Abstract This study aimed to determine the mutational spectrum of familial Parkinson’s disease and sporadic early-onset Parkinson’s disease (sEOPD) in a mainland Chinese population and the clinical features of mutation carriers. We performed multiplex ligation-dependent probe amplification assays and whole-exome sequencing for 1676 unrelated patients with Parkinson’s disease in a mainland Chinese population, including 192 probands from families with autosomal-recessive Parkinson’s disease, 242 probands from families with autosomal-dominant Parkinson’s disease, and 1242 sEOPD patients (age at onset ≤ 50). According to standards and guidelines from the American College of Medical Genetics and Genomics, pathogenic/likely pathogenic variants in 23 known Parkinson’s disease-associated genes occurred more frequently in the autosomal-recessive Parkinson’s disease cohort (65 of 192, 33.85%) than in the autosomal-dominant Parkinson’s disease cohort (10 of 242, 4.13%) and the sEOPD cohort (57 of 1242, 4.59%), which leads to an overall molecular diagnostic yield of 7.88% (132 of 1676). We found that PRKN was the most frequently mutated gene (n = 83, 4.95%) and present the first evidence of an SNCA duplication and LRRK2 p.N1437D variant in mainland China. In addition, several novel pathogenic/likely pathogenic variants including LRRK2 (p.V1447M and p.Y1645S), ATP13A2 (p.R735X and p.A819D), FBXO7 (p.G67E), LRP10 (c.322dupC/p.G109Rfs*51) and TMEM230 (c.429delT/p.P144Qfs*2) were identified in our cohort. Furthermore, the age at onset of the 132 probands with genetic diagnoses (median, 31.5 years) was about 14.5 years earlier than that of patients without molecular diagnoses (i.e. non-carriers, median 46.0 years). Specifically, the age at onset of Parkinson’s disease patients with pathogenic/likely pathogenic variants in ATP13A2, PLA2G6, PRKN, or PINK1 was significantly lower than that of non-carriers, while the age at onset of carriers with other gene pathogenic/likely pathogenic variants was similar to that of non-carriers. The clinical spectrum of Parkinson’s disease-associated gene carriers in this mainland Chinese population was similar to that of other populations. We also detected 61 probands with GBA possibly pathogenic variants (3.64%) and 59 probands with GBA p.L444P (3.52%). These results shed insight into the genetic spectrum and clinical manifestations of Parkinson’s disease in mainland China and expand the existing repertoire of pathogenic or likely pathogenic variants involved in known Parkinson’s disease-associated genes. Our data highlight the importance of genetic testing in Parkinson’s disease patients with age at onset < 40 years, especially in those from families with a recessive inheritance pattern, who may benefit from early diagnosis and treatment.

Background: Growing evidence has shown that the gut-renal connection and gut microbiota dysbiosis play a critical role in immunoglobulin A nephropathy (IgAN). However, the fecal microbiome profile in Chinese patients with IgAN remains unknown. A cross-sectional study was designed for the first time to investigate the fecal microbiota compositions in patients with primary IgAN in China and to evaluate the relationship between the fecal microbiome and IgAN clinical presentation. Methods: Fecal samples were collected from 17 IgAN patients and 18 age-, sex-, and body mass index-matched healthy controls, and bacterial DNA was extracted for 16S ribosomal RNA gene sequencing targeting the V3-V4 region. Results: Fecal samples from the IgAN patients and healthy controls showed differences in gut microbiota community richness and compositions. Compared to the healthy controls, IgAN patients at the phylum level had an increased abundance of Fusobacteria, but a decreased abundance of Synergistetes. The significantly increased genera in the IgAN group were Escherichia-Shigella, Hungatella, and Eggerthella, all of which possess pathogenic potential. Furthermore, the genus Escherichia-Shigella was negatively associated with the estimated glomerular filtration rate (eGFR) but was positively associated with the urinary albumin-to-creatinine ratio (uACR). However, the genus rectale_group was present in the IgAN group with a low abundance and was negatively associated with the uACR. Functional analysis disclosed that infection-related pathways were enriched in the IgAN group. Conclusions: We demonstrate that gut microbiota dysbiosis occurs in patients with IgAN, and that changes in gut bacterial populations are closely related to IgAN clinical features, suggesting that certain specific gut microbiota may be a potential therapeutic target for IgAN.

