Towards Exploring Large Molecular Space: An Efficient Chemical Genetic Algorithm.

Generating molecules with desired properties is an important task in chemistry and pharmacy. An efficient method may have a positive impact on finding drugs to treat diseases like COVID-19. Data mining and artificial intelligence may be good ways to find an efficient method. Recently, both the generative models based on deep learning and the work based on genetic algorithms have made some progress in generating molecules and optimizing the molecule's properties. However, existing methods need to be improved in efficiency and performance. To solve these problems, we propose a method named the Chemical Genetic Algorithm for Large Molecular Space (CALM). Specifically, CALM employs a scalable and efficient molecular representation called molecular matrix. Then, we design corresponding crossover, mutation, and mask operators inspired by domain knowledge and previous studies. We apply our genetic algorithm to several tasks related to molecular property optimization and constraint molecular optimization. The results of these tasks show that our approach outperforms the other state-of-the-art deep learning and genetic algorithm methods, where the z tests performed on the results of several experiments show that our method is more than 99% likely to be significant. At the same time, based on the experimental results, we point out the insufficiency in the experimental evaluation standard which affects the fair evaluation of previous work. Supplementary Information: The online version contains supplementary material available at 10.1007/s11390-021-0970-3.

Investigation of the Association between 45 Tag SNPs and Type 2 Diabetes Mellitus in Han Chinese Adults: A Prospective Cohort Study.

INTRODUCTION: The objective of this study was to examine the association between type 2 diabetes mellitus (T2DM) and genes identified in previous genome-wide association studies (GWASs) in rural Han Chinese adults. METHODS: This prospective study included 1,832 adults aged ≥18 years in Deqing without diabetes at baseline. The subjects were followed up for 8.7 years on average. We selected 45 susceptible tag single-nucleotide polymorphisms (SNPs) for T2DM that have been identified in GWASs and genotyped. A Cox model was constructed to calculate the adjusted hazard ratios (aHRs) for the association between SNPs and incident T2DM. RESULTS: The incidence rate of T2DM was 12.0 per 1,000 person-years. After adjustment for covariates and a Bonferroni correction, rs17584499 of protein tyrosine phosphatase, receptor-type D (PTPRD), rs11257655 and rs10906115 of cell division cycle 123 gene (CDC123), and rs12970134 of melanocortin-4 receptor (MC4R) were significantly associated with incident T2DM. The aHRs for incident T2DM were 1.75 (95% confidence interval [CI]: 1.28-2.40) and 1.61 (95% CI: 1.27-2.04) in association with an increasing number of T alleles in rs17584499 and rs11257655 under an additive genetic model, and the aHR was 1.72 (95% CI: 1.33-2.22) with an increasing number of A alleles in rs10906115. The aHRs under the dominant model were 1.82 (95% CI: 1.25-2.66) for TT + CT versus CC of rs17584499 and 2.04 (95% CI: 1.47-2.86) for AA + AG versus GG of rs10966115. The aHRs under the recessive model were 2.99 (95% CI: 1.30-6.89) for TT versus CT + CC of rs17584499, 1.92 (95% CI: 1.39-2.70) for TT versus CT + CC of rs11257655, and 2.54 (95% CI:1.22-5.29) for AA versus AG + GG of rs12970134. In addition, an increased incidence of T2DM was significantly associated with the TA haplotype of rs11257655 and rs10906115 (aHR = 1.81, 95% CI: 1.12-2.92), while a decreased incidence was associated with the CG haplotype (aHR = 0.49, 95% CI: 0.35-0.68) and the CT haplotype of rs1111875 and rs5015480 (aHR = 0.61, 95% CI: 0.37-0.98). CONCLUSION: Variants of the PTPRD, CDC123, and MC4R genes were associated with the T2DM incidence in a rural Han Chinese population.

Prevalence and associated factors of poor sleep quality among Chinese returning workers during the COVID-19 pandemic.

