Kunming Children's Hospital

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.

Importance: A randomized clinical trial is needed to determine whether the second-generation Abl-tyrosine kinase inhibitor dasatinib is more effective than the first-generation inhibitor imatinib mesylate for childhood Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). Objective: To determine whether dasatinib given at a daily dosage of 80 mg/m2 is more effective than imatinib mesylate at a daily dosage of 300 mg/m2 to improve event-free survival of children with Philadelphia chromosome-positive ALL in the context of intensive chemotherapy without prophylactic cranial irradiation. Design, Setting, and Participants: This open-label, phase 3 randomized clinical trial was conducted at 20 hospitals in China. Enrollment occurred from January 1, 2015, through September 18, 2018, and randomization was stopped on October 4, 2018, when the early stopping criterion of the trial was met. Patients aged 0 to 18 years were recruited. Of the 225 patients with the diagnosis, 35 declined participation and 1 died before treatment, leaving 189 patients available for analysis. Data were analyzed from January 1 through August 4, 2019. Interventions: Patients were randomized to receive daily dasatinib (n = 92) or imatinib (n = 97) continuously for the entire duration of ALL therapy from the time of diagnosis made during remission induction to the end of continuation therapy. Main Outcomes and Measures: The primary outcome was event-free survival, analyzed based on intention to treat. The secondary outcomes were relapse, death due to toxic effects, and overall survival. Results: Among the 189 participants (136 male [72.0%]; median age, 7.8 [interquartile range (IQR), 5.2-11.3] years) and a median follow-up of 26.4 (IQR, 16.3-34.1) months, the 4-year event-free survival and overall survival rates were 71.0% (95% CI, 56.2%-89.6%) and 88.4% (95% CI, 81.3%-96.1%), respectively, in the dasatinib group and 48.9% (95% CI, 32.0%-74.5%; P = .005, log-rank test) and 69.2% (95% CI, 55.6%-86.2%; P = .04, log-rank test), respectively, in the imatinib group. The 4-year cumulative risk of any relapse was 19.8% (95% CI, 4.2%-35.4%) in the dasatinib group and 34.4% (95% CI, 15.6%-53.2%) in the imatinib group (P = .01, Gray test), whereas the 4-year cumulative risk of an isolated central nervous system relapse was 2.7% (95% CI, 0.0%-8.1%) in the dasatinib group and 8.4% (95% CI, 1.2%-15.6%) in the imatinib group (P = .06, Gray test). There were no significant differences in the frequency of severe toxic effects between the 2 treatment groups. Conclusions and Relevance: Intensive chemotherapy including dasatinib at a dosage of 80 mg/m2 per day yielded superior results in the treatment of Philadelphia chromosome-positive ALL compared with imatinib mesylate at a dosage of 300 mg/m2 per day and provided excellent control of central nervous system leukemia without the use of prophylactic cranial irradiation. Trial Registration: Chinese Clinical Trial Registry: ChiCTR-IPR-14005706.

Triple-negative breast cancer (TNBC) exhibits poor prognosis, with high metastasis and low survival. Long non-coding RNAs (lncRNAs) play critical roles in tumor progression. Here, we identified lncRNA MIR100HG as a pro-oncogene for TNBC progression. Knockdown of MIR100HG decreased cell proliferation and induced cell arrest in the G1 phase, whereas overexpression of MIR100HG significantly increased cell proliferation. Furthermore, MIR100HG regulated the p27 gene to control the cell cycle, and subsequently impacted the progression of TNBC. In analyzing its underlying mechanism, bioinformatics prediction and experimental data demonstrated that MIR100HG participated in the formation of RNA-DNA triplex structures. MIR100HG in The Cancer Genome Atlas (TCGA) and breast cancer cell lines showed higher expression in TNBC than in other tumor types with poor prognosis. In conclusion, our data indicated a novel working pattern of lncRNA in TNBC progression, which may be a potential therapeutic target in such cancers.

