The paleoclimate of the late Pliocene Longmen flora from Yongping County located at the southeastern boundary of the Qinghai-Tibet Plateau was reconstructed using two leaf-physiognomy-based methods, i.e., leaf margin analysis (LMA) and Climate Leaf Analysis Multivariate Program (CLAMP), to understand the paleoclimate condition and geographical pattern of monsoonal climate in southwestern China during the late Pliocene. The mean annual temperatures (MATs) estimated by LMA and CLAMP are 17.4 ± 3.3 C and 17.4 ± 1.3 C, respectively, compared with 15.9 C at present. Meanwhile, the growing season precipitation (GSP) estimated by CLAMP is 1735.5 ± 217.7 mm in the Longmen flora, compared with 986.9 mm nowadays. The calculated monsoon intensity index (MSI) of the Longmen flora is significantly lower than that of today. These results appear consistent with previous studies on the late Pliocene floras in western Yunnan based on the coexistence approach (CA), and further suggest that there was a slightly warmer and much wetter climate during the late Pliocene than the present climate in western Yunnan. We conclude that the significant change of the monsoonal climate might have been resulted from the continuous uplift of mountains in western Yunnan, as well as the intensification of the eastern Asian winter monsoon, both occurring concurrently in the post-Pliocene period.

Humans express at least seven alcohol dehydrogenase (ADH) isoforms that are encoded by ADH gene cluster (ADH7-ADH1C-ADH1B-ADH1A-ADH6-ADH4-ADH5) at chromosome 4. ADHs are key catabolic enzymes for retinol and ethanol. The functional ADH variants (mostly rare) have been implicated in alcoholism risk. In addition to catalyzing the oxidation of retinol and ethanol, ADHs may be involved in the metabolic pathways of several neurotransmitters that are implicated in the neurobiology of neuropsychiatric disorders. In the present study, we comprehensively examined the associations between common ADH variants [minor allele frequency (MAF) >0.05] and 11 neuropsychiatric and neurological disorders. A total of 50,063 subjects in 25 independent cohorts were analyzed. The entire ADH gene cluster was imputed across these 25 cohorts using the same reference panels. Association analyses were conducted, adjusting for multiple comparisons. We found 28 and 15 single nucleotide polymorphisms (SNPs), respectively, that were significantly associated with schizophrenia in African-Americans and autism in European-Americans after correction by false discovery rate (FDR) (q < 0.05); and 19 and 6 SNPs, respectively, that were significantly associated with these two disorders after region-wide correction by SNPSpD (8.9 × 10-5 ≤ p ≤ 0.0003 and 2.4 × 10-5 ≤ p ≤ 0.0003, respectively). No variants were significantly associated with the other nine neuropsychiatric disorders, including alcohol dependence. We concluded that common ADH variants conferred risk for both schizophrenia in African-Americans and autism in European-Americans.

Background: There are urgent needs for rapid and accurate drug susceptibility testing of M. tuberculosis. GenoType MTBDRsl is a new molecular kit designed for rapid identification of the resistance to the second-line antituberculosis drugs with a single strip. In recent years, it has been evaluated in many settings, but with varied results. The aim of this meta-analysis was to synthesize the latest data on the diagnostic accuracy of GenoType MTBDRsl in detecting drug resistance to fluoroquinolones, amikacin, capreomycin, kanamycin and ethambutol, in comparison with the phenotypic drug susceptibility test. Methods: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. The search terms of "MTBDRsl" and "tuberculosis" were used on PubMed, EMBASE, and Web of Science. QUADAS-2 was used to assess the quality of included studies. Data were analyzed by Meta-Disc 1.4. We calculated the sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and corresponding 95% confidence interval (CI) for each study. From these calculations, forest plots and summary receiver operating characteristic (SROC) curves were produced. Results: Patient selection bias as well as flow and timing bias were observed in most studies. The summarized sensitivity (95% CI) was 0.874(0.845-0.899), 0.826(0.777-0.869), 0.820(0.772-0.862), 0.444(0.396-0.492), and 0.679(0.652-0.706) for fluoroquinolones, amikacin, capreomycin, kanamycin, and ethambutol, respectively. The specificity (95% CI) was 0.971(0.961-0.980), 0.995(0.987-0.998), 0.973(0.963-0.981), 0.993(0.985-0.997), and 0.799(0.773-0.823), respectively. The AUC (standard error) were 0.9754(0.0203), 0.9300(0.0598), 0.9885(0.0038), 0.9689(0.0359), and 0.6846(0.0550), respectively. Conclusion: Genotype MTBDRsl showed good accuracy for detecting drug resistance to fluoroquinolones, amikacin and capreomycin, but it may not be an appropriate choice for kanamycin and ethambutol. The lack of data did not allow for proper evaluation of the test on clinical specimens. Further systematic assessment of diagnostic performance should be carried out on direct clinical samples.