OBJECTIVES: The 2019 novel coronavirus (COVID-19) pandemic is a severe global crisis which has resulted in many public health problems. This study aimed to investigate the prevalence of poor sleep quality and its related factors among employees who returned to work during the COVID-19 pandemic. METHODS: Our online cross-sectional study included 2,410 participants aged ≥17 years in Deqing and Taizhou, Zhejiang Province, China from 5th to 14th March 2020. The questionnaire covered information on demographic characteristics, health status, workplace, lifestyle, attitude towards COVID-19, assessment of anxiety, depression and sleep quality. The Chinese version of the Pittsburgh Sleep Quality Index (CPSQI) was administered to measure the poor sleep quality. Poor sleep quality was defined as a global PSQI score>5. Factors associated with sleep quality were analyzed by logistic regression models. RESULTS: In sum near half (49.2%) of 2,410 returning workers were females and the average year of subjects was 36.3 ± 9.1 years. The overall prevalence of poor sleep quality was 14.9% (95%CI: 13.5%-16.3%). The average score of PSQI was 3.0 ± 2.5 and average sleep duration was 7.6 ± 1.2 h. Independent related factors of poor sleep quality included age older than 24 years, higher education level, negative attitude towards COVID-19 control measures, anxiety and depression. CONCLUSIONS: Poor sleep quality was common and there was a shorter sleep duration among returning workers during the COVID-19 pandemic. Possible risk factors identified from this study may be of great importance in developing proper intervention for the targeted population to improve the sleep health during the COVID-19 public health emergency.

Modification effects of T2DM-susceptible SNPs on the reduction of blood glucose in response to lifestyle interventions.

In recent years, it has been demonstrated that some susceptible gene loci of type 2 diabetes mellitus (T2DM) are not only associated with the susceptibility risk of T2DM, but also the modifying effects of lifestyle interventions. To further explore the modifying effects of the single nucleotide polymorphism (SNP) on the onset of T2DM and the reduction of blood glucose in response to lifestyle interventions among the high-risk population, we performed a lifestyle intervention study in two Deqing rural communities during the period from June to December in 2017. The intensive lifestyle interventions were conducted among the study subjects of the intervention group while those in the control group only received conventional and general health education. All participants were genotyped by the MassARRY system. This study showed that for SNP rs9502570, fasting blood glucose showed a significantly greater reduction for individuals with CC + CT genotype than those with TT genotype (P=0.031). In the intervention group, the glycated hemoglobin A1C (HbA1C) decreased by 0.03% for those with CC+CT genotype, while HbA1C increased by 0.27% for those with TT genotype (P=0.012). The difference in the reduction of fasting blood glucose and HbA1c between the intervention and control groups was also statistically significant between individuals with TT and those with CC+CT genotype. For SNP rs10811661, the reduction of fasting blood glucose was significantly higher in people with TT genotype than those with CC + CT genotype (0.44 mmol/L vs 0.12 mmol/L, P=0.021). The difference in reduction of fasting blood glucose between the intervention group and control group was also statistically significant between TT and CC+CT genotype (P<0.001). In summary, the SNP genotypes of both rs9502570 and rs10811661 could modify the effects of lifestyle interventions on reducing fasting blood glucose and HbA1C among the high risk rural population for T2DM. The present study has provided supporting evidence for future development of individualized intervention measures for high-risk population of T2DM.

Factors influencing the treatment of severe gluteal muscle contracture in children.

Usually the treatment of severe gluteal muscle contracture in children does not achieve a satisfactory clinical result and the disease is prone to recurrence after surgery. The aim of this study was to analyze the factors influencing the recovery of children with severe gluteal muscle contracture. Between 1997 and 2008, 428 children (mean age: 8 years) were subjected to surgical operations combined with functional exercises and physical therapy and were followed for 12-24 months with satisfactory clinical outcomes. In this series, the outcomes were found to be excellent in 400 cases, good in 22 cases, and fair in six cases with no patient having a poor result. No serious complications, such as sciatic nerve injury, dislocation, or osteonecrosis of the femoral head were found in the patients. Unsteadiness in walking and positive Trendelenburg sign were found in postoperative functional exercises in 16 patients, which may be the result of excessive resection of the gluteus medius and the gluteus minimus. However, the symptoms in all the cases disappeared within 3 months by rigorous functional exercise. We evaluated the factors that potentially influence the clinical outcome retrospectively and it was concluded that the surgery was highly beneficial for the treatment of the patients. Postoperative functional exercise and physical therapy could reduce the complications and maintain the favorable effects of surgery. In addition, the identification of the disease, the age of patients, and the rehabilitation procedures after hospital discharge were found to be very important for the successful treatment of this condition.

[Study on the prevalence and genotype of hepatitis E virus among commercial swine population in Eastern and Southern China].