OBJECTIVES/HYPOTHESIS: To develop a deep-learning-based computer-aided diagnosis system for distinguishing laryngeal neoplasms (benign, precancerous lesions, and cancer) and improve the clinician-based accuracy of diagnostic assessments of laryngoscopy findings. STUDY DESIGN: Retrospective study. METHODS: A total of 24,667 laryngoscopy images (normal, vocal nodule, polyps, leukoplakia and malignancy) were collected to develop and test a convolutional neural network (CNN)-based classifier. A comparison between the proposed CNN-based classifier and the clinical visual assessments (CVAs) by 12 otolaryngologists was conducted. RESULTS: In the independent testing dataset, an overall accuracy of 96.24% was achieved; for leukoplakia, benign, malignancy, normal, and vocal nodule, the sensitivity and specificity were 92.8% vs. 98.9%, 97% vs. 99.7%, 89% vs. 99.3%, 99.0% vs. 99.4%, and 97.2% vs. 99.1%, respectively. Furthermore, when compared with CVAs on the randomly selected test dataset, the CNN-based classifier outperformed physicians for most laryngeal conditions, with striking improvements in the ability to distinguish nodules (98% vs. 45%, P < .001), polyps (91% vs. 86%, P < .001), leukoplakia (91% vs. 65%, P < .001), and malignancy (90% vs. 54%, P < .001). CONCLUSIONS: The CNN-based classifier can provide a valuable reference for the diagnosis of laryngeal neoplasms during laryngoscopy, especially for distinguishing benign, precancerous, and cancer lesions. LEVEL OF EVIDENCE: NA Laryngoscope, 130:E686-E693, 2020.

PURPOSE: To compare the efficacy of intravitreal injection of ranibizumab (IVR) monotherapy and laser therapy for treatment-requiring retinopathy of prematurity (ROP) in Zone II. METHODS: A prospective, randomized, controlled single-center trial was applied from January 2014 to December 2014; infants who were diagnosed as Zone II treatment-requiring ROP (i.e., Zone II Stage 2 or 3 ROP with plus disease) were randomly assigned to receive IVR monotherapy or laser therapy, and the follow-up interval was at least 6 months. Any eyes that developed recurrence of ROP underwent crossover re-treatment. RESULTS: A total of 100 eyes of 50 ethnic Han Chinese infants were enrolled. At the last follow-up, 26 eyes of 13 infants developed recurrence of ROP in the IVR group and 2 eyes of 1 infant developed recurrence of ROP in the laser therapy group. There was a significant statistical difference in the rate of ROP recurrence between IVR and laser therapy to treat Zone II treatment-requiring ROP (P = 0.001). CONCLUSION: Although IVR appears to regress ROP to certain levels and continue to promote the vascularization of peripheral retinal vessels, a substantial proportion of infants developed recurrence of ROP after a single-dose IVR. Therefore, IVR is not recommended as a single-dose monotherapy for Zone II treatment-requiring ROP.