Background Pseudomonas aeruginosa (PA) bloodstream infection (BSI) is a common complication in patients with acute leukemia (AL), and the prevalence of antibiotic-resistant strains poses a serious problem. However, there is limited information regarding antibiotic resistance, clinical characteristics, and outcomes of PA BSI in AL patients. This study explored characteristics associated with the clinical outcomes of AL patients with PA BSI and analyzed factors associated with BSI caused by multidrug-resistant (MDR) or carbapenem-resistant strains. Methods This single-center retrospective study enrolled hospitalized AL patients who developed PA BSI during January 2014–December 2019. The Kaplan-Meier method was used to plot survival curves. Multivariate logistic regression analyses were also performed. Results Of 293 eligible patients with PA BSI, 55 (18.8%) received inappropriate empirical antibiotic therapy within 48 hours of BSI onset, whereas up to 65.8% MDR-PA BSI patients received inappropriate empirical treatment. The 30-day mortality rate was 8.5% for all patients. However, the 30-day mortality rates were 28.9% and 5.5% in MDR-PA BSI and non–MDR-PA BSI patients, respectively (P < .001). On multivariate analysis, previous use of quinolones (odds ratio [OR], 5.851 [95% confidence interval {CI}, 2.638–12.975]) and piperacillin/tazobactam (OR, 2.837 [95% CI, 1.151–6.994]) were independently associated with MDR-PA BSI; and MDR-PA BSI (OR, 7.196 [95% CI, 2.773–18.668]), perianal infection (OR, 4.079 [95% CI, 1.401–11.879]), pulmonary infection (OR, 3.028 [95% CI, 1.231–7.446]), and age ≥55 years (OR, 2.871 [95% CI, 1.057–7.799]) were independent risk factors for 30-day mortality. Conclusions MDR increases mortality risk in PA BSI patients, and previous antibiotic exposure is important in MDR-PA BSI development. Rational antibiotic use based on local antimicrobial susceptibility and clinical characteristics can help reduce antibiotic resistance and mortality.

Abstract. The aim of this study was to evaluate the diagnostic efficiency of red blood cell distribution width (RDW), platelet distribution width (PDW), the neutrophil-lymphocyte count ratio (NLCR), procalcitonin (PCT) and C-reactive protein (CRP) for the prediction of sepsis. A total of 120 consecutive patients who underwent blood culture testing were included. The PCT and CRP levels, and RDW, PDW and NLCR percentages were determined and compared between patients with positive blood cultures and those without. The PCT, CRP, RDW, PDW and NLCR values were significantly higher in patients with positive blood culture compared with those without. PCT and NLCR each had a high diagnostic performance for the prediction of sepsis, with an area under the curve (AUC) for sepsis of 0.829 and 0.718, respectively. A combination of RDW, PDW and NLCR also exhibited a good diagnostic performance for sepsis (AUC, 0.704). NLCR is easily obtained by automated hematological analysis. Moreover, NLCR was found to have a high diagnostic efficiency for the prediction of sepsis, with greater sensitivity and accuracy than CRP. In conclusion, PCT exhibited the optimal diagnostic performance among the tested markers. The combination of the three parameters of RDW, PDW and NLCR, demonstrated a high diagnostic performance similar to that of PCT.

Aims: To examine the pattern and extent of cardiovascular developmental alterations among children conceived by assisted reproductive technology (ART) and its association with potential confounders. Methods: The present study was a prospective single-blind pilot design lasting 15 months. The ART group was recruited by a non-random, consecutive sample on the basis of the unique personal identification number assigned to ART children, whereas spontaneous conception controls were recruited by a population-based random sample from the same hospital by age. Echocardiography was available for the measurement of 128 ART children and 100 controls with respect to cardiovascular geometric morphology and cardiac function. Results: The majority of cardiac geometric morphology parameters were comparable among the study groups (P>0.05), except for significant increases in left ventricular (LV) relative wall thickness (P=0.038), LV mass index (P=0.005) and LV remodeling index (P=0.005) in ART children after adjustment for age, gender, body surface area and heart rate. The results showed similarity in LV systolic function characterized by ejection fraction (P=0.140) and shortening fraction (P=0.167) between the groups. However, ART children had a significant tendency toward a decrease in mitral A (P=0.008) and mitral E′ (P=0.012) compared with controls after adjusting for confounders. Additionally, Cox analysis suggested an independent association (P<0.05) of anthropometrics and perinatal outcomes in addition to the ART procedure itself with the differences in cardiac developmental status. Conclusion: Our findings support the presence of remodeling in the left cardiac geometric morphology and diastolic dysfunction and the absence of any change to the aortocoronary morphometry or systolic function in ART children compared with controls, which may be independently associated with the anthropometrics and perinatal outcomes in addition to the ART procedure.

