Extremely unbalanced data refers to datasets with independent or dependent variables showing severe imbalances in proportions, which might lead to deviation of classical test statistics from theoretical distribution and difficulties in controlling type Ⅰ error. The increased availability of genome-wide resources from large population cohorts has highlighted the growing demand for efficient and accurate statistical methods for the process of extremely unbalanced data to improve the development of genetic statistical methods. This paper introduces two widely used correction methods in current genome-wide association study for extremely unbalanced data, i.e. Firth correction and saddle point approximation, describes their effectiveness in controlling type Ⅰ errors confirmed by simulation experiments, finally, and summarizes the commonly used software for extremely unbalanced genomic data to provide theoretical reference and suggestion for its application for the statistical analysis on extremely unbalanced data in future.

Objective:To compare and analyze the application efficacy of active surveillance versus passive surveillance in post-marketing safety monitoring of the group A and C meningococcal polysaccharide vaccine(MPSV-AC).Methods:Safety data for MPSV-AC from its market launch in November 2011 to June 2024 were collected from Beijing Zhifei Lyuzhu Biopharmaceutical Co., Ltd., and categorized into active and passive surveillance data based on acquisition methods. Active surveillance data were derived from adverse events cases observed in the company′s phase Ⅳ clinical trial. Passive surveillance data were carried out by the Pharmacovigilance Department through the drug adverse reaction direct reporting system, which downloaded all adverse events following immunization(AEFI) case reports. Cases of adverse events under active surveillance that were "definitely related", "probably related", "possibly related", or "possibly unrelated" were classified as adverse reaction cases, and cases of passive surveillance that were classified as "general reaction" or "abnormal reaction" were classified as adverse reaction cases, and were counted according to the number of cases. For cases where different clinical manifestations of adverse reactions or preferred terminology were present in the same one patient, the number was counted separately. Descriptive epidemiological methods were used to describe the incidence of adverse reaction reports, the distribution of clinical manifestations, adverse reactions recorded and not recorded in the instructions and adverse reactions outcomes of two monitoring methods. The differences in the incidence of reported adverse reactions between active and passive surveillance were compared and analysed.Results:A total of 922 patients with MPSV-AC adverse reaction reports were obtained through two monitoring modes, and 1 308 adverse reactions were occurred. In the active surveillance, the number of vaccination doses was 9 999, and 579 patients with adverse reactions were reported with 911 adverse reactions. In the passive surveillance, the number of vaccination doses was 4 185 800, and 343 patients with adverse reactions were reported with 397 adverse reactions. The incidence of reported adverse reactions in the passive surveillance was lower than in the active surveillance, and the difference was statistically significant [0.008% (343/4 185 800) vs. 5.791% (579/9 999), P<0.001]. The age range for active surveillance was ≥2 to<7 years old; the age range of passive surveillance was 0-15 years old, with the highest proportion of those aged ≥2 to<7 years old [79.30% (273/343)]. The clinical manifestation that topped the composition ratio of major adverse reactions for both surveillanceme thods was fever, but systemic symptoms such as malaise and anorexia were more frequently reported in active surveillance, whereas signs visible on the surface such as allergic rash, erythema and hard nodules were reported in passive surveillance. The proportion of serious adverse reactions from active surveillance was 0.22%(2/922), which were upper respiratory tract infection and febrile convulsions. Of the adverse reactions not included in the specification, those from active surveillance mainly involved infections and invasive diseases [77.32% (75/97)], and those from passive surveillance mainly involved diseases of the skin and subcutaneous tissues(6/12). All 579 patients in the active surveillance adverse reaction reports were monitored until cured; in the passive surveillance, 199 cases (50.13%, 199/397) were cured, 168 cases (42.32%, 168/397) were improved, and 30 cases (7.56%, 30/397) were unknown. Conclusions:Active surveillance is irreplaceable for postmarketing safety evaluation of vaccines, as it comprehensively captures safety signals, indicating good safety of MPSV-AC. A multi-source data integration platform could be established in the future.

