A Case Report of Malignant Perivascular Epithelioid Cell Tumors of the Uterus and Literature Review.

Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal tumors originating from perivascular epithelioid cells. In gynecological system, the uterus is one of the most common sites affected by PEComas. Most PEComas are benign, and patients usually have a good prognosis. However, malignant uterus PEComa is rare, and better comprehensive epidemiological investigations are needed. To date, there are a few reported cases of uterus PEComa. We herein report a rare case of malignant PEComa occurred in the uterine corpus and cervix, possibly accompanied by pulmonary lymphangioleiomyomatosis (PLAM). In addition, 55 cases of malignant uterus PEComa were picked out and collected in the data base of PubMed and Medline. On the one hand, the age of onset, population distribution, clinical manifestations, metastatic sites and routes of metastasis were analysed. On the other hand, a summary of the epidemiology, pathogenesis, diagnosis, and treatments of uterus PEComa was given.

Predictive effect of estimated glomerular filtrate rate by creatinine or cystatin C on mortality in patients with coronary artery disease.

BACKGROUND: Renal dysfunction leads to poor prognosis of patients with coronary artery disease (CAD). Current studies have reported the prognosis or mortality of various diseases using different estimated glomerular filtrate rate (eGFR) formulas, while the performance of these equations is unclear in CAD patients. We aim to evaluate the predict effect of creatinine-based eGFR (eGFRcr), cystatin C-based eGFR (eGFRcys), and both creatinine and cystatin C-based eGFR (eGFRcr-cys) in CAD patients. METHODS: A total of 23,178 patients with CAD were included from CIN-II cohort study. The association of eGFRcr, eGFRcys and eGFRcr-cys with cardiovascular and all-cause mortality was detected by Cox regression analysis. The predictive effect of eGFRcr, eGFRcys and eGFRcr-cys on mortality was assessed. RESULTS: During a median follow up of 4.3 years, totally 2051 patients (8.8%) experience all-cause mortality, of which 1427 patients (6.2%) died of cardiovascular disease. For the detection of cardiovascular mortality among CAD patients, eGFRcr-cys had high discriminatory capacity with area under the curve (AUC) in receiver operator characteristic analysis of 0.730, which was significantly better than eGFRcr (AUC = 0.707, p < 0.001) and eGFRcys (AUC = 0.719, p < 0.001). Similar results were observed in all-cause mortality. Restricted cubic spline showed a U-shaped association between eGFRcr and all outcomes in patients with both reduced and supranormal eGFR levels, while a L-shaped association in eGFRcys and eGFRcr-cys. CONCLUSIONS: Estimated GFR based on both creatinine and cystatin C has highest predictive effect for cardiovascular and all-cause mortality among CAD patients. Meanwhile, supranormal eGFRcr may indicate a higher risk of mortality.

Cost-related medication nonadherence in adults with COPD in the United States 2013-2020.

BACKGROUND: Cost-related medication nonadherence (CRN) is associated with poor prognosis among patients with chronic obstructive pulmonary disease (COPD), a population that requires long-term treatment for secondary prevention. In this study, we aimed to estimate the prevalence and sociodemographic characteristics of CRN in individuals with COPD in the US. METHODS: In a nationally representative survey of US adults in the National Health Interview Survey (2013-2020), we identified individuals aged ≥18 years with a self-reported history of COPD. Cross-sectional study. RESULTS: Of the 15,928 surveyed individuals, a weighted 18.56% (2.39 million) reported experiencing CRN, including 12.50% (1.61 million) missing doses, 13.30% (1.72 million) taking lower than prescribed doses, and 15.74% (2.03 million) delaying filling prescriptions to save costs. Factors including age < 65 years, female sex, low family income, lack of health insurance, and multimorbidity were associated with CRN. CONCLUSIONS: In the US, one in six adults with COPD reported CRN. The influencing factors of CRN are multifaceted and necessitating more rigorous research. Targeted interventions based on the identified influencing factors in this study are recommended to enhance medication adherence among COPD patients.

Effects of finerenone and glucagon-like peptide 1 receptor agonists on cardiovascular and renal outcomes in type 2 diabetes mellitus: a systematic review and meta-analysis.

