogeneity parameter α correlated significantly with the expression of PR. CONCLUSION: Diffusion parameters derived from the CTRW model could effectively discriminate the malignancy of breast lesions. Meanwhile, the hormone receptor expression could be distinguished by combined diffusion parameters, and have the potential to reflect the prognosis.

Recombinant Treponema pallidum protein Tp47 promoted the phagocytosis of macrophages by activating NLRP3 inflammasome induced by PKM2-dependent glycolysis.

BACKGROUND: Glycolysis is a critical pathway in cellular glucose metabolism that provides energy and participates in immune responses. However, whether glycolysis is involved in NOD-like receptor family protein 3 (NLRP3) inflammasome activation and phagocytosis of macrophages in response to Treponema pallidum infection remains unclear. OBJECTIVES: To investigate the role of glycolysis in activating the NLRP3 inflammasome for regulating phagocytosis in macrophages in response to T. pallidum protein Tp47 and its associated mechanisms. METHODS: Interactions between activation of the NLRP3 inflammasome and phagocytosis and the role of glycolysis in Tp47-treated macrophages were investigated through experiments on peritoneal macrophages and human monocytic cell line-derived macrophages. RESULTS: Activation of phagocytosis and NLRP3 inflammasome were observed in Tp47-treated macrophages. Treatment with NLRP3 inhibitor MCC950 or si-NLRP3 attenuated Tp47-induced phagocytosis. Glycolysis and glycolytic capacity were enhanced by Tp47 stimulation in macrophages, and a change in the levels of glycolytic metabolites (phosphoenolpyruvate, citrate and lactate) was induced by Tp47 in macrophages. Inhibition of glycolysis with 2-deoxy-D-glucose, a glycolysis inhibitor, decreased the activation of NLRP3. Expression of M2 isoform of pyruvate kinase (PKM2), an enzyme catalysing a rate-limiting reaction in the glycolytic pathway, was upregulated in Tp47-stimulated macrophages. Inhibition of PKM2 with shikonin or si-PKM2 decreased glycolysis and NLRP3 activation. CONCLUSION: Tp47 promotes phagocytosis in macrophages by activating the NLRP3 inflammasome, which is induced by the enhancement of PKM2-dependent glycolysis.

Multitrait meta-analyses identify potential candidate genes for growth-related traits in Holstein heifers.

Understanding the underlying pleiotropic relationships among growth and body size traits is important for refining breeding strategies in dairy cattle for optimal body size and growth rate. Therefore, we performed single-trait GWAS for monthly-recorded body weight (BW), hip height, body length, and chest girth from birth to 12 mo of age in Holstein animals, followed by stepwise multiple regression of independent or lowly-linked markers from GWAS loci using conditional and joint association analyses (COJO). Subsequently, we conducted a multitrait meta-analysis to detect pleiotropic markers. Based on the single-trait GWAS, we identified 170 significant SNPs, in which 59 of them remained significant after the COJO analyses. The most significant SNP, located at BTA7:3,676,741, explained 2.93% of the total phenotypic variance for BW6 (BW at 6 mo of age). We identified 17 SNPs with potential pleiotropic effects based on the multitrait meta-analyses, which resulted in 3 additional SNPs in comparison to those detected based on the single-trait GWAS. The identified quantitative trait loci regions overlap with genes known to influence human growth-related traits. According to positional and functional analyses, we proposed HMGA2, HNF4G, MED13L, BHLHE40, FRZB, DMP1, TRIB3, and GATAD2A as important candidate genes influencing the studied traits. The combination of single-trait GWAS and meta-analyses of GWAS results improved the efficiency of detecting associated SNPs, and provided new insights into the genetic mechanisms of growth and development in Holstein cattle.

Low anterior resection syndrome and quality of life after intersphincteric resection for rectal cancer: a propensity score-matched study.