Extremely unbalanced data refers to datasets with independent or dependent variables showing severe imbalances in proportions, which might lead to deviation of classical test statistics from theoretical distribution and difficulties in controlling type Ⅰ error. The increased availability of genome-wide resources from large population cohorts has highlighted the growing demand for efficient and accurate statistical methods for the process of extremely unbalanced data to improve the development of genetic statistical methods. This paper introduces two widely used correction methods in current genome-wide association study for extremely unbalanced data, i.e. Firth correction and saddle point approximation, describes their effectiveness in controlling type Ⅰ errors confirmed by simulation experiments, finally, and summarizes the commonly used software for extremely unbalanced genomic data to provide theoretical reference and suggestion for its application for the statistical analysis on extremely unbalanced data in future.

Objective:To compare and analyze the application efficacy of active surveillance versus passive surveillance in post-marketing safety monitoring of the group A and C meningococcal polysaccharide vaccine(MPSV-AC).Methods:Safety data for MPSV-AC from its market launch in November 2011 to June 2024 were collected from Beijing Zhifei Lyuzhu Biopharmaceutical Co., Ltd., and categorized into active and passive surveillance data based on acquisition methods. Active surveillance data were derived from adverse events cases observed in the company′s phase Ⅳ clinical trial. Passive surveillance data were carried out by the Pharmacovigilance Department through the drug adverse reaction direct reporting system, which downloaded all adverse events following immunization(AEFI) case reports. Cases of adverse events under active surveillance that were "definitely related", "probably related", "possibly related", or "possibly unrelated" were classified as adverse reaction cases, and cases of passive surveillance that were classified as "general reaction" or "abnormal reaction" were classified as adverse reaction cases, and were counted according to the number of cases. For cases where different clinical manifestations of adverse reactions or preferred terminology were present in the same one patient, the number was counted separately. Descriptive epidemiological methods were used to describe the incidence of adverse reaction reports, the distribution of clinical manifestations, adverse reactions recorded and not recorded in the instructions and adverse reactions outcomes of two monitoring methods. The differences in the incidence of reported adverse reactions between active and passive surveillance were compared and analysed.Results:A total of 922 patients with MPSV-AC adverse reaction reports were obtained through two monitoring modes, and 1 308 adverse reactions were occurred. In the active surveillance, the number of vaccination doses was 9 999, and 579 patients with adverse reactions were reported with 911 adverse reactions. In the passive surveillance, the number of vaccination doses was 4 185 800, and 343 patients with adverse reactions were reported with 397 adverse reactions. The incidence of reported adverse reactions in the passive surveillance was lower than in the active surveillance, and the difference was statistically significant [0.008% (343/4 185 800) vs. 5.791% (579/9 999), P<0.001]. The age range for active surveillance was ≥2 to<7 years old; the age range of passive surveillance was 0-15 years old, with the highest proportion of those aged ≥2 to<7 years old [79.30% (273/343)]. The clinical manifestation that topped the composition ratio of major adverse reactions for both surveillanceme thods was fever, but systemic symptoms such as malaise and anorexia were more frequently reported in active surveillance, whereas signs visible on the surface such as allergic rash, erythema and hard nodules were reported in passive surveillance. The proportion of serious adverse reactions from active surveillance was 0.22%(2/922), which were upper respiratory tract infection and febrile convulsions. Of the adverse reactions not included in the specification, those from active surveillance mainly involved infections and invasive diseases [77.32% (75/97)], and those from passive surveillance mainly involved diseases of the skin and subcutaneous tissues(6/12). All 579 patients in the active surveillance adverse reaction reports were monitored until cured; in the passive surveillance, 199 cases (50.13%, 199/397) were cured, 168 cases (42.32%, 168/397) were improved, and 30 cases (7.56%, 30/397) were unknown. Conclusions:Active surveillance is irreplaceable for postmarketing safety evaluation of vaccines, as it comprehensively captures safety signals, indicating good safety of MPSV-AC. A multi-source data integration platform could be established in the future.

