Optimal sample size determination in adaptive seamless phase II/III design

The adaptive seamless phase II/III design combines the conventional separate phases II and III trials into a single trial, and it allows for adaptations (e.g. sample size reassessment and early stopping for futility or success) after the interim analysis. In this study, we propose a simulation-based method to determine the optimal sample size for the adaptive seamless phase II/III design. We assume that a power law relationship exists between the overall sample size and statistical power of the final test. The optimal sample size is defined as the minimum sample size that provides adequate power with overall type I error rate under control. To find the optimal size, we also take correlations between the early and the final outcomes into consideration. The methodology is applied to determining sample sizes in a study for a candidate treatment that can avoid renal damage during cardiac operations while the most effective dose of the treatment will be selected at the interim analysis. PUBLIC HEALTH SIGNIFICANCE Adaptive seamless phase II/III design eliminates the time between the traditional separate trials and better utilizes the data collected before the interim analysis, thus will result in faster clinical trials. Treatment effect can be confirmed at the final test if adequate power is achieved and the overall type I error rate is under control. Using these faster clinical trials, effective treatment can be approved sooner to benefit more patients. In addition, in an adaptive seamless phase II/III design more patients will be allocated to the more effective treatment than they would in conventional clinical trials

De novo assembly and transcriptome characterization: novel insights into the natural resistance mechanisms of Microtus fortis against Schistosoma japonicum

BACKGROUND: Microtus fortis is a non-permissive host of Schistosoma japonicum. It has natural resistance against schistosomes, although the precise resistance mechanisms remain unclear. The paucity of genetic information for M. fortis limits the use of available immunological methods. Thus, studies based on high-throughput sequencing technologies are required to obtain information about resistance mechanisms against S. japonicum. RESULTS: Using Illumina single-end technology, a de novo assembly of the M. fortis transcriptome produced 67,751 unigenes with an average length of 868 nucleotides. Comparisons were made between M. fortis before and after infection with S. japonicum using RNA-seq quantification analysis. The highest number of differentially expressed genes (DEGs) occurred two weeks after infection, and the highest number of down-regulated DEGs occurred three weeks after infection. Simultaneously, the strongest pathological changes in the liver were observed at week two. Gene ontology terms and pathways related to the DEGs revealed that up-regulated transcripts were involved in metabolism, immunity and inflammatory responses. Quantitative real-time PCR analysis showed that patterns of gene expression were consistent with RNA-seq results. CONCLUSIONS: After infection with S. japonicum, a defensive reaction in M. fortis commenced rapidly, increasing dramatically in the second week, and gradually decreasing three weeks after infection. The obtained M. fortis transcriptome and DEGs profile data demonstrated that natural and adaptive immune responses, play an important role in M. fortis immunity to S. japonicum. These findings provide a better understanding of the natural resistance mechanisms of M. fortis against schistosomes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi: 10.1186/1471-2164-15-417) contains supplementary material, which is available to authorized users

Interactive Effects of Methionine and Lead Intake on Cognitive Function among Chinese Adults.

The association between methionine intake and cognitive function is inconclusive. We aimed to assess the association between methionine intake and cognitive function in Chinese adults and to explore the interaction between methionine and lead intake. Data from 4852 adults aged ≥55 years from the China Health and Nutrition Survey were used. Cognitive function was measured in 1997, 2000, 2004, and 2006. A 3-day, 24-hour recall was used to assess methionine and lead intake from different protein sources. Multivariable mixed linear regression was used in the analyses. Total methionine intake was positively correlated with cognition. There was a significant interaction between animal methionine and lead intakes. In subgroup analyses, across the quartiles of animal methionine intake, the regression coefficients (95% CI) for global cognition were 0.00, 0.57 (0.17 to 0.98), 1.18 (0.73 to 1.62), and 1.80 (1.31 to 2.29), respectively, while they were 0.00, -0.73 (-1.12 to -0.34), -0.83 (-1.26 to -0.41), and -1.72 (-2.22 to -1.22) across the quartiles of plant methionine intake, respectivelyThe association between animal methionine intake and cognition was stronger among adults with a low lead intake. In conclusion, animal methionine and plant methionine intake were positively and inversely associated with cognition, respectively. Lead intake modified the association between animal methionine intake and cognition.This study was supported in part by research grants from the Natural Scientific Foundation in Qinghai Province (2019-ZJ-932Q), and the National Key Research and Development Program of China (grant numbers: 2017YFC0907200 and 2017YFC0907201)

