Single-cell mitochondrial sequencing reveals low-frequency mitochondrial mutations in naturally aging mice.

Mitochondria play a crucial role in numerous biological processes; however, limited methods and research have focused on revealing mitochondrial heterogeneity at the single-cell level. In this study, we optimized the DNBelab C4 single-cell ATAC (assay for transposase-accessible chromatin) sequencing workflow for single-cell mitochondrial sequencing (C4_mtscATAC-seq). We validated the effectiveness of our C4_mtscATAC-seq protocol by sequencing the HEK-293T cell line with two biological replicates, successfully capturing both mitochondrial content (~68% of total sequencing data) and open chromatin status simultaneously. Subsequently, we applied C4_mtscATAC-seq to investigate two mouse tissues, spleen and bone marrow, obtained from two mice aged 2 months and two mice aged 23 months. Our findings revealed higher mitochondrial DNA (mtDNA) content in young tissues compared to more variable mitochondrial content in aged tissues, consistent with higher activity scores of nuclear genes associated with mitochondrial replication and transcription in young tissues. We detected a total of 22, 15, and 21 mtDNA mutations in the young spleen, aged spleen, and bone marrow, respectively, with most variant allele frequencies (VAF) below 1%. Moreover, we observed a higher number of mtDNA mutations with higher VAF in aged tissues compared to young tissues. Importantly, we identified three mtDNA variations (m.9821A>T, m.15219T>C, and m.15984C>T) with the highest VAF in both aged spleen and aged bone marrow. By comparing cells with and without these mtDNA variations, we analyzed differential open chromatin status to identify potential genes associated with these mtDNA variations, including transcription factors such as KLF15 and NRF1. Our study presents an alternative single-cell mitochondrial sequencing method and provides crude insights into age-related single-cell mitochondrial variations.

Effect of laterality on the postoperative survival of non-small cell lung cancer patients undergoing pneumonectomy.

Background: Pneumonectomy is one of the important surgical methods for non-small cell lung cancer (NSCLC). This study evaluated the effects of laterality on the short- and long-term survival of NSCLC patients undergoing pneumonectomy. Methods: We reviewed the Surveillance, Epidemiology, and End Results database to retrieve the data of patients who underwent pneumonectomy for stage I-III NSCLC from 2004 to 2015. Propensity score matching (PSM) was used to reduce the selection bias. Logistic regression was used to analyze the correlation between laterality and mortality at 3, 6, and 9 months. The Kaplan-Meier curve was used to further assess the effect of laterality on overall survival (OS). Results: A total of 4,763 patients met the enrollment criteria [right-sided, 1,988 (41.7%); left-sided, 2,775 (58.3%)]. After PSM, 1,911 patients for each side were included in the further analysis. The first 6 months following pneumonectomy was the main period of death, with 32.0% (428/1,336) and 19.9% (250/1,258) of right- and left-sided deaths occurring during this period. The logistic regression analysis showed that right-sided pneumonectomy was an independent risk factor for 3- (P<0.001) and 6-month (P<0.001) mortality. However, laterality had no significant effect on postoperative death at 7-9 months (P=0.82). In the total cohort, right-sided patients had worse OS (P<0.001), but the subgroup survival analysis of patients with a follow-up period >6 months revealed that laterality had no statistically significant effect on OS (P=0.75). Conclusions: Right-sided pneumonectomy was associated with a higher perioperative mortality risk that lasted about 6 months. After that period, laterality was not observed to have a significant prognostic effect on the OS of patients undergoing pneumonectomy.

Heatwave and upper urinary tract stones morbidity: effect modification by heatwave definitions, disease subtypes, and vulnerable populations.