Objective To explore the clinical efficacy of low molecular weight heparin combined with insulin in the treatment of hyper-triglyceridemic-acute pancreatitis(HTG-AP).Methods A total of 106 patients diagnosed with HTG-AP who were admitted to the department of gastroenterology of Huaibei People's Hospital from May 2022 to July 2023 were selected as the research objects.According to the random number table method,the low-molecular heparin group(35 cases,received a 5 000 U subcutaneous injection low-molecular heparin once every 12 hours for 6 days),the insulin group(35 cases,received intravenous insulin pumping at a rate of 2 U/h,with careful monitoring of the patient's random blood glucose levels to prevent hypoglycemia),and the combination therapy group(36 cases,received both low-molecular heparin and insulin).Before treatment and at 1,2,and 6 days after treatment,the difference of serum triacylglycerol(TG),total cholesterol(TC),blood amylase,inflammatory factors[C-reactive protein(CRP),interleukin-6(IL-6)],calcium ions,and creatinine levels among the three groups were compared.The modified computed tomography severity index(MCTSI)scores,acute physiology and chronic health evaluationⅡ(APACHEⅡ),hospital length of stay,and hospital costs before and after 6 days of treatment were observed.Results After treatment,the TC of all three groups significantly decreased compared to before treatment(P<0.05),but there was no significant difference among the three groups.The calcium ion levels of the three groups did not show a statistically significant difference before and after treatment.After 6 days of treatment,the creatinine levels of the three groups significantly decreased compared to before treatment,but there was no significant difference among the three groups.After 2 days of treatment,serum TG levels were significantly lower in the combination therapy group and insulin group compared to the low-molecular heparin group(mmol/L:4.6±1.7,4.4±1.8 vs.5.6±2.0,both P<0.05).However,there was no statistically significant difference between the combination therapy group and the insulin group.After 6 days of treatment,the combination therapy group showed significantly lower levels of serum TG,blood amylase,CRP,and IL-6 compared to the insulin group and the low-molecular heparin group[TG(mmol/L):2.8±1.9 vs.4.3±1.9,5.0±2.2,blood amylase(U/L):36.0(32.0,45.0)vs.59.0(43.0,71.0),52.0(45.0,64.0),CRP(mg/L):12.9(8.8,29.7)vs.35.3(21.7,50.3),31.4(23.0,45.1),IL-6(ng/L):15.4(9.8,23.5)vs.25.6(16.4,51.5),32.9(14.7,41.4),all P<0.05].After 6 days of treatment,the APACHEⅡscores of all three groups decreased significantly(all P<0.05).The MCTSI scores of the insulin group and the combined treatment group also decreased significantly compared to before treatment.Furthermore,the MCTSI and APACHEⅡscores of the combination therapy group were significantly lower than those of the low-molecular heparin group and the insulin group(MCTSI score:2.3±0.7 vs.3.3±1.7,2.9±1.3,APACHEⅡscore:1.3±1.2 vs.2.5±2.4,2.6±2.5,all P<0.05).The combination therapy group had significantly lower length of hospital stay and treatment cost compared to the low molecular heparin and insulin groups[length of hospital stay(days):6.9±1.6 vs.8.8±3.4,8.5±2.8,and cost of treatment(yuan):6 040.5(5 239.4,7 105.9)vs.6 696.4(5 791.5,11 026.2),6 918.5(6 087.9,10 080.8),all P<0.05].Conclusions The combination of low-molecular heparin and insulin treatment can significantly reduce serum TG and inflammatory factor levels,as well as the severity and duration of the disease.This approach can also reduce the cost of treatment.Therefore,it is worth promoting and applying in clinical settings.

Extremely unbalanced data here refers to datasets where the values of independent or dependent variables exhibit severe unbalance in proportions, such as extremely unbalanced case-control ratio, very low incidence rate of disease, heavily censored time-to-event data, and low-frequency or rare variants. In such scenarios, the statistic derived from hypothesis test using the classical statistical method, e.g., logistic regression model and Cox proportional hazard regression model, might deviate from theoretical asymptotic distribution, resulting in inflation or deflation of type I error. With the increased availability and exploration of resources from large-scale population cohorts in genome-wide association study (GWAS), there is a growing demand for effective and accurate statistical approaches to handle extremely unbalanced data in independent and non-independent samples. Our study introduces classical statistical methods in genetic statistics firstly, then, summarizes the failure of classical statistical methods in dealing with extremely unbalanced data through simulation experiments to draw researchers' attention to the extremely unbalanced data in GWAS.