OBJECTIVE: To determine the prevalence and genotype of hepatitis E virus (HEV) among commercial swine population in Eastern and Southern China. METHODS: Six hundred specimens of swine bile collected from 5 slaughterhouses in Eastern and Southern China from 2007 to 2009 were tested for HEV RNA using nested RT-PCR. PCR products were sequenced for phylogenetic analysis. RESULTS: Forty-seven out of the 600 samples (7.83%) were positive for HEV RNA. Based on the 150 nt fragment within HEV ORF2, data from phylogenetic analysis revealed that all the 47 HEV isolates were identified to be genotype IV, sharing 75.0% - 83.4%, 75.0% - 84.6%, 71.9% - 80.7% and 88.1% - 91.5% nucleotide identities with prototype I, II, III and IV HEV strains respectively while majority of the isolates clustered within their respective isolation sites. CONCLUSION: HEV was widespread in commercial swine population in Eastern and Southern China that raised a serious concern about the safety regarding the consumption of pork products.

[Seasonal pattern and phylogenetic analysis with human isolates of genotype-IV hepatitis E virus in swine herds, eastern China].

OBJECTIVE: To determine the seasonal prevalence of genotype-IV hepatitis E virus (HEV) in swine herds in Eastern China and explore the phylogenetic relationship between swine HEV and human HEV in the situation that zoonotic features of HEV had been confirmed. METHODS: From September 2007 to June 2008, a total of 1200 swine bile specimens were collected from three slaughter houses located in Zhejiang, Anhui and Jiangsu, the Eastern China, and detected for HEV RNA by using nested RT-PCR. The positive PCR products were sequenced. Then the swine HEV were phylogenetically determined with human HEV isolated in Eastern China. RESULTS: The positive rate for HEV RNA in swine herds was 4.5% totally. Significant differences of HEV detection were not observed among seasonal pattern (Sep - Oct: 6%, Dec - Jan: 4.33%, Mar - Apr: 4.33%, May - Jun: 3.33%) but in geographic distribution (Jiangsu: 6%, Anhui: 5%, Zhejiang: 2.5%). Regardless of isolation from different areas,swine and human genotype-IV HEV shared a high similarity. Phylogenetically, there were 80% - 100% and 96% - 100% identities within swine genotype-lV HEV at the nucleotide and amino acid levels respectively. Between swine HEV and human HEV, there were also similarities of 76% -99% and 95% - 100%. It was noted that some human and swine isolates were clustered with bootstrap values of > 90%. CONCLUSION: Genotype-IV HEV is widely prevalent in swine herds in Eastern China and original common ancestor of evolution and transmission was implied. The sustaining prevalence within swine herds should have a probable influence on the epidemic situation of hepatitis E in human beings.

[Phylogenetic analysis of sporadic hepatitis E virus in Eastern China].

OBJECTIVE: To understand phylogenetic characteristics of sporadic hepatitis E virus (HEV) in eastern China. METHODS: Four hundred and thirteen sera were collected from sporadic hepatitis E cases in 14 second- or first-class hospitals in Eastern China from 2005 to 2008 and detected with a nested RT-PCR assay. Partial nucleotide sequences of the HEV isolates were determined for phylogenetic analysis with prototype sequences in the GenBank. RESULTS: The male-to-female sex ratio of the patients was 1.75:1 with 61.5% of them aged 40 - 69 years old. HEV RNA was detected in 140 out of 413(34%)serum samples. Phylogenetic analysis revealed that all the 140 HEV isolates belonged to genotype IV, sharing 77.9% - 88.3%, 80.8% - 90.6%, 73.4% - 85.2% and 91.0% - 95.4% nucleotide sequence identities with prototype I, II, III and IV HEV isolates respectively. CONCLUSION: It was evident that genotype IV HEV served as the main causative agent of sporadic HEV infection in Eastern China. However the viral origin and evolution needs further clarification.

Clindamycin versus Unasyn in the treatment of facial cellulitis of odontogenic origin in children.