As heatwave occurs with increased frequency and intensity, the disease burden for urolithiasis, a heat-specific disease, will increase. However, heatwave effect on urolithiasis subtypes morbidity and optimal heatwave definition for urolithiasis remain unclear. Distributed lagged linear models were used to assess the associations between 32 defined heatwave and upper urinary tract stones morbidity. Relative risk (RR) and attributable fraction (AF) of upper urinary tract stone morbidity associated with heatwave of different intensities (low, middle, and high) were pooled by meta-analysis. Optimal heatwave definition was selected based on the combined score of AF, RR, and quasi-Akaike Information Criterion (QAIC) value. Stratified analyses were conducted to investigate the modification effects of gender, age, and disease subtypes. Association between heatwave and upper urinary tract stones morbidity was mainly for ureteral calculus, and AF was highest for low-intensity heatwave. This study's optimal heatwave was defined as average temperature > 93rd percentile for ≥ 2 consecutive days, with AF of 7.40% (95% CI: 2.02%, 11.27%). Heatwave was associated with ureteral calculus morbidity in males and middle-aged adults. While heatwave effect was statistically insignificant in females and other age groups. Managers should develop appropriate definitions to address heatwave based on regional characteristics and focus on heatwave effects on urolithiasis.

Case report: A novel TLK2 variant with a neuropsychiatric phenotype from a Chinese family.

Background: Tousled-like kinase 2 (TLK2) gene variant-related neurodevelopmental disorder was recently described. The haploinsufficiency of TLK2 was considered the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. So far, only four studies, conducted on 49 patients from North America and Europe, have been reported. Case presentation: In this study, we reported a Chinese family with a TLK2-related neuropsychiatric phenotype. The proband, a boy aged 2 years and 6 months, presented with temper tantrums, mood lability, aggressiveness, congenital astigmatism, and distinctive facial dysmorphism. Whole-exome sequencing identified a novel heterozygous variation in TLK2 gene (c.49dupG, p. E17Gfs*10) in them. His father carried the same TLK2 gene variant and exhibited anxiety and irritability. The parental grandparents and other family members had no such variation. Moreover, the proband was found to have global developmental delay, autism-like symptoms, and mild elevated homo-vanillic acid (HVA) and 2,3-dihydroxy-2-methylbutyric acid levels tested in urine. Conclusion: Herein, we identified a novel TLK2 variant from a Chinese family and reported a new neuropsychiatric phenotype. This study also expanded the genotype profile of the newly defined TLK2-related neurodevelopmental disorder.

Clinical immunological characteristics of anti-interferon-γ autoantibodies syndrome: a 3 year prospective cohort study.

Anti-interferon-γ autoantibodies (AIGAs) syndrome is susceptible to disseminated opportunistic infections due to increased AIGAs, but its clinical immunological characteristics remain unrecognized. We conducted a prospective cohort study between January 2021 and December 2023, recruiting patients with opportunistic infections who were categorized into AIGAs-positive and AIGAs-negative groups. Clinical immunological data and outcomes were documented. A subset of AIGAs-positive patients received glucocorticoid treatment, and its effectiveness was evaluated. A total of 238 patients were enrolled, with 135 AIGAs-positive and 103 AIGAs-negative patients. AIGAs-positive patients showed higher rates of multiple pathogen dissemination, shorter progression-free survival (PFS), and increased exacerbation frequency. They also showed elevated erythrocyte sedimentation rate (ESR), globulin (GLB), immunoglobulin (Ig)G, IgE, and IgG4 levels. Among the 70 AIGAs-positive patients monitored for at least six months, three subtypes were identified: high AIGAs titer with immune damage, high AIGAs titer without immune damage, and low AIGAs titer without immune damage. Of the 55 patients followed for 1 year, decreasing AIGAs titer and immune indices (GLB, IgG, IgE, IgG4) were observed. Among the 31 patients with high AIGAs titer and immune damage treated with low-dose glucocorticoids at the stable phase, reductions were observed in immune indices and AIGAs titer in 67.74% of cases. In summary, AIGAs-positive patients exhibit infectious and immunological characteristics. Elevated AIGAs, IgG, IgG4, and IgE indicate abnormal immune damages. AIGAs titer generally decrease over time. Stable-phase AIGAs-positive patients can be categorized into three subtypes, with those having high AIGAs titer and increased immune indices potentially benefitting from glucocorticoid treatment.