OBJECTIVE: To assess the effects of finerenone and glucagon-like peptide 1 receptor agonists (GLP1-RA) on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus (T2DM), and the relative cardiovascular benefits in patients with or without established atherosclerotic cardiovascular disease for different outcomes with these classes of drugs. METHODS: We searched PubMed, the Cochrane Library, and Embase from January 1, 2000, to December 30, 2022, to identify randomized controlled trials. The primary outcomes were the composite of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death (MACE); hospitalization for heart failure (HHF); and a composite of renal outcomes. The results were reported as hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: In total, we identified 11 trials and 73,927 participants, 13,847 (18.7%) in finerenone trials and 60,080 (81.3%) in GLP1-RA trials. Finerenone reduced the risk of MACE by 13% (HR, 0.87; 95% CI, 0.79-0.95; P = 0.003), while GLP1-RA reduced the risk in a similar magnitude by 13% (HR, 0.87; 95% CI, 0.83-0.92; P < 0.001). For both drug classes, the effect on lowering the risk of MACE was restricted to approximately 14% in patients with established atherosclerotic cardiovascular disease (HR, 0.86; 95% CI, 0.82-0.90; P < 0.001), whereas no effect was observed in patients without established atherosclerotic cardiovascular disease (HR, 0.93; 95% CI, 0.85-1.02; P = 0.12). GLP1-RA reduced myocardial infarction, stroke and cardiovascular death more than finerenone (which appeared to have no effect). Only finerenone was beneficial for reducing the risk of HHF (HR, 0.78; 95% CI, 0.66-0.92; P = 0.003). Both finerenone (HR, 0.84; 95% CI, 0.77-0.92; P < 0.001) and GLP1-RA (HR, 0.81; 95% CI, 0.76-0.86; P < 0.001) reduced the risk of kidney disease progression, including macroalbuminuria, and finerenone was superior to GLP1-RA in delaying deterioration of kidney function. CONCLUSIONS: Finerenone and GLP1-RA lead to a risk reduction in MACE to a similar degree in patients with established atherosclerotic cardiovascular disease. For both drug classes, the effect on lowering the risk of progression of kidney disease was also in a similar magnitude in patients with T2DM, whereas only finerenone had a significant protective effect against HHF. Treatment decisions for patients with T2DM should consider the clinical benefit profiles of each drug.

Melatonin alleviates necrotizing enterocolitis by reducing bile acid levels through the SIRT1/FXR signalling axis.

Bile acids (BAs) have increasingly been implicated in the onset and progression of necrotizing enterocolitis (NEC); multiple findings have demonstrated their ability to induce damage to the intestinal epithelium, thereby exacerbating disease severity. Although we previously showed that melatonin was able to treat NEC by correcting the Treg/Th17 imbalance, the modulatory effect of melatonin on BAs remains unclear. In this study, we conducted transcriptome analysis on intestinal tissues from patients with NEC and validated these findings. Subsequently, we treated mice with melatonin alone or in combination with an agonist/inhibitor of Sirtuin 1 (SIRT1) to assess faecal and serum BA levels, the expression levels of BA transporters and regulators, and the extent of intestinal injury. Our transcriptome results indicated dysregulation of BA metabolism and abnormal expression of BA transporters in patients with NEC, which were also observed in our NEC mouse model. Furthermore, exogenous BAs were found to aggravate NEC severity in mice. Notably, melatonin effectively restored the aberrant expression of BA transporters, such as apical membrane sodium-dependent bile acid transporters (ASBT), ileal bile acid-binding protein (IBABP), and organic solute transporter-alpha (OST-α), by upregulating SIRT1 expression while reducing farnesoid X receptor (FXR) acetylation, consequently leading to decreased serum and faecal BA levels and mitigated NEC severity. Thus, we propose a potential mechanism through which melatonin reduces BA levels via the SIRT1/FXR signalling axis in an NEC mouse model. Collectively, these results highlight that melatonin holds promise for reducing BA levels and represents a promising therapeutic strategy for treating NEC.

The D ~ Sense ex-vivo viability assay application in a patient with stage IV lung adenocarcinoma: a case report.

BACKGROUND: The treatment resistance is a problem for lung cancer. In this study, we used a vitro tissue culturing system to select a new therapy strategy for a patient with tyrosine kinase inhibitors (TKIs) resistance. CASE PRESENTATION: A 42-year-old male Asian patient was diagnosed with advanced lung adenocarcinoma harboring an exon 19 deletion in the epidermal growth factor receptor (EGFR) gene. The patient was treated with Gefitinib, resulting in an almost complete remission for over a year. The patient relapsed after 13 months treatment, and received four cycles of chemotherapy. At 20 months, the patient had developed multiple lung metastases and a solitary cerebellar metastasis. An EGFR T790M mutation was identified in the peripheral blood sample. Subsequent treatment with Osimertinib resulted in a complete response of the intracranial metastasis. By 33 months, the patient had developed a mediastinal tumor mass that responded well to local radiotherapy. By 39 months, an EGFR C797S cis-mutation had been identified and the patient was treated with Brigatinib and Cetuximab. By 44 months, the tumor cells from the pleural effusion had been tested for sensitivity against 30 targeted and cytostatic drugs using the D ~ Sense ex-vivo viability assay. The assay identified 8 drugs with moderate to high sensitivity. Combination therapy of Gemcitabin and Lobaplatin had resulted in disease stabilization. CONCLUSIONS: The case showed that individualized treatment aided by D ~ Sense ex-vivo viability assay can be a viable option for patients with advanced lung adenocarcinoma with pleural effusions.