Schizophrenia is a chronic and debilitating psychiatric condition affecting slightly more than 1% of the population worldwide and it is a multifactorial disorder with a high degree of heritability (80%) based on family and twin studies. Increasing lines of evidence suggest intermediate phenotypes/endophenotypes are more associated with causes of the disease and are less genetically complex than the broader disease spectrum. Negative symptoms in schizophrenia are attractive intermediate phenotypes based on their clinical and treatment response features. Therefore, our objective was to identify genetic variants underlying the negative symptoms of schizophrenia by analyzing two genome-wide association (GWA) data sets consisting of a total of 1,774 European-American patients and 2,726 controls. Logistic regression analysis of negative symptoms as a binary trait (adjusted for age and sex) was performed using PLINK. For meta-analysis of two datasets, the fixed-effect model in PLINK was applied. Through meta-analysis we identified 25 single nucleotide polymorphisms (SNPs) associated with negative symptoms with p<5×10-5. Especially we detected five SNPs in the first two genes/loci strongly associated with negative symptoms of schizophrenia (Pmeta-analysis<6.22×10-6), which included three SNPs in the BCL9 gene: rs583583 showed the strongest association at a Pmeta-analysis of 6.00×10-7 and two SNPs in the C9orf5 (the top SNP is rs643410 with a p = 1.29 ×10-6). Through meta-analysis, we identified several additional negative symptoms associated genes (ST3GAL1, RNF144, CTNNA3 and ZNF385D). This is the first report of the common variants influencing negative symptoms of schizophrenia. These results provide direct evidence of using of negative symptoms as an intermediate phenotype to dissect the complex genetics of schizophrenia. However, additional studies are warranted to examine the underlying mechanisms of these disease-associated SNPs in these genes.

Objective: In the present study, we scanned the whole exome in three independent samples to search for replicable risk non synonymous (ns) variants (ns single-nucleotide polymorphisms [nsSNPs]) for alcohol dependence. Method: A total of 10,554 subjects in three independent samples were analyzed for association with alcohol dependence, including one European American sample (1,409 cases with alcohol dependence and 1,518 controls), one African American sample (681 cases and 508 controls), and one European Australian sample (a total of 6,438 family subjects with 1,645 alcohol-dependent probands). RNA expression of the risk genes in human, mouse, and rat brains was also explored. Results: We identified a total of 70 nsSNPs at 65 genes with nominally replicable associations; 22 nsSNPs at 21 genes among them survived corrections for multiple testing in meta-analysis (α =.0007). By incorporating the information from bioinformatics and RNA expression analyses, we identified at least two of the most promising risk genes for alcohol dependence: APOER2 and UBAP2. Conclusions: The gene coding for apolipoprotein E receptor 2 (APOER2) and the gene coding for ubiquitin associated protein-2 (UBAP2) are among the most appropriate for follow-up in human and nonhuman species as contributors to risk for alcohol dependence.

Non-parametric methods such as Wilcoxon test have the advantages of no assumptions for the underlying survival distributions. Alzheimer’s disease (AD) is a chronic neurodegenerative disease while the ectopic P-granules autophagy protein 5 homolog (EPG5 gene) is highly expressed in human brain and may implicate in the pathogenesis of neurodegenerative disorders. The present study explored the associations of 26 single-nucleotide polymorphisms (SNPs) in the EPG5 gene with the age at onset (AAO) of AD using a family-based association test (FBAT)-Wilcoxon statistic in a family-based study. Then a replication study using a case-control sample was conducted to perform Wilcoxon test in Kaplan–Meier survival analysis of AAO. The results from FBAT-generalized estimating equations (FBAT-GEE) statistics and FBAT-Wilcoxon test showed that seven SNPs (top SNP rs495078 with p = 1.29 × 10−3) were significantly associated with the risk of AD, and eight SNPs (top SNP rs11082498 with p = 3.55 × 10−4) were associated with the AAO of AD in the family-based study (p < 0.05). In the replicated data, three SNPs were associated with AAO by using the Wilcoxon test, where the mean AAO was approximately 2.2 years earlier in individuals who had at least one minor allele of the top AAO-associated SNP rs9963463 (p = 0.0018) compared with those who were homozygous for the major allele. These findings from non-parametric survival analyses provide evidence for several genetic variants in EPG5 influencing the AAO of AD and will serve as a resource for replication in other populations.