BACKGROUND: Mycoplasma pneumoniae (M. pneumoniae) is a significant contributor to community-acquired pneumonia among children. Since 1968, when a strain of M. pneumoniae resistant to macrolide antibiotics was initially reported in Japan, macrolide-resistant M. pneumoniae (MRMP) has been documented in many countries worldwide, with varying incidence rates. MRMP infections lead to a poor response to macrolide antibiotics, frequently resulting in prolonged fever, extended antibiotic treatment, increased hospitalization, intensive care unit admissions, and a significantly higher proportion of patients receiving glucocorticoids or second-line antibiotics. Since 2000, the global incidence of MRMP has gradually increased, especially in East Asia, which has posed a serious challenge to the treatment of M. pneumoniae infections in children and attracted widespread attention from pediatricians. However, there is still no global consensus on the diagnosis and treatment of MRMP in children. METHODS: We organized 29 Chinese experts majoring in pediatric pulmonology and epidemiology to write the world's first consensus on the diagnosis and treatment of pediatric MRMP pneumonia, based on evidence collection. The evidence searches and reviews were conducted using electronic databases, including PubMed, Embase, Web of Science, CNKI, Medline, and the Cochrane Library. We used variations in terms for "macrolide-resistant", "Mycoplasma pneumoniae", "MP", "M. pneumoniae", "pneumonia", "MRMP", "lower respiratory tract infection", "Mycoplasma pneumoniae infection", "children", and "pediatric". RESULTS: Epidemiology, pathogenesis, clinical manifestations, early identification, laboratory examination, principles of antibiotic use, application of glucocorticoids and intravenous immunoglobulin, and precautions for bronchoscopy are highlighted. Early and rapid identification of gene mutations associated with MRMP is now available by polymerase chain reaction and fluorescent probe techniques in respiratory specimens. Although the resistance rate to macrolide remains high, it is fortunate that M. pneumoniae still maintains good in vitro sensitivity to second-line antibiotics such as tetracyclines and quinolones, making them an effective treatment option for patients with initial treatment failure caused by macrolide antibiotics. CONCLUSIONS: This consensus, based on international and national scientific evidence, provides scientific guidance for the diagnosis and treatment of MRMP in children. Further studies on tetracycline and quinolone drugs in children are urgently needed to evaluate their effects on the growth and development. Additionally, developing an antibiotic rotation treatment strategy is necessary to reduce the prevalence of MRMP strains.

OBJECTIVE: To document the findings of a newborn eye examination programme for detecting ocular pathology in the healthy full-term newborn. METHODS: This is a cross-sectional study of the majority of newborns born in the Kunming Maternal and Child Healthcare Hospital, China, between May 2010 and June 2011. Infants underwent ocular examination within 42 days after birth using a flashlight, retinoscope, hand-held slit lamp microscope and wide-angle digital retinal image acquisition system. The retinal fundus examination utilised the RetCam wide-field digital imaging system (Clarity Medical Systems, Pleasanton, California, USA). The external eye, pupillary light reflex, red reflex, opacity of refractive media, anterior chamber and posterior segments were also examined. RESULTS: A total of 3573 healthy full-term newborns were enrolled and examined in the programme. There was detection of 871 abnormal cases (24.4%). The majority of abnormal exams were 769 (21.52%) retinal haemorrhages. Of these, there were 215 cases of significant retinal haemorrhage, possible sight threatening or amblyogenic, representing 6.02% of the total. In addition, 67 cases (1.88%) involved macular haemorrhage. The other 107 cases (2.99%) with abnormal ocular findings included subconjunctival haemorrhage, congenital microphthalmos, congenital corneal leukoma, posterior synechia, persistent pupillary membrane, congenital cataract, enlarged C/D ratio, retinal hamartoma versus retinoblastoma, optic nerve defects, macular pigment disorder and non-specific peripheral retinopathy. CONCLUSION: Ocular examination of healthy newborns leads to the detection of a significant number of ocular pathologies. The most commonly discovered ocular abnormality during examination of the newborns in this study is retinal haemorrhage. The long-term impact of these findings is unknown. Although presumed by some to benign, neonatal retinal haemorrhages due to birth trauma could be involved in altering visual development. Further work, including prospective examination of newborns with long-term follow-up, is needed and supported by our findings.

China has the second largest birth cohort in the world and the second highest number of deaths due to rotavirus infection. It is also the only country with a licensed rotavirus vaccine. Chinese policy makers now need credible estimates of the burden of rotavirus disease, to decide about vaccine use. From August 2001 through July 2003, prospective hospital-based surveillance for rotavirus diarrhea among children <5 years of age was conducted in 6 sentinel hospitals. Rotavirus isolates were characterized to determine the G and P genotypes circulating during the study. Of 3149 children who were admitted to the hospitals for diarrhea and for whom screening for rotavirus was performed, 1590 (50%) had positive results of an antigen detection assay. Of all episodes of rotavirus diarrhea, 95% occurred during the first 2 years of life. The most common rotavirus strain was P[8]G3 (49% of episodes), and all the common strains were detected, including G9 strains (4% of episodes). Ongoing efforts are under way to more precisely define the burden of rotavirus diarrhea in urban and rural populations, to assess the proportion of episodes that may be due to unusual or emerging strains, and to estimate the economic burden of rotavirus disease.