Explore the alterations of downstream molecular pathways caused by ARID1A mutation/knockout in human endometrial cancer cells.

PURPOSE: As one of the most common gynecologic malignancies, endometrial cancer (EC) is driven by multiple genetic alterations that may be targeted for treatments. AT-rich interaction domain 1A (ARID1A) gene mutations were reported as early events in endometrial carcinogenesis. METHODS: To explore the alterations of downstream molecular pathways caused by ARID1A mutations and the associated therapeutic implications, we edited ARID1A gene in human endometrial cancer cell line Ishikawa using the Clustered Regularly Interspaced Short Palindromic Repeats and CRISPR-Associated Proteins (CRISPR/Cas9) technology. We successfully constructed a stable Ishikawa cell line with a confirmed 10 bp deletion on the ARID1A gene, which resulted in a code-shift mutation and gene knockout. RESULTS: Compared with unedited wild-type cells, ARID1A knockout (KO) led to reduced apoptosis, accelerated transformation from G0/G1 to S phase, and enhanced cell proliferation. ARID1A deficiency would reduce the protein levels of p21, caspase 7, and caspase 9 in Ishikawa endometrial cancer cells compared with the wild-type cells. In addition, ARID1A KO resulted in high levels of microsatellite instability (MSI-H). Moreover, transcriptomic analyses showed that ARID1A KO can lead to activated phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling. Furthermore, experimental analyses demonstrated that ARID1A KO cells had reduced expression of genetic instability-associated markers mutL homologue 1 (MLH1) and progesterone receptor B (PR) and increased p-Akt expression. CONCLUSION: These findings support further exploration of ARID1A as a therapeutic target for EC and provide insight into developing more effective treatments in EC, such as the combinatory use of immune checkpoint inhibitors.

Long Noncoding RNA Gpr137b-ps Promotes Advanced Atherosclerosis via the Regulation of Autophagy in Macrophages.

BACKGROUND: Current therapies cannot completely reverse advanced atherosclerosis. High levels of amino acids, induced by Western diet, stimulate mTORC1 (mammalian target of rapamycin complex 1)-autophagy defects in macrophages, accelerating atherosclerotic plaque progression. In addition, autophagy-lysosomal dysfunction contributes to plaque necrotic core enlargement and lipid accumulation. Therefore, it is essential to investigate the novel mechanism and molecules to reverse amino acid-mTORC1-autophagy signaling dysfunction in macrophages of patients with advanced atherosclerosis. METHODS: We observed that Gpr137b-ps (G-protein-coupled receptor 137B, pseudogene) was upregulated in advanced atherosclerotic plaques. The effect of Gpr137b-ps on the progression of atherosclerosis was studied by generating advanced plaques in ApoE-/- mice with cardiac-specific knockout of Gpr137b-ps. Bone marrow-derived macrophages and mouse mononuclear macrophage cell line RAW264.7 cells were subjected to starvation or amino acid stimulation to study amino acid-mTORC1-autophagy signaling. Using both gain- and loss-of-function approaches, we explored the mechanism of Gpr137b-ps-regulated autophagy. RESULTS: Our results demonstrated that Gpr137b-ps deficiency led to enhanced autophagy in macrophages and reduced atherosclerotic lesions, characterized by fewer necrotic cores and less lipid accumulation. Knockdown of Gpr137b-ps increased autophagy and prevented amino acid-induced mTORC1 signaling activation. As the downstream binding protein of Gpr137b-ps, HSC70 (heat shock cognate 70) rescued the impaired autophagy induced by Gpr137b-ps. Furthermore, Gpr137b-ps interfered with the HSC70 binding to G3BP (Ras GTPase-activating protein-binding protein), which tethers the TSC (tuberous sclerosis complex) complex to lysosomes and suppresses mTORC1 signaling. In addition to verifying that the NTF2 (nuclear transport factor 2) domain of G3BP binds to HSC70 by in vitro protein synthesis, we further demonstrated that HSC70 binds to the NTF2 domain of G3BP through its W90-F92 motif by using computational modeling. CONCLUSIONS: These findings reveal that Gpr137b-ps plays an essential role in the regulation of macrophage autophagy, which is crucial for the progression of advanced atherosclerosis. Gpr137b-ps impairs the interaction of HSC70 with G3BP to regulate amino acid-mTORC1-autophagy signaling, and these results provide a new potential therapeutic direction for the treatment of advanced atherosclerosis.