Statin use and development and progression of non-alcohol fatty liver disease based on ultrasonography: a cohort study.

INTRODUCTION: Non-alcohol fatty liver disease (NAFLD) has emerged as a public health issue, while no drugs have been specifically approved for treatment. This study aimed to examine the association between statin use and NAFLD occurrence, progression, and regression. METHODS: A cohort study was designed based on the Kailuan Study and electronic medical records (EMRs) from the Kailuan General Hospital. Participants aged 18 years with statin indication, including statin and non-statin users, were enrolled in 2010-2017. Propensity score-matched cohorts were also used. RESULTS: In the entire cohort, 21 229 non-NAFLD and 22 419 NAFLD patients (including 12 818 mild NAFLD) were included in the final analysis. After a median follow-up of about four years, the incidence of NAFLD occurrence and progression for statin users were lower than those for non-statin users (occurrence: 84.7 vs. 106.5/1000 person-years; progression: 60.7 vs. 75.5/1000 person-years). Compared with non-statin users, the risk of NAFLD occurrence (hazard ratio [HR]: 0.78, 95% confidence interval [CI]: 0.70-0.87) and regression (HR [95%CI], 0.71[0.60-0.84]) was decreased in statin users. The significantly negative association was only observed in those with cumulative statin duration ≥ 2 years (HR [95%CI] for occurrence 0.56 [0.46-0.69] vs. 0.52 [0.30-0.90] for progression) and those with low or moderate ASCVD-risk (HR [95%CI] for occurrence 0.74 [0.66-0.82] vs. 0.68 [0.57-0.80] for progression). No significant correlation was observed between statin use, statin use duration, and NAFLD regression. The PS-matched cohort had similar results. CONCLUSION: Taking statin may decrease the risk of NAFLD occurrence and progression in the population with statin indication, suggesting the potential role of statin in both primary and secondary prevention strategies for NAFLD, especially among those with low or moderate ASCVD risk.

Modification effects of immigration status and comorbidities on associations of heat and heatwave with stroke morbidity.

BACKGROUND: Heat and heatwave have been associated with stroke morbidity, but it is still unclear whether immigrants from different geographic regions and patients with comorbidity are more vulnerable to heat and heatwave. METHODS: Time-stratified case-crossover design combined with generalized additive quasi-Poisson models were used to quantify the relative risks (RRs) of heat and heatwave on first-ever stroke morbidity during 0-7 lag days. Attributable fractions (AFs) were estimated to assess the first-ever stroke morbidity burden due to heat and heatwave. Stratified analyses for sex, age, disease subtypes, resident characteristics, and comorbidity type were performed to identify potential modification effects. RESULTS: Heat and heatwave were associated with first-ever stroke morbidity, with the AF of 2.535% (95% empirical confidence interval (eCI) = 0.748, 4.205) and 2.409% (95% confidence interval (CI) = 1.228, 3.400), respectively. Among northern and southern immigrants, the AF for heat was 2.806% (0.031, 5.069) and 2.798% (0.757, 4.428), respectively, and the AF for heatwave was 2.918% (0.561, 4.618) and 2.387% (1.174, 3.398), respectively, but the effects of both on natives were statistically insignificant. Among patients with hypertension, dyslipidemia, or diabetes, the AF for heat was 3.318% (1.225, 5.007), 4.237% (1.037, 6.770), and 4.860% (1.171, 7.827), respectively, and the AF for heatwave was 2.960% (1.701, 3.993), 2.771% (0.704, 4.308), and 2.652% (0.653, 4.185), respectively. However, the effects of both on patients without comorbidity were statistically insignificant. CONCLUSION: Heat and heatwave are associated with an increased risk of first-ever stroke morbidity among immigrants and those with comorbid hypertension, dyslipidemia, or diabetes, with the effects primarily due to non-native individuals. DATA ACCESS STATEMENT: The author(s) are not authorized to share the data.

Facile Synthesis of PtP2 Nanocrystals as Highly Active Electrocatalysts for Methanol Oxidation.