As part of a national rotavirus surveillance activity, we collected fecal specimens from 3,177 children with acute diarrhea in 10 regions of China between April 1998 and April 2000 and screened them for rotavirus. Rotavirus was detected in 41% (n = 1,305) of specimens, and in these, G1 was the predominant serotype (72.6%), followed by G3 (14.2%), G2 (12.1%), G4 (2.5%), G9 (0.9%), and G untypeable (0.7%). Among 327 G-typed strains tested for P genotype, 14 different P-G combinations were identified, with the globally common strains P[8]G1, P[4]G2, P[8]G3, and P[8]G4 representing 75.6% of all typed rotavirus strains. Among the uncommon strains, 11 were P[6]G9, and others included P[6]G1, P[6]G3, and five novel P-G combinations (P[9]G1, P[4]G1, P[4]G3, P[4]G4, and P[8]G2). Our results indicate that while the common rotavirus strains remain predominant, the diversity of strains is much greater than was previously recognized.

To identify the prognostic factors that are useful to improve central nervous system (CNS) control in children with acute lymphoblastic leukemia (ALL), we analyzed the outcome of 7640 consecutive patients treated on Chinese Children's Cancer Group ALL-2015 protocol between 2015 and 2019. This protocol featured prephase dexamethasone treatment before conventional remission induction and subsequent risk-directed therapy, including 16 to 22 triple intrathecal treatments, without prophylactic cranial irradiation. The 5-year event-free survival was 80.3% (95% confidence interval [CI], 78.9-81.7), and overall survival 91.1% (95% CI, 90.1-92.1). The cumulative risk of isolated CNS relapse was 1.9% (95% CI, 1.5-2.3), and any CNS relapse 2.7% (95% CI, 2.2-3.2). The isolated CNS relapse rate was significantly lower in patients with B-cell ALL (B-ALL) than in those with T-cell ALL (T-ALL) (1.6%; 95% CI, 1.2-2.0 vs 4.6%; 95% CI, 2.9-6.3; P < .001). Independent risk factors for isolated CNS relapse included male sex (hazard ratio [HR], 1.8; 95% CI, 1.1-3.0; P = .03), the presence of BCR-ABL1 fusion (HR, 3.8; 95% CI, 2.0-7.3; P < .001) in B-ALL, and presenting leukocyte count ≥50×109/L (HR, 4.3; 95% CI, 1.5-12.2; P = .007) in T-ALL. Significantly lower isolated CNS relapse was associated with the use of total intravenous anesthesia during intrathecal therapy (HR, 0.2; 95% CI, 0.04-0.7; P = .02) and flow cytometry examination of diagnostic cerebrospinal fluid (CSF) (HR, 0.2; 95% CI, 0.06-0.6; P = .006) among patients with B-ALL. Prephase dexamethasone treatment, delayed intrathecal therapy, use of total intravenous anesthesia during intrathecal therapy, and flow cytometry examination of diagnostic CSF may improve CNS control in childhood ALL. This trial was registered with the Chinese Clinical Trial Registry (ChiCTR-IPR-14005706).