Association Between Systemic Immune Inflammation Level and Poor Prognosis Across Different Glucose Metabolism Status in Coronary Artery Disease Patients.

Background: Blood glucose levels significantly affect the clinical prognosis of patients with coronary artery disease (CAD), and systemic immune inflammation is a common risk factor for both CAD and diabetes. However, the relationship between immune inflammation levels and poor prognosis in patients with CAD with different glucose metabolic statuses remains unclear. Methods: Between January 2007 and December 2020, we recruited 84,645 patients with CAD. The systemic immune inflammation index (SII) was used to comprehensively reflect the immune and inflammatory levels of patients and was calculated using the following formula: neutrophils × platelets/lymphocytes. The patients were classified into nine groups according to their glucose metabolism status (diabetes mellitus [DM], pre-diabetes mellitus [pre-DM], and normal glucose regulation [NGR]). Cox regression models and competing risk Fine and Gray models were used to investigate the association between SII and clinical outcomes. Results: During the follow-up period, 12,578 patients died, including 5857 cardiovascular-related and 1251 cancer-related deaths. The risk of all-cause and cause-specific mortality increased with increasing SII tertiles in CAD patients with NGR, pre-DM, and DM. When considering glucose metabolism status, the multivariate cox regression revealed that CAD patients with DM and SII-H levels had the highest risk of all-cause mortality (1.69 [1.56-1.83]), cardiovascular mortality (2.29 [2.02-2.59]), and cancer mortality (1.29 [1.01-1.66]). Moreover, incorporating the SII into traditional risk factor models significantly improved the C-index for predicting all-cause and cardiovascular mortality. Conclusion: Systemic immune inflammation levels on admission were correlated with a higher risk of all-cause and cause-specific mortality in patients with CAD, particularly in those with DM.

CircRNAs in BALF exosomes and plasma as diagnostic biomarkers in patients with acute respiratory distress syndrome caused by severe pneumonia.

Background: The transcriptomic studies targeting circular RNAs (circRNAs) in bronchoalveolar lavage fluid (BALF) exosomes of acute respiratory distress syndrome (ARDS) patients caused by severe pneumonia have rarely been reported. This study aimed to screen and validate abnormally expressed circRNAs in exosomes from BALF of patients with ARDS caused by severe pneumonia and then evaluate the diagnostic values of these circRNAs for ARDS. Method: BALF was collected from four patients with ARDS caused by severe pneumonia and four healthy subjects. CircRNA expression profile was obtained by microarray analysis in BALF exosomes of the discovery cohort. The differentially expressed circRNAs in BALF exosomes were verified by real-time quantitative PCR (RT-qPCR) and underwent competitive endogenous RNA (ceRNA) network construction and functional enrichment analysis. Results: A total of 629 circRNAs were differentially expressed in BALF exosomes between ARDS patients and healthy subjects. Nine differentially expressed circRNAs were validated by RT-qPCR, and seven were consistent with the results of microarray analysis. CeRNA network analysis was performed for hsa_circRNA_002809, hsa_circRNA_042882, and hsa_circRNA_104034. Functional enrichment analysis showed that the target genes were mainly associated with hypoxia-induced damage, inflammatory response, and the HIF-1 signaling pathway. Hsa_circRNA_042882 and hsa_circRNA_104034 can be regarded as promising diagnostic biomarkers for patients with ARDS caused by severe pneumonia, with remarkable sensitivity and specificity of the area under the curve of 0.8050 and 1 or 0.835 and 0.799, respectively. Conclusion: This study obtained circRNA expression profiles of ARDS patients, and hsa_circRNA_042882 and hsa_circRNA_104034 were regarded as promising diagnostic biomarkers for patients with ARDS caused by severe pneumonia.

CUL3 induces mitochondrial dysfunction via MRPL12 ubiquitination in renal tubular epithelial cells.