Aberrant GlyRS-HDAC6 interaction linked to axonal transport deficits in Charcot-Marie-Tooth neuropathy.

Dominant mutations in glycyl-tRNA synthetase (GlyRS) cause a subtype of Charcot-Marie-Tooth neuropathy (CMT2D). Although previous studies have shown that GlyRS mutants aberrantly interact with Nrp1, giving insight into the disease\u27s specific effects on motor neurons, these cannot explain length-dependent axonal degeneration. Here, we report that GlyRS mutants interact aberrantly with HDAC6 and stimulate its deacetylase activity on α-tubulin. A decrease in α-tubulin acetylation and deficits in axonal transport are observed in mice peripheral nerves prior to disease onset. An HDAC6 inhibitor used to restore α-tubulin acetylation rescues axonal transport deficits and improves motor functions of CMT2D mice. These results link the aberrant GlyRS-HDAC6 interaction to CMT2D pathology and suggest HDAC6 as an effective therapeutic target. Moreover, the HDAC6 interaction differs from Nrp1 interaction among GlyRS mutants and correlates with divergent clinical presentations, indicating the existence of multiple and different mechanisms in CMT2D. Nat Commun 2018 Mar 8; 9(1):1007

Transient Pulmonary Atelectasis after Ketamine Sedation during Cardiac Catheterization in Spontaneously Breathing Children with Congenital Heart Disease

Background: Ketamine is applied widely for sedation during cardiac catheterization in spontaneously breathing children with congenital heart disease (CHD). However, a rare and unreported respiratory complication, transient and reversible atelectasis of lungs (TRAL), was identified. Purpose: The study was performed to investigate retrospectively the prevalence and clinical characteristics of TRAL after ketamine sedation in pediatric cardiac catheterization. Methods: Four thousand four hundred and seventy-four sick children were sedated with ketamine, and pediatric cardiac catheterization was carried out under spontaneous breathing. TRAL was detected in 33 children (17 M/16 F, age was 2.1±1.7 years) by retrospective analysis. The clinical and radiographic characteristics were recorded before, during and after TRAL. Results: In pediatric cardiac catheterization, the prevalence of TRAL was 0.74% after ketamine sedation. TRAL occurred in 23 children with cyanotic CHD, and 10 with acyanotic CHD. All TRALs had common clinical and radiographic features: the diffuse opacity of bilateral lungs developed rapidly (identified under X-ray fluoroscopy), associated with decrease in lung volume, and then the decrease in SpO2 (94.2±9.2% vs. 59.4±2.2%, P<0.05), and heart rates (143.5±14.3 bpm vs. 58.3±9.7 bpm, P<0.05) followed quickly. TRAL was relieved by supportive oxygen in 32 children (23 with face mask, and 9 with endotracheal intubation), and the duration of TRAL was 1.6±0.5 minutes. However, TRAL caused the death of one child. Conclusions: TRAL is a rare and urgent respiratory complication after ketamine sedation, and the mechanism is unclear. Rapid and diffuse opacity of bilateral lungs is the earliest sign of TRAL in pediatric cardiac catheterization, and the immediate supportive oxygen is crucial

Determination of reference intervals of serum levels of human epididymis protein 4 (HE4) in Chinese women