Although significant efforts have been made in the past few decades, the development of affordable, durable, and effective electrocatalysts for direct methanol fuel cells (DMFCs) remains a formidable challenge. Herein, we present a facile and efficient phosphorization approach for synthesizing PtP2 intermetallic nanocrystals and utilize them as electrocatalysts in the methanol oxidation reaction (MOR). Impressively, the synthesized PtP2 nanocatalysts exhibit a mass activity of 2.14 mA µg-1 and a specific activity of 6.28 mA cm-2, which are 5.1 and 9.5 times higher than those achieved by the current state-of-the-art commercial Pt/C catalyst, respectively. Moreover, the PtP2 nanocatalysts demonstrate improved stability toward acidic MOR by retaining 92.1% of its initial mass activity after undergoing 5000 potential cycles, far surpassing that of the commercial Pt/C (38%). Further DMFC tests present a 2.7 times higher power density than that of the commercial Pt/C, underscoring their potential for application in methanol fuel cells. Density functional theory calculations suggest that the accelerated MOR kinetics and improved CO tolerance on PtP2 can be attributed to the attenuated binding strength of CO intermediates and the enhanced stability due to strong Pt-P interaction. To our knowledge, this is the first report identifying the MOR performance on PtP2 intermetallic nanocrystals, highlighting their potential as highly active and stable nanocatalysts for DMFCs.

Sub-2 nm IrRuNiMoCo High-Entropy Alloy with Iridium-Rich Medium-Entropy Oxide Shell to Boost Acidic Oxygen Evolution.

Ensuring high catalytic activity and durability at low iridium (Ir)usage is still a big challenge for the development of electrocatalysts toward oxygen evolution reaction (OER) in proton exchange membrane water electrolysis (PEMWE). Here, a rapid liquid-reduction combined with surface galvanic replacement strategy is reported to synthesize the sub 2 nm high-entropy alloy (HEA) nanoparticles featured with Ir-rich IrRuNiMo medium-entropy oxide shell (Ir-MEO) and a IrRuCoNiMo HEA core (HEA@Ir-MEO). Advanced spectroscopies reveal that the Ir-rich MEO shell inhibits the severe structural evolution of transition metals upon the OER, thus guaranteeing the structural stability. In situ differential electrochemical mass spectrometry, activation energy analysis and theoretical calculations unveil that the OER on HEA@Ir-MEO follows an adsorbate evolution mechanism pathway, where the energy barrier of rate-determining step is substantially lowered. The optimized catalyst delivers the excellent performance (1.85 V/3.0 A cm-2@80 °C), long-term stability (>500 h@1.0 Acm-2), and low energy consumption (3.98 kWh Nm-3 H2 @1.0 A cm-2) in PEMWE with low Ir usage of ≈0.4 mg cm-2, realizing the dramatical reduction of hydrogen (H2) production cost to 0.88 dollar per kg (H2).

Cost-effectiveness of latent tuberculosis infection testing and treatment with 6-week regimen among key population in rural communities in China: a decision analysis study.

PURPOSE: Several model studies suggested the implementation of latent tuberculosis infection (LTBI) testing and treatment could greatly reduce the incidence of tuberculosis (TB) and achieve the 2035 target of the "End TB" Strategy in China. The present study aimed to evaluate the cost-effectiveness of LTBI testing and TB preventive treatment among key population (≥ 50 years old) susceptible to TB at community level in China. METHODS: A Markov model was developed to investigate the cost-effectiveness of LTBI testing using interferon gamma release assay (IGRA) and subsequent treatment with 6-month daily isoniazid regimen (6H) (as a standard regimen for comparison) or 6-week twice-weekly rifapentine and isoniazid regimen (6-week H2P2) in a cohort of 10,000 adults with an average initial age of 50 years. RESULTS: In the base-case analysis, LTBI testing and treatment with 6H was dominated (i.e., more expensive with a lower quality-adjusted life year (QALY)) by LTBI testing and treatment with 6-week H2P2. LTBI testing and treatment with 6-week H2P2 was more effective than no intervention at a cost of $20,943.81 per QALY gained, which was below the willingness-to-pay (WTP) threshold of $24,211.84 per QALY gained in China. The one-way sensitivity analysis showed the change of LTBI prevalence was the parameter that most influenced the results of the incremental cost-effectiveness ratios (ICERs). CONCLUSION: As estimated by a Markov model, LTBI testing and treatment with 6-week H2P2 was cost-saving compared with LTBI testing and treatment with 6H, and it was considered to be a cost-effective option for TB control in rural China.