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease worldwide and the strongest predictor of mortality in patients with diabetes. Despite its significance, the pathological mechanism underlying the onset and progression of DKD remains incompletely understood. In this study, we have shown that mitochondrial ribosomal protein L12 (MRPL12) plays a significant role in DKD by modulating mitochondrial function. We demonstrated that MRPL12 was mainly ubiquitinated at K150 in renal tubular epithelial cells. We have found that Cullin3 (CUL3), an E3 ubiquitin ligase, directly interacts with MRPL12 and induces the K63-linked ubiquitination of MRPL12, resulting in mitochondrial biosynthesis dysfunction. Moreover, under high-glucose (HG) conditions in renal tubular epithelial cells, we observed up-regulation of CUL3 expression, significant increase in CUL3-mediated ubiquitination of MRPL12 and dysregulation of mitochondrial biosynthesis. Notably, CUL3 knockdown stabilised the MRPL12 protein and protected mitochondrial biosynthesis under HG conditions. Our findings provide novel insight into how CUL3 affects mitochondrial biosynthesis in renal tubular epithelial cells through MRPL12 ubiquitination and suggest a potential therapeutic strategy for DKD in the future.

Combination of transbronchial cryobiopsy based clinic-radiologic-pathologic strategy and metagenomic next-generation sequencing for differential diagnosis of rapidly progressive diffuse parenchymal lung diseases.

Background: The complicated spectrum of rapidly progressive diffused parenchymal lung diseases (RP-DPLD) creates obstacles to the precise diagnosis and treatment. We evaluated the differential diagnostic value of transbronchial cryobiopsy (TBCB) based clinic-radiologic-pathologic (CRP) strategy combined with bronchoalveolar lavage fluid (BALF) metagenomic next-generation sequencing (mNGS) in RP-DPLD patients. Methods: RP-DPLD patients who underwent the diagnostic strategy of TBCB-based CRP combined with BALF mNGS at Shanghai East Hospital from May 2020 to Oct 2022 were retrospectively analyzed. Clinical characteristics were summarized, including demographic data, high-resolution computed tomography (HRCT) findings, histopathology of TBCB and microbiological results. Diagnostic value of the combined strategy, as well as the sensitivity, specificity, and positive detection rates of mNGS were evaluated. Results: A total of 115 RP-DPLD patients were enrolled, with a mean age of 64.4 years old and a male proportion of 54.8%. The pulmonary imaging findings in most patients were complex and diverse, with all patients showing bilateral lung diffuse lesions in HRCT, and progressively aggravated imaging changes within one month. After combining TBCB-based CRP strategy with mNGS, all participants received a corresponding diagnosis with 100% diagnostic yield. In these patients, 58.3% (67/115) were diagnosed with noninfectious RP-DPLD and 41.7% (48/115) with infection-related RP-DPLD. There were 86.1% of cases with known etiology according to the DPLD classification. BALF mNGS and traditional pathogen detection methods were performed in all patients, the positive detection rates were 50.4% (58/115) and 32.2% (37/115), respectively. Meanwhile, the mNGS showed significantly higher sensitivity and negative predictive value than the traditional pathogen detection methods for the diagnosis of infection-related RP-DPLD (100% vs 60.4% (p<0.001), 100% vs 75.6% (p<0.001), respectively). Among noninfectious RP-DPLD patients, the true negative rate of mNGS was 85.1% (57/67). All patients had their treatment regimen modified and the 30-day mortality was 7.0%. Conclusion: The novel strategy of TBCB-based CRP combined with mNGS provided dependable and sufficient evidence for the diagnosis, meanwhile further improved the accuracy of RP-DPLD treatment, as well as the prognosis of patients. Our results highlight the significant value of combined strategy in determining whether the RP-DPLD patients were infection associated or not.

Cost-related medication nonadherence in US adults with asthma: The National Health Interview Survey, 2013-2020.

BACKGROUND: Asthma is a chronic disease that needs long-term control for secondary prevention. Health-related expenditures resulting from asthma are rising in the United States, and medication nonadherence is associated with adverse health outcomes in patients with asthma. OBJECTIVE: To estimate the prevalence and risk factors of cost-related medication nonadherence (CRN) in individuals with asthma in the United States. METHODS: We identified patients aged above or equal to 18 years with a history of asthma in nationally representative cross-sectional data, the National Health Interview Survey 2013 to 2020. Participants were considered to have experienced CRN if at any time in the 12 months they reported skipping doses, taking less medication, or delaying filling a prescription to save money. The weighted prevalence of CRN was estimated overall and by subgroups. Logistic regression was used to identify CRN-related characteristics. RESULTS: Of the 26,539 National Health Interview Survey participants with a history of asthma, 4360 (15.77%; representing 3.92 million of the US population) reported CRN, with 10.12% (weighted 2.51 million) of patients skipping doses to save money, 10.82% (weighted 2.69 million) taking less medication to save money, and 13.35% (weighted 3.31 million) delaying filling a prescription to save money. The subgroups young, women, low income, no health insurance, currently smoking, and with comorbidities had a higher prevalence of CRN. The results of this sensitivity analysis did not differ from the overall results. CONCLUSION: In the United States, 1 in 6 adults with a history of asthma is nonadherence with medications due to costs. Removing financial barriers to accessing medication can improve medication adherence in patients with asthma.