It is critical to regulate the senescence-associated secretory phenotype (SASP) due to its effect on promoting malignant phenotypes and limiting the efficiency of cancer therapy. In this study, we demonstrated that marchantin M (Mar-M, a naturally occurring bisbibenzyl) suppressed pro-inflammatory SASP components which were elevated in chemotherapy-resistant cells. Mar-M treatment attenuated the pro-tumorigenic effects of SASP and enhanced survival in drug-resistant mouse models. No toxicity was detected on normal fibroblast cells or in animals following this treatment. Inactivation of transcription factor EB (TFEB) and nuclear factor-B (NF-B) by Mar-M significantly accounted for its suppression on the components of SASP. Furthermore, inhibition of SASP by Mar-M contributed to a synergistic effect during co-treatment with doxorubicin to lower toxicity and enhance antitumor efficacy. Thus, chemotherapy-driven pro-inflammatory activity, seen to contribute to drug-resistance, is an important target for Mar-M. By decreasing SASP, Mar-M may be a potential approach to overcome tumor malignancy.

Objective To evaluate the clinical effect of direct identification of microorganisms from the midstream urine by MALDI-TOF MS combined with separation gel tube and differential centrifugation. Methods A total of 2150 samples of midstream urine were collected from the outpatient and inpatients in Huadong Hospital affiliated to Fudan University from May 2017 to April 2018, including 934 males and 1216 females with an age of (72.0 ± 17.5) years. After preliminary quantification by microscopic examination, samples with a bacterial acount of ≥ 105cfu/ml were treated with two kinds of pretreatment methods to enrich the bacteria for directly identification by MS. Based on the results of quantitative urine culture and MS identification,the coincidence rates of two kinds of pretreatment methods combined with MS were analyzed. All statistical analyses were performed using Stata/SE 14.0, differences between the groups were compared by Pearson Chi-square tests. Results 464 out of 2150 midstream urine samples (21.6％) had a bacterial count ≥ 105cfu/ml after microscopic examination. In traditional culture combined with MALDI-TOF MS, 436(94.0％)cases were single species, 28(6.0％)cases were double species. Among single species of bacteria samples infection, the gram-negative bacteria accounted for 78.9％(344/436),the Gram-positive bacteria accounted for 15.8％(69/436),and the fungus accounted for 5.3％(23/436). In two methods that the separation gel tube combined MALDI-TOF MS and the differential centrifugation combined MALDI-TOF MS, the gram-negative bacteria coincidence rates were 92.4％(318/344)and 89.0％(306/344) respectively, the Gram-positive bacteria coincidence rates were 68.1％(47/69)and 62.3％(43/69) respectively,and the fungi coincidence rates were 56.5％(13/23) and 34.8％(8/23)respectively. Meanwhile,the double bacteria infection coincidence rates were 64.3％(18/28)and 60.7％(17/28). Conclusions The separation gel tube combined MALDI-TOF MS and the differential centrifugation combined MALDI-TOF MS identify directly the gram-negative bacteria in the midstream urine samples with high detection rate and accuracy,and they are rapid and simple pretreatment method,suitable for rapid screening of midstream urine.