Bidirectional modification effects on nonlinear associations of summer temperature and air pollution with first-ever stroke morbidity.

High temperature and air pollution may induce stroke morbidity. However, whether associations between high temperature and air pollution with stroke morbidity are modified by each other is still unclear. Data on 23,578 first-ever stroke patients in Shenzhen, China, during the summers of 2014-2018 were collected. Distributed lag nonlinear models were used to assess the modifying effects of air pollution stratified by the median for the associations between summer temperature and stroke morbidity at 0-3 lag days; modifying effects of temperature stratified by the minimum morbidity temperature on the associations between air pollution and stroke morbidity at the same lags were also estimated. The attributable risks of high temperature and high pollution on stroke morbidity were quantified. Stratified analyses of gender, age, migration type, and complication type were conducted to assess vulnerable population characteristics. Summer high temperature may induce stroke morbidity at high-level PM2.5, PM10, O3, SO2, and NO2 conditions, with attributable fraction (AF) of 2.982% (95% empirical confidence interval [eCI]: 0.943, 4.929), 3.113% (0.948, 5.200), 2.841% (0.943, 4.620), 3.617% (1.539, 5.470), and 2.048% (0.279, 3.637), respectively. High-temperature effects were statistically insignificant at corresponding low-level air pollution conditions. High-level PM2.5, PM10, and O3 may induce stroke morbidity at high-temperature conditions, with AF of 3.664% (0.036, 7.196), 4.129% (0.076, 7.963), and 4.574% (1.009, 7.762), respectively. High-level PM2.5, PM10, and O3 were not associated with stroke morbidity at low-temperature conditions. The effects of high temperature and high pollution on stroke morbidity were statistically significant among immigrants and patients with hypertension, dyslipidemia, or diabetes but insignificant among natives and patients without complications. The associations of summer temperature and air pollution with first-ever stroke morbidity may be enhanced bidirectionally. Publicity on the health risks of combined high temperature and high pollution events should be strengthened to raise protection awareness of relevant vulnerable populations.

Prevalence, risk factors, and clinical characteristics of pulmonary embolism in patients with acute exacerbation of COPD in Plateau regions: a prospective cohort study.

BACKGROUND AND OBJECTIVE: To investigate pulmonary thromboembolism (PE) in acute exacerbation of chronic obstructive pulmonary disease (AE-COPD) patients in plateau regions, we performed a prospective cohort study to evaluate the prevalence, risk factors and clinical characteristics of PE in the cohort of hospitalized patients at high altitude. METHODS: We did a prospective study with a total of 636 AE-COPD patients in plateau regions. Demographic and clinical data, laboratory data, including ultrasound scans of the lower extremities and cardiac ultrasound, and computed tomographic pulmonary angiography (CTPA) variables were obtained, and comparisons were made between groups with and without PE. We also conducted logistic regression to explore the risk factors of PE. RESULTS: Of the 636 patients hospitalized with AE-COPD (age 67.0 ± 10.7 years, 445[70.0%] male), 188 patients developed PE (29.6% [95% CI: 26.0%, 33.1%]). Multivariable logistic regression showed that ethnic minorities, D-dimer > 1 mg/L, AST > 40 U/L, chest pain, cardiac insufficiency or respiratory failure, Padua score > 3, and DVT were associated with a higher probability of PE. CONCLUSIONS: The prevalence of PE is high and those with a higher Padua score, the occurrence of deep venous thrombosis, higher neutrophil count, chest pain, cardiac insufficiency or respiratory failure, higher levels of AST, and a higher level of D-dimer had a higher risk of PE. The analysis of AE-COPD may help to provide more accurate screening for PE and improve clinical outcomes of patients with AE-COPD in plateau regions.