The association between sarcopenia and incident chronic lung disease in the general population: A longitudinal study based on CHARLS data.

BACKGROUND: Data regarding the association of sarcopenia with chronic lung disease (CLD) has led to inconclusive results. The main goal of this research was to investigate the association between sarcopenia and CLD in middle-aged and elderly individuals in China. METHODS: The study sample consisted of 11,077 individuals without CLD at baseline chosen from the China Health and Retirement Longitudinal Study (CHARLS) data from 2015, followed up until 2018. Sarcopenia was identified utilizing the criteria set by the Asian Working Group on Sarcopenia (AWGS 2019) in 2019. Individuals were categorized into no-sarcopenia, possible-sarcopenia, and sarcopenia groups. The outcome of the study was considered to be incident CLD, which included chronic bronchitis, emphysema, pulmonary heart disease, and asthma. The association between sarcopenia and the risk of CLD was also examined by employing weighted Cox proportional hazard regression models. RESULTS: A total of 356 (3.20 %) participants developed CLD during the 3.6-year follow-up period. The cumulative incidence of CLD in the no-sarcopenia, possible-sarcopenia, and sarcopenia groups was 2.80 % (230/8222), 4.37 % (55/1260), and 4.45 % (71/1595), respectively. Individuals with possible sarcopenia {hazard ratio [HR] [95 % confidence interval (CI)]: 1.48 [1.04-2.09]} and sarcopenia [HR (95 % CI): 1.68 (1.12-2.51)] demonstrated a considerably high risk of developing CLD compared to individuals in the no-sarcopenia group. Moreover, individuals diagnosed with sarcopenia, as per the criteria established by the European Working Group on Sarcopenia in Older People (EWGSOP) 2018, were at considerably high risk for developing CLD compared to those in the no-sarcopenia group. CONCLUSION: This research involving adult Chinese individuals demonstrated a significant association between, possible sarcopenia and sarcopenia with an elevated risk of incident CLD, thereby emphasizing the importance of monitoring respiratory health in this population. KEY POINTS: Question: Whether muscle mass and sarcopenia are associated with the development of chronic lung disease (CLD) in Asian middle-aged and elderly individuals. FINDINGS: This longitudinal study encompassing 11,077 adults aged ≥45 years from the China Health and Retirement Longitudinal Study (CHARLS) data with 3.6 years of follow-up revealed a positive association between sarcopenia at baseline and incidence of CLD. Meaning: The findings suggest that possible sarcopenia and sarcopenia are linked to the development of CLD. Consequently, middle-aged and elderly individuals with possible sarcopenia and sarcopenia can be considered vulnerable regarding the primary prevention strategies for CLD.

Increased acylcarnitine ratio indices in newborn screening for carnitine-acylcarnitine translocase deficiency shows increased sensitivity and reduced false-positivity.

Background: Carnitine-acylcarnitine translocase (CACT) deficiency is a rare autosomal recessive metabolic disorder of mitochondrial long-chain fatty acid oxidation. Newborn screening via tandem mass spectrometry (MS/MS) technology enables early diagnosis. However, previous analyses of MS/MS data of patients showed that some results were misdiagnosed because they did not show typical acylcarnitine profiles of CACT deficiency. This study aimed to identify additional indices to assist the diagnosis of CACT deficiency. Methods: To evaluate the acylcarnitine profile and the acylcarnitine ratios of individuals with CACT deficiency, the MS/MS data of 15 patients diagnosed via genetic testing were retrospectively analysed. The sensitivity and false-positive rates of primary acylcarnitine markers and ratio indices were validated using the data from 28,261 newborns and 53 false-positive cases. Additionally, the MS/MS data of 20 newborns carrying the c.199-10T>G mutation in SLC25A20 and 40 normal controls were compared to verify whether the carriers had abnormal acylcarnitine concentrations. Results: The acylcarnitine profiles from 15 patients were classified into three categories using C12, C14, C16, C18, C16:1, C18:1, and C18:2 as the primary diagnostic markers. The first category represented a typical profile (P1-P6). The second category for patients P7 and P8 showed a significant decrease in the C0 level and a normal concentration of long-chain acylcarnitines. The third category for patients P9-P15 showed the presence of interfering acylcarnitines. The second and third categories may have been misdiagnosed. An acylcarnitine ratio analysis showed that C14/C3, C16/C2, C16/C3, C18/C3, C16:1/C3, and C16:1-OH/C3 were significantly increased in all 15 patients. The verification of 28,261 newborn screening results showed that the false-positive rate of ratios, except for (C16 + C18)/C0, was lower than that of acylcarnitine indices (0.02-0.08% vs. 0.16-0.88%). None of the single long-chain acylcarnitines could separate patients from the false-positive cases; however, all ratios produced good discrimination between the two groups. Conclusions: Based on the primary acylcarnitine markers alone, CACT deficiency can be misdiagnosed in newborn screening. The ratios of the primary markers (C16 + C18:1)/C2, C16/C2, C16:1/C3, and C16:1-OH/C3 can facilitate the diagnosis of CACT deficiency, thereby increasing sensitivity and reducing false-positivity.