OBJECTIVES: To determine the diagnostic and clinical utility of trio-rapid genome sequencing in critically ill infants. DESIGN: In this prospective study, samples from critically ill infants were analyzed using both proband-only clinical exome sequencing and trio-rapid genome sequencing (proband and biological parents). The study occurred between April 2019 and December 2019. SETTING: Thirteen member hospitals of the China Neonatal Genomes Project spanning 10 provinces were involved. PARTICIPANTS: Critically ill infants (n = 202), from birth up until 13 months of life were enrolled based on eligibility criteria (e.g., CNS anomaly, complex congenital heart disease, evidence of metabolic disease, recurrent severe infection, suspected immune deficiency, and multiple malformations). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 202 participants, neuromuscular (45%), respiratory (22%), and immunologic/infectious (18%) were the most commonly observed phenotypes. The diagnostic yield of trio-rapid genome sequencing was higher than that of proband-only clinical exome sequencing (36.6% [95% CI, 30.1-43.7%] vs 20.3% [95% CI, 15.1-26.6%], respectively; p = 0.0004), and the average turnaround time for trio-rapid genome sequencing (median: 7 d) was faster than that of proband-only clinical exome sequencing (median: 20 d) (p < 2.2 × 10-16). The metagenomic analysis identified pathogenic or likely pathogenic microbes in six infants with symptoms of sepsis, and these results guided the antibiotic treatment strategy. Sixteen infants (21.6%) experienced a change in clinical management following trio-rapid genome sequencing diagnosis, and 24 infants (32.4%) were referred to a new subspecialist. CONCLUSIONS: Trio-rapid genome sequencing provided higher diagnostic yield in a shorter period of time in this cohort of critically ill infants compared with proband-only clinical exome sequencing. Precise and fast molecular diagnosis can alter medical management and positively impact patient outcomes.

Organoids are derived from stem cells or organ-specific progenitors. They display structures and functions consistent with organs in vivo. Multiple types of organoids, including lung organoids, can be generated. Organoids are applied widely in development, disease modelling, regenerative medicine, and other multiple aspects. Various human pulmonary diseases caused by several factors can be induced and lead to different degrees of lung epithelial injury. Epithelial repair involves the participation of multiple cells and signalling pathways. Lung organoids provide an excellent platform to model injury to and repair of lungs. Here, we review the recent methods of cultivating lung organoids, applications of lung organoids in epithelial repair after injury, and understanding the mechanisms of epithelial repair investigated using lung organoids. By using lung organoids, we can discover the regulatory mechanisms related to the repair of lung epithelia. This strategy could provide new insights for more effective management of lung diseases and the development of new drugs.

Purpose: Familial exudative vitreoretinopathy (FEVR) is a severe hereditary retinal disorder characterized by defects in retinal vascular development. To date, six genes have been reported to be responsible for this disease, including LRP5, FZD4, TSPAN12, NDP, ZNF408, and KIF11. The purpose of our study was to investigate the genetic defects in Chinese patients with FEVR through mutational analyses of 31 pedigrees. Methods: Clinical data and peripheral blood were collected from 31 pedigrees with FEVR. All coding sequences and intron/exon junctions were amplified and sequenced comprehensively, followed by cosegregation testing to verify suspected variants in the family members. Finally, we assessed clinical relevance of the identified mutations, according to the standards and guidelines from the American College of Medical Genetics and Genomics. Results: Twelve index cases (12/31, 38.7%) were confirmed to harbor mutations in the known genes, including one previously reported mutation and 11 novel mutations. Among the detected mutations, LRP5 accounted for the largest proportion with a mean mutation rate of 16.1% (5/31, 16.1%), followed by NDP (3/31, 9.7%), FZD4 (2/31, 6.5%), TSPAN12 (1/31, 3.2%), and KIF11 (1/31, 3.2%). All the novel changes were predicted to be pathogenic by a series of bioinformatics analyses. Conclusions: We comprehensively screened six known disease-causing genes in 31 pedigrees with FEVR and achieved a clear picture of the mutation spectrum in Chinese patients with FEVR, which highlights the importance and utility of clinical genetic diagnosis.