Optimizing BP neural network algorithm for Pericarpium Citri Reticulatae (Chenpi) origin traceability based on computer vision and ultra-fast gas-phase electronic nose data fusion.

This study utilized computer vision to extract color and texture features of Pericarpium Citri Reticulatae (PCR). The ultra-fast gas-phase electronic nose (UF-GC-E-nose) technique successfully identified 98 volatile components, including olefins, alcohols, and esters, which significantly contribute to the flavor profile of PCR. Multivariate statistical Analysis was applied to the appearance traits of PCR, identifying 57 potential marker-trait factors (VIP > 1 and P < 0.05) from the 118 trait factors that can distinguish PCR from different origins. These factors include color, texture, and odor traits. By integrating multivariate statistical Analysis with the BP neural network algorithm, a novel artificial intelligence algorithm was developed and optimized for traceability of PCR origin. This algorithm achieved a 100% discrimination rate in differentiating PCR samples from various origins. This study offers a valuable reference and data support for developing intelligent algorithms that utilize data fusion from multiple intelligent sensory technologies to achieve rapid traceability of food origins.

Perioperative outcomes comparison of robotic and video-assisted thoracoscopic thymectomy for thymic epithelial tumor: a single-center experience.

BACKGROUND: The advent of robot-assisted thoracoscopic surgery (RATS) has completely revolutionized the modality of thymectomy, which could reportedly achieve equivalent efficacy compared with a minimally invasive approach. This study was conducted to further compare the perioperative outcomes between these two modalities. METHODS: A retrospective single-center study that included patients receiving either a robotic or video-assisted thoracoscopic (VAT) thymectomy between February 2021 and January 2023 was conducted. All the patients were pathologically confirmed with thymic epithelial tumors. Clinical and pathological characteristics and perioperative outcomes were collected and compared between these two cohorts. RESULTS: A total of 190 patients were included in this study, with 61 (32.1%) and 129 (67.9%) receiving robotic and video-assisted thymectomy, respectively. The clinicopathological characteristics were not significantly different between these 2 groups. The size of the resected specimens in the RATS cohort was larger than the VATS cohort [median (IQR), 13.0 (8.0-16.0) vs. 9.0 (6.7-12.0) cm, p < 0.001], while the procedural duration was longer for the RATS group than its counterpart [median (IQR), 105 (85-143) vs. 85 (69-115) min, p = 0.001]. Moreover, no other significant difference was observed between these two groups. Since more than half of the robotic thymectomy was performed using a subxiphoid approach, a subgroup analysis was further conducted. Similarly, the robotic group through a subxiphoid approach harbored a longer procedural duration, and the size of the specimens obtained was larger than the VATS group [median (IQR), 14.0 (11.0-16.5) vs. 12.5 (8.5-15.0) cm, p = 0.061]. CONCLUSIONS: The early clinical efficacy of robotic thymectomy was proven comparable to the established VATS approach, and such a modality might have strength when obtaining larger specimens, which could contribute to improving long-term efficacy. Despite the longer procedural duration recorded in the early stage of conducting robotic thymectomy, further accumulation would help decrease the time.

Extracts of Dunkelfelder Grape Seeds and Peel Increase the Metabolic Rate and Reduce Fat Deposition in Mice Maintained on a High-Fat Diet.