Review of the Potential Therapeutic Effects and Molecular Mechanisms of Resveratrol on Endometriosis.

Endometriosis is a hormone-dependent inflammatory disease characterized by the existence of endometrial tissues outside the uterine cavity. Pharmacotherapy and surgery are the current dominant management options for endometriosis. The greater incidence of recurrence and reoperation after surgical treatment as well as the adverse effects of medical approaches predispose patients to potential limitations for their long-term usage. Consequently, it is essential to explore novel supplementary and alternative drugs to ameliorate the therapeutic outcomes of endometriotic patients. Resveratrol is a phenolic compound that has attracted increasing interest from many researchers due to its pleiotropic biological activities. Here, we review the possible therapeutic efficacies and molecular mechanisms of resveratrol against endometriosis based on in vitro, animal, and clinical studies. The potential mechanisms of resveratrol include anti-proliferative, pro-apoptotic, anti-angiogenic, anti-oxidative stress, anti-invasive and anti-adhesive effects, thereby suggesting that resveratrol is a promising candidate for endometriosis. Because most studies have investigated the effectiveness of resveratrol on endometriosis via in vitro trials and/or experimental animal models, further high-quality clinical trials should be undertaken to comprehensively estimate the clinical application feasibility of resveratrol on endometriosis.

Adipose tissue macrophage-derived exosomal miR-210-5p in modulating insulin sensitivity in rats born small for gestational age with catch-up growth.

Background: Insulin resistance has been implicated in the pathogenesis of children born small for gestational age (SGA) with catch-up growth (CUG). Adipose tissue macrophages (ATMs) regulate insulin resistance by secreting exosomes containing microRNA (miRNA) cargo; however, their pathogenic roles and molecular mechanism are not fully understood. This study aimed to investigate the role of miR-210-5p in rats born SGA with CUG and insulin resistance. Methods: The dietary needs of pregnant rats were restricted to ensure the birth of SGA rats. Transmission electron microscopy (TEM) and Western blot analysis were used to identify the exosomes from ATMs of CUG-SGA and adequate-for-gestational-age (AGA) rats. PKH-67 staining was performed to confirm the uptake of exosomes. miR-210-5p expression was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Glucose uptake and output were detected with glucose uptake and output assays, respectively. Insulin resistance was detected with glucose and insulin tolerance tests in vivo. The interaction between miR-210-5p and SID1 transmembrane family member 2 (SIDT2) was validated with dual-luciferase reporter assay. Results: miR-210-5p was observed to be highly expressed in the exosomes derived from the ATMs of CUG-SGA rats. ATM-derived exosomes can serve as vehicles to deliver miR-210-5p into adipocytes, myocytes, and hepatocytes, where it can enhance cellular insulin resistance. SIDT2 was identified as a direct target gene of miR-210-5p. The miR-210-5p-induced insulin resistance was reversed by the restored SIDT2 expression. However, overexpression of SIDT2 abolished the inhibitory effect of CUG-SGA-ATM-exosomal miR-210-5p on insulin sensitivity in vivo. Conclusions: ATM-derived exosomal miR-210-5p promoted insulin resistance in CUG-SGA rats by targeting SIDT2, which may act as a new potential therapeutic target for children born SGA with CUG.

L-shaped association between dietary zinc intake and the risk of developing cardiovascular disease in Chinese adults: A cohort study.