Objective: To evaluate the efficacy and safety of Saccharomyces boulardii in the prevention of antibiotic-associated diarrhea (AAD) in infants and young children. Method: From November 2012 to September 2013, ten research units of large teaching hospitals or children′s hospitals participated in this multicenter randomized controlled clinical trial. Hospitalized young children aged between 1 month and 3 years (nongastrointestinal infection and antibiotic therapy required)were involved in our study. The children were randomly divided into control group and prevention group by means of block random allocation method. The control group received antibiotic therapy and other conventional treatment. The prevention group was given additional Saccharomyces boulardii (250 mg/d) orally. Diarrhea rates of two groups were compared both during the usage of antibiotics and within 14 days after the antibiotics withdrawal. The adverse reactions of Saccharomyces boulardii were observed all through this study. The results were analyzed by χ² test or Kruskal-Wallis test or t test. Result: Totally 408 cases (213 cases in prevention group and 195 cases in control group) were enrolled. The age ranged from 1 month to 3 years, with an average age of 1.14 years. The basic diseases were parenteral infections: 368 cases with different kinds of respiratory tract infections or pneumonia, 10 cases of bacterial meningitis, 9 cases with septicemia or sepsis, 6 cases with pertussis or pertussis like syndrome, 5 cases with urinary infection, 5 cases with skin or subcutaneous tissue infections, 3 cases of Kawasaki disease, one with scarlet fever and one with congenital syphilis. During the administration of antibiotics, the incidence of AAD in prevention group was 10.3% (22 cases), which was significantly lower than that of control group (57 cases, 29.2%, χ²=23.296, P<0.05). Within 14 days after the discontinuation of antibiotics, the percent of new diarrhea cases in prevention group (2.4%, 5/213) was also significantly lower than that in control group (16.4%, 32/195, χ²=23.4, P<0.05). Further analysis revealed that the rate of AAD in children less than or equal to 1 year old (25.1%, 52/207) was significantly higher than that of over 1 year old (13.4%, 27/201, χ²=8.922, P<0.05). The incidence of AAD in children treated with antibiotics for more than 5 days was 22.2%(60/270), which was significantly higher than that of less than or equal to 5 days (13.8%, 19/138, χ²=4.180, P<0.05). Although no significant difference was observed, the AAD rate of patients with combined use of two antibiotics was higher than that of using one. During the antibiotic therapy, compared with the control group, the risk of AAD in children under 1 year old was reduced by 52% (χ²=9.217, P<0.05), and 91% (χ²=20.35, P<0.05) in the children over 1 year old in prevention group. The risk of AAD of prevention group decreased by 66% (χ²=13.67, P<0.05) in patients treated with one antibiotics, and 65% in children with combined use of antibiotics (χ²=10.57, P<0.05). In patients treated with antibiotics for less than or equal to 5 days, the risk of AAD decreased by 74% in prevention group (χ²=7.38, P<0.05); and 63% if the course lasted for over 5 days (χ²=16.87, P<0.05). Within 14 days after the withdrawal of antibiotics, compared with the control group, the risk of diarrhea in the prevention group decreased by 82% (χ²=13.35, P<0.05) in infants (≤1 year old) and 93% (χ²=12.00, P<0.05) in children (>1 year old); the risk of diarrhea was reduced by 86% (χ²=9.57, P<0.05) and 87% (χ²=17.71, P<0.05) respectively in prevention group with single and combined use of antibiotics. In patients treated with antibiotics for more than 5 days, the risk of diarrhea in prevention group was reduced by 63% (χ²=22.79, P<0.05), while there was no significant difference if the antibiotics course was less than or equal to 5 days (χ²=2.97, P>0.05). No adverse effects related with Saccharomyces boulardii were observed in our study. Conclusion Saccharomyces boulardii is effective and safe to prevent AAD of infants and young children both during the usage of antibiotics and up to 14 days after drug discontinuance. It can be one of the drugs of for choice prevention of AAD in infants and young children. Trial registration Chinese Clinical Trial Tegister, ChiECRCT-2012-25.

The formation of osteolytic bone lesions is a key process for osteolytic cancer to metastasize to the bone and is under the control of a set of transcription factors. Recently, the inhibitor of differentiation 1 (Id1) has been linked with angiogenesis, tumorigenesis, metastasis and bone formation. However, the function of Id1 during the process of bone destruction caused by cancer in vivo has not yet been elucidated. We, therefore, examined whether and how Id1 affects the ability of cancer to form osteolytic lesion in vivo. The study used a lentiviral vector overexpressing short hairpin RNA (shRNA) targeting Id1 gene. PC3 cells, a prostate cancer cell line, were transduced with Id1 shRNA or negative control (NC) shRNA before implantation in BALB/c mice. Cells were implanted in a tibial injection model. Tumor formation in bone was monitored by X-ray. The relationship between parathyroid hormone-related protein (PTHrP), an osteolytic factor, and Id1 was analyzed by using immunohistochemistry in tissue sections from osteolytic lesion of the BALB/c mice. Our results showed that Id1 shRNA delivery to PC3 cells by lentivirus caused efficient and stable Id1 gene silencing. In the intratibial model, PC3 cells produced primarily osteolytic lesions in the bone. Eleven of 14 mice in Id1 shRNA group but only 4 of 14 mice in the NC shRNA group developed osteolytic lesions with cortical destruction at 4th week. Mice treated with Id1 shRNA had larger tumor volume in the bone and larger cortical destruction. The expression of PTHrP protein in PC3 cells was not affected by Id1 knockdown in vivo. These results indicate that Id1 may down-regulate the ability of PC3 cells to form osteolytic lesions in vivo and the signal pathway needs to be further investigated.
Animals ; Bone Neoplasms ; genetics ; metabolism ; secondary ; Cell Line, Tumor ; Gene Silencing ; Humans ; Inhibitor of Differentiation Protein 1 ; genetics ; metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Osteolysis ; genetics ; metabolism ; pathology ; Prostatic Neoplasms ; genetics ; metabolism ; pathology