Oral submucous fibrosis (OSF) is a chronic, insidious, and progressive oral mucosal disease that affects entire oral cavity and sometimes pharynx. It is precancerous and characterized by blanching and burning sensation of oral mucosa, staining of teeth and gingiva, and restricted mouth opening. It is multifactorial with a high incidence in chewers of areca nut (AN). This oral potentially malignant disorder has a high rate of malignant transformation rate (7%-30%) to oral squamous cell carcinoma (OSCC). 1 It is prevalent in Asian countries and has spread in Europe and North America. The prevalence of OSF was reported to be 1.0%-3.03% in Hunan Province, mainland China, 2 0.15%-14.4% in Vietnam, 3 and 0.086%-17.6% in Taiwan. 4 In the past decades, many efforts have been devoted to etiology, pathogenesis, and treatment of OSF. However, the research progress is still unsatisfactory. For instance, the etiology of OSF is commonly attributed to AN chewing, but some OSF patients did not have the habit. Also, there is no staging or grading scheme universally accepted and employed by clinicians, pathologists, and surgeons. Moreover, the pathogenesis and mechanism of OSF transformation into carcinomas are still obscure. Undoubtedly, it is crucial to make further studies of OSF to fill in the gaps. This article, for the first time, provided a detailed review of research advances of OSF in Asian countries, based on a comprehensive literature search using several primary databases (Figure 1), in which the terminologies, for example, OSF and oral potential malignant diseases (OPMD), were used. The OSF's etiology, histopathology, pathogenesis, clinical manifestations, diagnosis and differential diagnosis, and treatments were reviewed. The main challenges and corresponding measures were also discussed for guiding clinical research and practice concerning the disease. | E TI O LO GYOral submucous fibrosis is characterized by its multifactorial etiology. The most commonly identified factors include AN chewing, nutritional disorders, and genetic predisposition. They act individually or synergistically in the development of OSF. AbstractOral submucous fibrosis (OSF) is a chronic, insidious, and progressive oral mucosal disease that affects entire oral cavity and sometimes pharynx. This oral potentially malignant disorder has a high rate of malignant transformation (7%-30%) to oral squamous cell carcinoma (OSCC), posing global problems for public health. Due to enormous efforts dedicated to this disease in the past decades, there have been significant advances in identification of its etiology and pathogenesis as well as development of corresponding therapeutic approaches, in spite of several challenges. This study reviewed the existing literature concerning OSF in Asian countries, encompassing its etiology, histopathology, pathogenesis, clinical manifestations, diagnosis and differential diagnosis, and treatments. For improving treatment of OSF, the multifactorial etiology analysis, incorporation of effective molecular pathways, cy...

MicroRNA (miR)-138 was found to have suppressive effects on the growth and metastasis of different human cancers. In this study, we aimed to investigate the regulatory mechanism of miR-138 in non-small cell lung cancer (NSCLC). We applied the Quantitative real-time PCR (qRT-PCR) to detect the miR-138 levels in NSCLC tissues (n=21) and cell lines, Bioinformatical predication, luciferase reporter assay and western blot to identify the target gene of miR-138. We also applied Cell transfection, MTT, transwell, and wound healing assays to reveal the role of miR-138 in NSCLC cell proliferation and malignant transformation. We observed that miR-138 expression level was significantly decreased in NSCLC tissues compared to their matched adjacent normal tissues. It was also downregulated in tissues with poor differentiation, advanced stage or lymph nodes metastasis, as well as in several NSCLC cell lines compared to normal lung epithelial cell. We further identified YAP1 as a direct target gene of miR-138, and observed that the protein level of YAP1 was negatively mediated by miR-138 in NSCLC A549 cells. Moreover, overexpression of miR-138 significantly inhibited A549 cell growth, invasion and migration, while knockdown of miR-138 enhanced such capacities. Further investigation showed that the cell proliferation capacity was higher in the miR-138+YAP1 group, when compared with that in the miR-138 group, suggesting that overexpression of YAP1 rescued the suppressive effects of miR-138 upregulation on NSCLC cell proliferation. However, we found no difference of cell invasion and migration capacities between miR-138+YAP1 group and miR-138 group. Finally, YAP1 was markedly upregulated in NSCLC tissues compared to their marched adjacent normal tissues. Its mRNA levels were reversely correlated with the miR-138 levels in NSCLC tissues. In summary, our study suggests that miR-138 may play a suppressive role in the growth and metastasis of NSCLC cells partly at least by targeting YAP1.

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