PURPOSE: Our aim was to perform a propensity score-matched study to compare the long-term functional outcomes and quality of life following intersphincteric resection vs. low anterior resection (LAR) with very low anastomosis. METHODS: Patients who underwent intersphincteric resection or low anterior resection with low anastomosis (≤ 4 cm from the anal verge) for rectal cancer between January 2017 and June 2020 were retrospectively included. A propensity score-matching process was performed. Functional outcomes and quality of life were assessed using the European Quality of Life 5 Dimensions 3 Level Version (EQ-5D-3L), EORC-QLQ C30, EORC-QLQ CR29, Low Anterior Resection Syndrome (LARS), Wexner, and International Prostate Symptom Score (IPSS) questionnaires. The primary outcome was the presence of LARS at least 12 months after surgery. The second outcome was the postoperative quality of life of included patients. RESULTS: After propensity matching, 128 patients were included, including 58 males and 70 females with a median age of 59.5. Patients in the intersphincteric resection group showed a higher incidence of incontinence to flatus (32.8% versus 14.0%, p = 0.043) and stools (42.2% versus 21.9%, p = 0.046), pain/discomfort (25.0% versus 7.8%, p = 0.001), and bowel dysfunction, while the LARS scores (15.0 versus 13.2, p = 0.461) and major LARS rates (26.6% versus 14.1%, p = 0.078) were comparable in both groups. CONCLUSION: ISR leads to increased bowel incontinence rate and increased anal pain, without affecting the grade of low anterior resection syndrome, fecal urgency, and clustering. LAR might be the preferred sphincteric-preserving approach when negative resection margins and a safe anastomosis are guaranteed. Patients should be fully informed about potential functional impairment after sphincter-preservation procedures.

[The analysis of a pedigree with hereditary coagulation factor â ¤ deficiency caused by compound heterozygous variation of F5 gene].

Objective: To analyze the gene variation of a genetic coagulation factor Ⅴ (FⅤ) deficiency pedigree and explore the molecular pathogenesis. Methods: The proband was a 32 years old female. The patient was prone to nose bleeding since childhood which was usually self-healed. On March 10, 2021, the proband went to the First Affiliated Hospital of Air Force Medical University for treatment of knee hematoma caused by a fall. None of the family members reported any history of bleeding. The prothrombin time (PT), activated partial thromboplastin time (APTT) and FⅤ activity (FⅤ: C) were detected by clotting method and the FⅤ antigen (FⅤ: Ag) was tested with enzyme-linked immunosorbent assay (ELISA). All exons and flanks of F5 gene were determined by Sanger sequencing. Clustalx-2.1-win, PolyPhen-2 and Swiss-PDBViewer software were used to analyze the conservatism of missense variation sites, whether the variations were harmful and their influences on protein structure and function. MutationTaster and NetGene2 software were used to analyze whether the splice site variation was harmful and its effect on the splice site. Results: The PT and APTT of the proband prolonged to 24.0 s and 69.8 s, respectively. The FⅤ: C and FⅤ: Ag decreased to 6% and 9%, respectively. There were compound heterozygous variations in F5 gene, which included c.911G>A heterozygous missense variation in exon 6 leading to p.Gly276Glu variation and c.5208+1G>A heterozygous missense variation in intron 15. The father and daughter had the p.Gly276Glu heterozygous variation. Her mother and son had the c.5208+1G>A heterozygous variation. Software analysis results of p.Gly276Glu heterozygous variation showed that Gly276 was conserved among homologous species, the variation was harmful, and it could affect the local structure and function of the protein. The c.5208+1G>A heterozygous variation was deleterious and resulted in the disappearance of the splice site, thereby affecting the protein function. Conclusion: The p.Gly276Glu and c.5208+1G>A compound heterozygous variants are deleterious variants associated with the patient's disease and may be the molecular pathogenesis of inherited FⅤ deficiency in this family.

[Evaluation effect of COMPERA 2.0 risk assessment model on prognosis of Chinese patients with pulmonary arterial hypertension].

Objectives: To clarify the evaluation effect of COMPERA 2.0 risk assessment model on prognosis of pulmonary arterial hypertension (PAH) in China. Methods: Patients with newly diagnosed PAH admitted in Fuwai hospital between April 2019 and March 2022 were enrolled retrospectively and divided in low, intermediate-low, intermediate-high and high strata by scores of COMPERA 2.0 risk assessment model. All the patients were followed up by clinic or telephone. The primary endpoint was defined as a composite of all-cause mortality, exacerbated heart failure and aggravated symptoms. Kaplan-Meier analysis and log-rank trend test were used to determine the risk of endpoints among the 4 groups. Multivariate Cox proportional hazards regression were used to analyze the association between COMPERA 2.0 scores and prognosis in patients with PAH. Results: A total of 951 patients with PAH were enrolled in this study. The age [M (Q1, Q3)] of the patients was 35 (28, 47) years, of which 706 cases (74.2%) were females. A total of 328 cases (34.5%) were assigned in low strata, 264 cases (27.8%) in intermediate-low strata, 193 cases (20.3%) in intermediate-high strata, and 166 cases (17.5%) in high strata. During the duration [M (Q1, Q3)] of follow-up after discharge of 1.8 (1.0, 2.8) years, the primary endpoint was occurred in 12.8% (42/328), 21.2% (56/264), 28.5% (55/193) and 42.8% (71/166) of low, intermediate-low, intermediate-high and high strata, respectively. The rates of primary endpoint were significantly increased with strata rising (P<0.001). Multivariate Cox proportional hazards regression showed that COMPERA 2.0 risk scores were associated with the primary endpoints in PAH patients (HR=1.801, 95%CI: 1.254-2.588, P=0.001) after adjusting confounders. Conclusion: COMPERA 2.0 risk assessment model is a simple and effective tool for evaluating the prognosis of newly diagnosed PAH patients in China.