Objective: To evaluate the risk factors for systemic inflammatory response syndrome (SIRS) after flexible ureteroscopic lithotripsy (FUL). Materials and Methods: Patients who underwent FUL between October 2012 and November 2013 were studied. Complete data was available for 260 adult patients who met this criteria. Preoperative and intraoperative risk factors that potentially contribute to SIRS were compared in patients who developed postoperative SIRS and those who did not. Furthermore, multivariable logistic regression analysis was performed and the odds ratio (OR) and 95% confidence interval (CI) were calculated to identify the independent risk factors for SIRS after FUL. Results: The incidence of SIRS after FUL was 8.1%. In the univariate test analysis, significant correlation between SIRS and four factors was noted: sex of the patient (P<0.001), stone size (P=0.001), irrigation flow rate (P<0.001), and irrigation volume (P<0.001). Multivariable logistic regression analysis identified stone size (OR=1.691; 95% CI,0.879-3.255), small-caliber ureteral access sheath (UAS) (OR=2.293; 95% CI, 0.730-7.200), irrigation flow rate (OR=1.161; 95% CI, 1.096-1.230), and struvite calculi (OR=3.331; 95% CI, 0.971-11.426) as independent risk factors for SIRS after FUL. Conclusions: We recommend that the length of lithotripsy be well controlled in patients with large stone burden and struvite calculi. Staging procedures are also required. Additionally, irrigating with a low flow rate and low pressure and using a large-caliber UAS for better drainage are required to keep a low renal pelvic pressure during FUL procedures.

Multiple correlated time-to-event endpoints often occur in clinical trials and some time-to-event endpoints are more important than others. Most weighted multiple testing adjustment methods have been proposed to control family-wise type I error rates either only consider the correlation among continuous or binary endpoints or totally disregard the correlation among the endpoints. For continuous or binary endpoints, the correlation matrix can be directly estimated from the corresponding correlated endpoints. However, it is challenging to directly estimate the correlation matrix from the multiple endpoints in survival data since censoring is involved. In this chapter, we propose a weighted multiple testing correction method for correlated time-to-event endpoints in survival data, based on the correlation matrix estimated from the WLW method proposed by Wei, Lin, and Weissfeld. Simulations are conducted to study the family-wise type I error rate of the proposed method and to compare the power performance of the proposed method to the nonparametric multiple testing methods such as the alpha-exhaustive fallback (AEF), fixed-sequence (FS), and the weighted Holm-Bonferroni method when used for the correlated time-to-event endpoints. The proposed method and others are illustrated using a real dataset from Fernald Community Cohort (formerly known as the Fernald Medical Monitoring Program).

Background and Objectives We previously reported a risk genomic region (ie, PTP4A1-PHF3-EYS) for alcohol dependence in a genome-wide association study (GWAS). We also reported a rare variant constellation across this region that was significantly associated with alcohol dependence. In the present study, we significantly increased the marker density within this region and examined the specificity of the associations of common variants for alcohol dependence. Methods One African-American discovery sample (681 cases with alcohol dependence and 508 controls), one European-American replication sample (1,409 alcohol dependent cases and 1,518 controls), and one European-Australian replication sample (a total of 6,438 family subjects with 1,645 alcohol dependent probands) underwent association analysis. A total of 38,714 subjects from 18 other cohorts with 10 different neuropsychiatric disorders served as contrast groups. Results We found 289 SNPs that were nominally associated with alcohol dependence in the discovery sample (p-<-.05). Fifty-six associations of them were significant after correction (1.9-×-10-6-≤-p-≤-1.6-×-10 -5). No markers were significantly associated with other neuropsychiatric disorders after experiment-wide correction. Conclusions and Scientific Significance We confirmed with our previous findings that PTP4A1-PHF3-EYS variants were significantly associated with alcohol dependence, which were replicable across multiple independent populations and were specific for alcohol dependence. These findings suggested that this region might harbor a causal variant(s) for alcohol dependence. (Am J Addict 2014;23:411-414)

Background: This longitudinal study examined maternal depression status from birth of a child to 36 months of age using data from the National Institute of Child Health and Human Development (NICHD) Study of Early Child Care and Youth Development. Methods: Maternal depression was assessed using the Center of Epidemiological Studies Depression Scale (CES-D) and defined as a score of ≥16. For this study, early onset depression was defined as depression within the 6 months after birth, and late onset depression was depression onset when the child was ≥24 months old. Chronic depression was defined as depression that started within 6 months after birth and lasted until 24 months of age or longer. Results: The prevalence of maternal depression was 32.2% for early onset, 7.4% for late onset, and 13.4% for chronic depression. The prevalence of maternal depression was highest at 1 month, decreased at 6 months, and then remained fairly stable until 36 months. Mothers 18-24 years of age, of black race, unemployed, with lower social support, single, or with poor general health had a higher prevalence of both early and chronic depression compared to other groups. Conclusions: Younger maternal age, poverty, lower education, and lack of social support were all significantly associated with increased maternal depression in multivariate regression models. Younger age, black race, unemployment, single status, lack of social support, and poor general health were all risk factors for increased prevalence of maternal depression.