Background: Although the association of zinc (Zn) with cardiovascular disease (CVD) has been studied, no consensus has been reached on this relationship, particularly dietary Zn intake. The purpose of this study was to assess the effect of dietary Zn intake on the risk of CVD and to analyze whether this effect varied according to zinc consumption using representative data from China. Methods: 11,470 adults from the China Health and Nutrition Survey (CHNS) were eventually enrolled. The dietary information was collected by the 3 day 24-h dietary recalls combined with dietary weighting method. CVD was defined as participants with self-reported physician-diagnosed apoplexy and/or myocardial infarction during the follow-up. Cox regression was used to calculate the hazard ratios (HRs) of CVD with 95% confidence intervals. Restricted cubic spline function plus Cox regression was used to visualize the influence trend of dietary Zn intake on new-onset CVD and to test whether this trend is linear. 2-segment Cox regression was established to address the nonlinear trend. Results: 431 participants developed CVD, including 262 strokes and 197 myocardial infarctions. Compared with the lowest quintile (Q1), the adjusted hazard ratios and 95% confidence interval (CI) of CVD in Q2 to Q5 of dietary Zn intake were 0.72 (0.54, 0.97), 0.59 (0.42, 0.81), 0.50 (0.34, 0.72) and 0.44 (0.27, 0.71), respectively. The influence trend of dietary Zn intake on new-onset CVD was nonlinear and L-shaped. When dietary Zn intake <13.66 mg/day, increased dietary Zn intake was significantly associated with decreased risk of developing CVD (HR = 0.87, 95% CI: 0.82-0.92, p-value <0.0001). Conclusion: An L-shaped trend was observed between dietary Zn intake and the risk of developing CVD, indicating that dietary Zn intake should be improved moderately, but not excessively, for the benefit of cardiovascular disease.

Dynamic changes of the gut microbial colonization in preterm infants with different time points after birth.

Risks associated with preterm birth are unevenly distributed across all gestations. At earlier gestational ages, complications such as necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) conditions are significantly more common and are associated with a shift in the composition of the gut microbiome. Conventional bacterial culture techniques demonstrate that the colonization of the gut microbiota of preterm infants differs significantly from that of healthy-term infants. The current study aimed to investigate the impact of preterm infancy on the dynamic changes of fecal microbiota in preterm infants at different time points (1, 7, 14, 21, 28, and 42 days) after birth. We selected 12 preterm infants hospitalized in the Sixth Affiliated Hospital of Sun Yat-sen University from January 2017 to December 2017. A total of 130 fecal specimens from preterm infants were analyzed using 16S rRNA gene sequencing. We found that the colonization process of fecal microbiota in preterm infants is highly dynamic at different time points after birth, i.e., Exiguobacterium, Acinetobacter, and Citrobacter showed a declining abundance pattern with the advancement of age, while the bacterial groups of Enterococcus (Klebsiella and Escherichia coli) gradually grew and became the main microbiota during the development of fecal microbiota in preterm infants at the age of 42 days. Furthermore, the colonization of intestinal Bifidobacteria in preterm infants was relatively late and did not rapidly become the predominant microbiota. Moreover, the results also showed the presence of Chryseobacterium bacterial group, whose colonization was different in different time point groups. Conclusively, our findings deepen our comprehension and offer new perspectives on targeting particular bacteria in the treatment of preterm infants at different time points after birth.

[Blood metabolites in preterm infants with retinopathy of prematurity based on tandem mass spectrometry: a preliminary study]. / åŸºäºŽè´¨è°±æŠ€æœ¯çš„æ—©äº§å„¿è§†ç½‘è†œç— è¡€ä»£è°¢äº§ç‰©çš„åˆæ­¥ç ”ç©¶.

OBJECTIVES: To study new biomarkers for the early diagnosis of retinopathy of prematurity (ROP) by analyzing the differences in blood metabolites based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) and metabolomics. METHODS: Dried blood spots were collected from 21 infants with ROP (ROP group) and 21 infants without ROP (non-ROP group) who were hospitalized in the Sixth Affiliated Hospital of Sun Yat-sen University from January 2013 to December 2016. LC-MS/MS was used to measure the metabolites, and orthogonal partial least squares-discriminant analysis was used to search for differentially expressed metabolites and biomarkers. RESULTS: There was a significant difference in blood metabolic profiles between the ROP and non-ROP groups. The pattern recognition analysis, Score-plot, and weight analysis obtained 10 amino acids with a relatively large difference. Further statistical analysis showed that the ROP group had significant increases in blood levels of glutamic acid, leucine, aspartic acid, ornithine, and glycine compared with the non-ROP group (P<0.05). The receiver operating characteristic curve analysis showed that glutamic acid and ornithine had the highest value in diagnosing ROP. CONCLUSIONS: Blood metabolites in preterm infants with ROP are different from those without ROP. Glutamic acid and ornithine are the metabolic markers for diagnosing ROP. LC-MS/MS combined with metabolomics analysis has a potential application value in the early identification and diagnosis of ROP.