OBJECTIVES: Before 2003, most children with acute lymphoblastic leukaemia (ALL) abandoned treatment, with only approximately 30% treated in China. With the development of national insurance for underprivileged patients, we assessed the current frequency and causes of treatment abandonment among patients with ALL who were enrolled in the Chinese Children's Cancer Group ALL protocol between 2015 and 2016. METHODS: Demographic, clinical and laboratory data on patients who abandoned treatment, as well as economic and sociocultural data of their families were collected and analysed. General health-related statistics were retrieved from publicly accessible databanks maintained by the Chinese government. RESULTS: At a median follow-up of 119 weeks, 83 (3.1%, 95% CI 2.5% to 3.8%) of the 2641 patients abandoned treatment. Factors independently associated with abandonment included standard/high-risk ALL (OR 2.62, 95% CI 1.43 to 4.77), presence of minimal residual disease at the end of remission induction (OR 3.57, 95% CI 1.90 to 6.74) and low-income economic region (OR 3.7, 95% CI 1.89 to 7.05). According to the family members, economic constraints (50.6%, p=0.0001) were the main reason for treatment abandonment, followed by the belief of incurability, severe side effects and concern over late complications. CONCLUSIONS: The rate of ALL treatment abandonment has been greatly reduced in China. Standard/high-risk ALL, residence in a low-income region and economic difficulties were associated with treatment abandonment. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR-IPR-14005706, pre-results.

Rotaviruses, double-stranded, non-enveloped RNA viruses, are a global health concern, associated with acute gastroenteritis and secretory-driven watery diarrhoea, especially in infants and young children. Conventionally, rotavirus is primarily viewed as a pathogen for intestinal enterocytes. This notion is challenged, however, by data from patients and animal models documenting extra-intestinal clinical manifestations and viral replication following rotavirus infection. In addition to acute gastroenteritis, rotavirus infection has been linked to various neurological disorders, hepatitis and cholestasis, type 1 diabetes, respiratory illness, myocarditis, renal failure and thrombocytopenia. Concomitantly, molecular studies have provided insight into potential mechanisms by which rotavirus can enter and replicate in non-enterocyte cell types and evade host immune responses. Nevertheless, it is fair to say that the extra-intestinal aspect of the rotavirus infectious process is largely being overlooked by biomedical professionals, and there are gaps in the understanding of mechanisms of pathogenesis. Thus with the aim of increasing public and professional awareness we here provide a description of our current understanding of rotavirus-related extra-intestinal clinical manifestations and associated molecular pathogenesis. Further understanding of the processes involved should prove exceedingly useful for future diagnosis, treatment and prevention of rotavirus-associated disease.

Enterovirus 71 (EV71) is one of the causative pathogens of hand-foot-and-mouth disease and effective antiviral agents and vaccines against this virus have, to date, not been available. MicroRNAs (miRNAs) are a recently discovered class of RNAs with the function of post-transcriptional gene expression regulation. It has been demonstrated that miRNAs play important roles in the complicated interaction network between virus and host, while few studies have explored the role of miRNAs in EV71 infection. A recent study showed that hsa-miR-23b was downregulated significantly in cell-infected viruses. To address this issue, biological software miRanda was first used to predict possible target sites of miR-23b at EV71 gene sequence, then to confirm it by luciferase assay. miR-23b mimics were transfected to verify its effects on infection of EV71. These results suggest that miR-23b and upregulation of miR-23b inhibited the replication of EV71 by targeting at EV71 3'UTR conserved sequence. Taken together, miR-23b could inhibit EV71 replication through downregulation of EV71 VPl protein. These results may enhance our understanding on the prevention and treatment of hand-foot-and-mouth disease caused by EV71 infection.

Neuroblastoma is the primary cause of cancer death in childhood. METTL14 is tightly linked to cancer. However, whether single-nucleotide polymorphisms (SNPs) in the METTL14 gene could predispose to neuroblastoma susceptibility lacks evidence. With an epidemiology case-control study, associations between METTL14 gene SNPs and overall risk for neuroblastoma were estimated in 898 cases and 1,734 controls. Following that, stratified analysis was performed. Among the five analyzed SNPs, rs298982 G>A and rs62328061 A>G exhibited a significant association with decreased susceptibility to neuroblastoma, whereas the associations with increased neuroblastoma susceptibility were observed for rs9884978 G>A and rs4834698 T>C. Moreover, subjects carrying two to five risk genotypes were more inclined to develop neuroblastoma than those with zero to one risk genotypes. The stratified analysis further demonstrated the protective effect of rs298982 G>A and rs62328061 A>G, as well as the predisposing effect of rs4834698 T>C and two to five risk genotypes, in certain subgroups. Haplotype analysis was performed. Moreover, false-positive report probability analysis validated the reliability of the significant results. The expression quantitative trait locus analysis revealed that rs298982 is correlated with the expression levels of its surrounding genes. Our results suggest that some SNPs in the METTL14 gene are associated with predisposition to neuroblastoma.