[Cardiac amyloidosis: pathological classification and clinical analysis of 48 cases].

Objective: To investigate the histological features and clinical manifestations in different types of cardiac amyloidosis to improve diagnostic accuracy. Methods: The histopathological features and clinical manifestations of 48 patients diagnosed with cardiac amyloidosis by Congo red stain and electron microscopy through endomyocardial biopsy were collected in West China Hospital of Sichuan University from January 2018 to December 2021. Immunohistochemical stains for immunoglobulin light chains (κ and λ) and transthyretin protein were carried out, and a review of literature was made. Results: The patients age ranged from 42 to 79 years (mean 56 years) and the male to female ratio was 1.1 to 1.0. The positive rate of endomyocardial biopsy was 97.9% (47/48), which was significantly higher than that of the abdominal wall fat (7/17). Congo red staining and electron microscopy were positive in 97.9% (47/48) and 93.5% (43/46), respectively. Immunohistochemical stains showed 32 cases (68.1%) were light chain type (AL-CA), including 31 cases of AL-λ type and 1 case of AL-κ type; 9 cases (19.1%) were transthyretin protein type (ATTR-CA); and 6 cases (12.8%) were not classified. There was no significant difference in the deposition pattern of amyloid between different types (P>0.05). Clinical data showed that ATTR-CA patients had less involvement of 2 or more organs and lower N-terminal pro-B-type natriuretic peptide (NT-proBNP) than the other type patients (P<0.05). The left ventricular stroke volume and right ventricular ejection fraction of ATTR-CA patients were better than the other patients (P<0.05). Follow-up data of 45 patients was obtained, and the overall mean survival time was 15.6±2.0 months. Univariate survival analysis showed that ATTR-CA patients had a better prognosis, while cardiac amyloidosis patients with higher cardiac function grade, NT-proBNP >6 000 ng/L, and troponin T >70 ng/L had a worse prognosis (P<0.05). Multivariate survival analysis showed that NT-proBNP and cardiac function grade were independent prognostic factors for cardiac amyloidosis patients. Conclusions: AL-λ is the most common type of cardiac amyloidosis in this group. Congo red staining combined with electron microscopy can significantly improve the diagnosis of cardiac amyloidosis. The clinical manifestations and prognosis of each type are different and can be classified based on immunostaining profile. However, there are still a few cases that cannot be typed; hence mass spectrometry is recommended if feasible.

[Macrophage heterogeneity role in NAFLD and NASH disease progression].

Nonalcoholic fatty liver disease (NAFLD) is a type of metabolic stress liver injury that is closely associated with insulin resistance and genetic susceptibility. The continuum of liver injury in NAFLD can range from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) and even lead to cirrhosis and liver cancer. The pathogenesis of NAFLD is complicated. Pro-inflammatory cytokines, lipotoxicity, and gut bacterial metabolites play a key role in activating liver-resident macrophages (Kupffer cells, KCs) and recruiting circulating monocyte-derived macrophages (MoDMacs) to deposit fat in the liver. With the application of single-cell RNA-sequencing, significant heterogeneity in hepatic macrophages has been revealed, suggesting that KCs and MoDMacs located in the liver exert distinct functions in regulating liver inflammation and NASH progression. This study focuses on the role of macrophage heterogeneity in the development and occurrence of NAFLD and NASH, in view of the fact that innate immunity plays a key role in the development of NAFLD.

[Treatment of oligoprogression to immunotherapy resistance in advanced non-small cell lung cancer].

In recent years, the incidence of lung cancer has been increasing year by year. Traditional treatments have limited clinical effects in advanced, driver-gene-negative non-small cell lung cancer. Immune checkpoint inhibitors (ICI) have dramatically changed the treatment landscape of advanced non-small cell lung cancer. However, most patients are suffered from primary and acquired resistance inevitably. Oligoprogression is one of the main progression patterns of acquired resistance. Therefore, it is essential to further understand treatment of oligoprogression to immunotherapy resistance. This article aimed to conduct a systematic review of the treatment of oligoprogression to immunotherapy resistance.