Chronic high-fat diet intake may induce obesity and increase the risk of metabolic syndrome. The pomace of grape (Vitis vinifera L.) is rich in polyphenols, which are candidates for anti-obesity therapy. The present study aimed to investigate the effects of Dunkelfelder grape seed extract (GSE) and grape peel extract (GPE) on lipid and energy metabolism disorders in mice maintained on a high-fat diet (HFD). Male nine-week C57BL/6J mice were randomly assigned to one of four groups, namely, the normal chow diet (ND), HFD, HFD plus GSE (400 mg/kg BW) administered by oral gavage, or HFD plus GPE (400 mg/kg BW) administered by oral gavage. There were eight mice per group, and the experiment was 14 weeks in duration. The results showed that GSE and GPE treatments did not affect energy intake in mice on a high-fat diet, but body weight gain was 24.5% and 17.3% lower in the GSE- and GPE-treated mice than in the HFD group, respectively. They also decreased blood triglyceride (TG), total cholesterol (TC), and fasting blood glucose levels and increased high-density lipoprotein cholesterol (HDL-C). In addition, GSE and GPE reduced adipose tissue weight and excessive lipid droplet accumulation in the adipocytes. The metabolic chamber test showed that the GSE and GPE treatments enhanced oxygen consumption, carbon dioxide production, and heat release while decreasing the respiratory exchange rate (RER). This suggests that GSE and GPE augmented fuel oxidation and energy generation and increased the proportion of lipids being utilized in energy metabolism. GSE and GPE also upregulated the genes controlling lipolysis and downregulated those controlling lipogenesis in adipose tissues. Moreover, they significantly increased the expression levels of the genes regulating thermogenesis in BAT, eWAT, and iWAT, and mitochondrial biogenesis in all three types of adipose tissue. In conclusion, the present study empirically demonstrated that GSE and GPE enhance body fat utilization by augmenting lipid and energy metabolism and could, therefore, ameliorate high-fat diet-induced obesity.

Zanubrutinib-induced aseptic meningitis: a case report and literature review.

Zanubrutinib is a Bruton tyrosine kinase (BTK) inhibitor used in B cell malignancy treatment and is generally well tolerated in most patients. Zanubrutinib-induced aseptic meningitis is currently not reported. Herein, we present the first case of zanubrutinib-induced aseptic meningitis. A 33-year-old woman was diagnosed with relapsed/refractory follicular lymphoma and subsequently developed aseptic meningitis after receiving zanubrutinib treatment. We reviewed the literature and uncovered the lack of current reports on zanubrutinib or other BTK inhibitor-induced aseptic meningitis. Moreover, we summarized cases on aseptic meningitis induced by common chemotherapy and targeted drugs used for hematological diseases. Drug-induced aseptic meningitis (DIAM) is a drug-induced meningeal inflammation. The possible pathogenesis is the direct stimulation of the meninges via intrathecal injection of chemotherapy drugs and immune hypersensitivity response caused by immunosuppressive drugs. It is more common in women with immune deficiency and mainly manifests as persistent headache and fever. Cerebrospinal fluid examinations mainly demonstrate a significant increase in cells and proteins. DIAM diagnosis needs to exclude bacterial, fungal, viral, and tuberculosis infections; neoplastic meningitis; and systemic diseases involving the meninges. The prognosis of DIAM is usually favorable, and physicians should detect and stop the causative drug. In conclusion, zanubrutinib-induced aseptic meningitis is a rare but serious complication, and physicians should be promptly aware of this adverse event to avoid serious consequences.

Risk factors for mortality in patients with acute exacerbation of cor pulmonale in plateau.

BACKGROUND: The risk factors for mortality might differ between patients with acute exacerbation of chronic pulmonary heart disease in plains and plateaus, while there is a lack of evidence. METHOD: Patients diagnosed with cor pulmonale at Qinghai Provincial People's Hospital were retrospectively included between January 2012 and December 2021. The symptoms, physical and laboratory examination findings, and treatments were collected. Based on the survival within 50 days, we divided the patients into survival and death groups. RESULTS: After 1:10 matching according to gender, age, and altitude, 673 patients were included in the study, 69 of whom died. The multivariable Cox proportional hazards analysis showed that NYHA class IV (HR = 2.03, 95%CI: 1.21-3.40, P = 0.007), type II respiratory failure (HR = 3.57, 95%CI: 1.60-7.99, P = 0.002), acid-base imbalance (HR = 1.82, 95%CI: 1.06-3.14, P = 0.031), C-reactive protein (HR = 1.04, 95%CI: 1.01-1.08, P = 0.026), and D-dimer (HR = 1.07, 95%CI: 1.01-1.13, P = 0.014) were risk factors for death in patients with cor pulmonale at high altitude. Among patients living below 2500 m, cardiac injury was a risk factor for death (HR = 2.47, 95%CI: 1.28-4.77, P = 0.007), while no significant association was observed at ≥ 2500 m (P = 0.057). On the contrary, the increase of D-dimer was only a risk factor for the death of patients living 2500 m and above (HR = 1.23, 95% CI: 1.07-1.40, P = 0.003). CONCLUSION: NYHA class IV, type II respiratory failure, acid-base imbalance, and C- reactive protein may increase the risk of death in patients with cor pulmonale. Altitude modified the association between cardiac injury, D-dimer, and death in patients with cor pulmonale.