BACKGROUND: Elevated total alkaline phosphatase (T-ALP) levels are usually indicative of enhanced osteoblastic activity and bone conversion status and are thus considered as a key factor needed for fresh bone mineralization and synthesis. To date, there is no consistent conclusion on the association between the serum T-ALP levels and bone mineral density (BMD). Therefore, the present study focused on exploring the association of serum T-ALP with lumbar BMD among young adults. METHODS: The present cross-sectional study included 6,331 subjects included in the National Health and Nutrition Examination Survey (NHANES) during 2011-2016. The participants aged 20-40 years included 3,349 males and 2,982 females. Serum T-ALP was our main variable, lumbar BMD was our outcome variable, and additional variables were the possible impact modifiers. The relations were analysed by the trend study, weighted multiple linear regression models, smooth curve fitting, and stratified analyses. RESULTS: In a completely corrected multiple regression model, a negative association between serum T-ALP and lumbar BMD was discovered (β = -0.0007, 95% CI: -0.0009- -0.0005, P < 0.000001). After converting the continuous variable serum T-ALP into the categorical one, the significant negative association was still observed (P < 0.001), and in the subgroup and smooth curve fitting analyses, this negative correlation remained significant, too. CONCLUSIONS: Our study results indicated that serum T-ALP was negatively associated with lumbar BMD among young adults. Serum T-ALP measurement in the near future might become an effective biomarker to diagnose and treat osteoporosis on time.

Rotaviruses cause acute diarrhea worldwide. Previous studies of rotavirus diarrhea in China found that rotavirus infection is the most common cause of severe diarrhea in young children. In the present study, surveillance of rotavirus diarrhea was conducted involving 9549 children aged <5 years who were admitted for treatment of diarrhea at 11 sentinel hospitals in China from August 2003 through July 2007. Group A rotavirus was detected in 3749 (47.8%) of the 7846 fecal specimens by using enzyme-linked immunosorbent assay. Rotavirus isolates were characterized by reverse-transcriptase polymerase chain reaction to determine G and P genotypes. All the strains that are common worldwide were detected; G3P[8] was the most common. An unusual G5 strain was detected in 2 specimens. Of all episodes of rotavirus diarrhea, 94% occurred during the first 2 years of life, peaking at 6-23 months of age. Our findings indicate that globally common rotavirus strains continue to be a major cause of severe childhood diarrhea in China. Introduction of routine immunization with effective rotavirus vaccines would substantially reduce this burden.

Milk lipid secretion is a critical process for the delivery of nutrition and energy from parent to offspring. However, the underlying molecular mechanism is less clear. Here we report that TDP-43, a RNA-binding protein, underwent positive selection in the mammalian lineage. Furthermore, TDP-43 gene (Tardbp) loss induces accumulation of large lipid droplets and severe lipid secretion deficiency in mammary epithelial cells to outside alveolar lumens, eventually resulting in lactation failure and pup starvation within three weeks postpartum. In human milk samples from lactating women, the expression levels of TDP-43 is positively correlated with higher milk output. Mechanistically, TDP-43 exerts post-transcriptional regulation of Btn1a1 and Xdh mRNA stability, which are required for the secretion of lipid droplets from epithelial cells to the lumen. Taken together, our results highlights the critical role of TDP-43 in milk lipid secretion, providing a potential strategy for the screening and intervention of clinical lactation insufficiency.