The study was undertaken to characterize the microbiology of dental abscesses in children and to compare clindamycin and ampicillin/sulbactam in the treatment of facial cellulitis of odontogenic origin. Sixty children with acute facial cellulitis of dental origin underwent surgery (extraction or root canal procedure) within 24 hours of presentation. Pus samples were cultured aerobically and anaerobically. Patients were randomized (1:1) to receive intravenous ampicillin/sulbactam or clindamycin for 48 hours followed by oral amoxicillin/clavulanate or clindamycin for 7 days. A total of 211 bacterial isolates were recovered from 54 samples. The most common aerobic and facultative organisms were viridans streptococci, Neisseria, and Eikenella species. Among anaerobes, Prevotella and Peptostreptococcus species were the most frequent. No treatment failure occurred in either group. Dental abscesses in children are polymicrobial aerobic/anaerobic infections. Treatment of complicated dental infections with ampicillin plus a beta-lactamase inhibitor or clindamycin in combination with surgical drainage is very effective.

[A cost-effectiveness study on a case-finding program of tuberculosis through screening those suspects with chronic cough symptoms in the rich rural areas].

OBJECTIVE: To study the feasibility and cost-effectiveness of a case-finding program on tuberculosis (TB) in richer rural areas. METHODS: Screening was implemented every three months for a total period of 9 months, in rural areas with high case notification rates. Three villages, each with ten thousand population, were selected to carry out a household screening program. A suspect was defined as who coughed for more than 3 weeks. The suspect was then referred to further diagnosis in county TB dispensary to undergo chest X-ray and sputum test. RESULTS: Of the 86,168 community population screened, 26 TB patients were identified with 7 of them were smear positive. The ratio of effectiveness vs. cost decreased on the second but slightly increased on the third screening program. The direct costs for the 3 screening programs were 6,312,397 and 1637 RMB respectively. Of total direct cost, 5.9% was paid by TB patients, whereas 35.9% was through financing of the county itself. CONCLUSION: The community household screening program could achieve higher case detection rate than passive case-finding approach which could be used in richer areas with low case detection rate in China.

[Detection and analysis of partial sequences isolated from human and swine in rural area of southern China].

OBJECTIVE: To study the genotype of swines isolated from humans and their relationships with hepatitis E virus (HEV) in the rural areas of southern China. METHODS: Specimens collected from normal people with HEV-IgM positive, acute hepatitis E patients and from swine in the same area were detected for HEV RNA using RT-nPCR with ORF2 primers. The positive PCR products were cloned and sequenced. RESULTS: 13 out of the 132 samples from swine stool, 4 of 26 HEV-IgM positive sera of normal people and 1 of 4 acute hepatitis E patients' stool sample and sera were tested positive for HEV RNA. Data from sequence analysis showed that the identity at nucleotide level was 89.3%-100.0% among the 10 isolates which shared 78.7% - 84.7%, 83.3% - 85.3%, 76.0% - 80.0% and 84.7% - 95.3% nucleotide sequence identity with HEV genotype I, II, III and IV respectively in the region (nt6317- 6466). CONCLUSION: HEV circulating in humans and swine in the area belonged to genotype IV.

The effects of midazolam on pediatric patients with asthma.

PURPOSE: This study was performed to evaluate the safety and efficacy of midazolam in asthmatic patients undergoing dental treatment. METHODS: Twenty-four children, aged 19 to 65 months, with a diagnosis of mild to moderate asthma were given an oral dose of 0.5 mg/kg of midazolam. Oxygen saturation, respiratory rate, and pulse rate were monitored before, during, immediately after, and 30 minutes following dental treatment. The child's asthma score was also determined before and after treatment. The dental operator assessed the overall sedation outcome immediately after treatment. RESULTS: Twenty-three of the 24 subjects had asthma scores of "0" before and after treatment. During dental treatment, 2 patients had oxygen saturations of 94% at one point during treatment. However, oxygen saturation increased when the patient's head and neck were repositioned. Twenty-three of the 24 subjects had oxygen saturations above 95% at 30 minutes following treatment. Pulse rates and respiratory rates exhibited transitory increases, linked to when the child was stimulated. Statistical analysis was conducted from within subjects repeated measures via ANOVA and with a general linear model approach. No statistically significant differences occurred in oxygen saturation and respiratory rate. However, significant differences did occur in pulse rate between 5 and 10 minutes (mean difference=10+/-3.84) and between 10 and 15 minutes (mean difference=19+/-5.50), as expected. No statistically significant differences occurred in asthma score before and after treatment. Twelve subjects were assessed to have excellent behavior, 5 subjects were satisfactory, and 7 subjects were unsatisfactory. No treatment was aborted. CONCLUSIONS: With adherence to the AAPD's sedation guidelines, midazolam at a dose of 0.5 mg/kg is a safe and effective mean for sedation of patients with mild to moderate asthma.