PABPN1 promotes clear cell renal cell carcinoma progression by suppressing the alternative polyadenylation of SGPL1 and CREG1.

Alternative polyadenylation (APA) is an important post-transcriptional regulatory mechanism in cancer development and progression. Poly(A) binding protein nuclear 1 (PABPN1) is a gene that encodes abundant nuclear protein, binds with high affinity to nascent poly(A) tails, and is crucial for 3'-UTR (3'-untranslated region) APA. Although PABPN1 has been recently reported as a dominant master APA regulator in clear cell renal cell carcinoma (ccRCC), the underlying functional mechanism remain unclear and the genes subject to PABPN1 regulation that contribute to ccRCC progression have not been identified. Here, we found that PABPN1 is upregulated in ccRCC, and its expression is highly associated with the clinical prognosis of ccRCC patients. PABPN1 promotes ccRCC cell proliferation, migration, invasion, and exerts an influence on sphingolipid metabolism and cell cycle. Moreover, PABPN1 depletion significantly suppressed cancer cell growth via induction of cell cycle arrest and apoptosis. In particular, we characterized PABPN1-regulated 3'-UTR APA of sphingosine-1-phosphate lyase 1 (SGPL1) and cellular repressor of E1A stimulated genes 1 (CREG1), which contribute to ccRCC progression. Collectively, our data revealed that PABPN1 promotes ccRCC progression at least in part, by suppressing SGPL1 and CREG1. Thus, PABPN1 may be a potential therapeutic target in ccRCC.

Arginine metabolism key enzymes affect the prognosis of myelodysplastic syndrome by interfering with macrophage polarization.

INTRODUCTION: Immune factors contribute to the onset of myelodysplastic syndrome (MDS). Arginine metabolism affects tumor-associated macrophage (TAM) polarization. This study investigated the infiltration of TAMs and effect of arginine metabolism key enzymes on MDS prognosis. METHODS: We used the GEO (Gene Express Omnibus database) dataset "GSE19429" to analyze and compare metabolism-associated pathways between MDS patients with excess blasts and those without. The markers of TAMs and arginine metabolism key enzymes, including CD68, iNOS, ARG1 and ASS1 were included in this study. A cohort of 79 patients with acute myeloid leukemia or MDS extracted from GenomicScape's online data mining platform was used to analyze the prognostic significance of the mRNA levels. Fifty-eight patients with primary MDS admitted to Sichuan University's West China Hospital from 2013 to 2017 were evaluated for protein levels. The coexpression of CD68, iNOS, and ARG1 was investigated using an Opal polychromatic immunofluorescence kit. RESULTS: The "Arginine and proline metabolism" pathways (padjusted = 0.01) were associated with excess blasts in patients with MDS. In the mRNA expression cohort, patients with low NOS2 (or iNOS) and high ARG1, ASS1, and CD68 expression levels had worse prognosis. Patients with high CD68 (p = 0.01), high iNOS (p < 0.01), low ARG1 (p = 0.01), and negative ASS1 (p = 0.02) protein expression levels had better prognoses. iNOS and ARG1 were coexpressed with CD68 in MDS patients with or without excess blasts, respectively. CONCLUSIONS: Arginine metabolism may contribute to the prognosis of patients with MDS by affecting TAM polarization.