The detailed numbers of subjects from different centers. (DOCX 17.3 kb

Identification of QTNs Controlling Seed Protein Content in Soybean Using Multi-Locus Genome-Wide Association Studies

Protein content (PC), an important trait in soybean (Glycine max) breeding, is controlled by multiple genes with relatively small effects. To identify the quantitative trait nucleotides (QTNs) controlling PC, we conducted a multi-locus genome-wide association study (GWAS) for PC in 144 four-way recombinant inbred lines (FW-RILs). All the FW-RILs were phenotyped for PC in 20 environments, including four locations over 4 years with different experimental treatments. Meanwhile, all the FW-RILs were genotyped using SoySNP660k BeadChip, producing genotype data for 109,676 non-redundant single-nucleotide polymorphisms. A total of 129 significant QTNs were identified by five multi-locus GWAS methods. Based on the 22 common QTNs detected by multiple GWAS methods or in multiple environments, pathway analysis identified 8 potential candidate genes that are likely to be involved in protein synthesis and metabolism in soybean seeds. Using superior allele information for 22 common QTNs in 22 elite and 7 inferior lines, we found higher superior allele percentages in the elite lines and lower percentages in the inferior lines. These findings will contribute to the discovery of the polygenic networks controlling PC in soybean, increase our understanding of the genetic foundation and regulation of PC, and be useful for molecular breeding of high-protein soybean varieties

Prevalence of the Cryptosporidium Pig Genotype II in Pigs from the Yangtze River Delta, China

Background: Cryptosporidium spp. is prevalent globally, pigs are an important Cryptosporidium reservoir. In China, little data regarding rates of Cryptosporidium infections in pigs are available. The present study was therefore aimed at characterizing the distribution of Cryptosporidium species in pigs from two different cities, Shaoxing and Shanghai, from the Yangtze River delta. Methodology/Principal Findings: Nested PCR to amplify the 18S rRNA locus on DNA extracted from fecal samples (n = 94) revealed the positive rate of Cryptosporidium in pigs from two cities was approximately 17.0%. The positive rates in Shanghai and Shaoxing were 14.3 % and 25.0 % respectively. Amplified sequences were verified by sequencing. The identified strain belonged to the C. pig genotype II using BLAST analysis in the NCBI database. Conclusion/Significance: Our finding of Cryptosporidium pig genotype II in pigs in the Yangtze River delta area suggests that pig farms in this region must be considered a public health threat and proper control measures be introduced

Signatures of divergence, invasiveness, and terrestrialization revealed by four apple snail genomes

The family Ampullariidae includes both aquatic and amphibious apple snails. They are an emerging model for evolutionary studies due to the high diversity, ancient history, and wide geographical distribution. Insight into drivers of ampullariid evolution is hampered, however, by the lack of genomic resources. Here, we report the genomes of four ampullariids spanning the Old World (Lanistes nyassanus) and New World (Pomacea canaliculata, P. maculata, and Marisa cornuarietis) clades. The ampullariid genomes have conserved ancient bilaterial karyotype features and a novel Hox gene cluster rearrangement, making them valuable in comparative genomic studies. They have expanded gene families related to environmental sensing and cellulose digestion, which may have facilitated some ampullarids to become notorious invasive pests. In the amphibious Pomacea, novel acquisition of an egg neurotoxin and a protein for making the calcareous eggshell may have been key adaptations enabling their transition from underwater to terrestrial egg deposition.Fil: Sun, Jin. Hong Kong University of Science and Technology; Hong KongFil: Mu, Huawei. Hong Kong Baptist University; Hong KongFil: Ip, Jack Chi Ho. Hong Kong Baptist University; Hong KongFil: Li, Runsheng. Hong Kong Baptist University; Hong KongFil: Xu, Ting. Hong Kong Baptist University; Hong KongFil: Accorsi, Alice. Howard Hughes Medical Institute; Estados Unidos. Stowers Institute for Medical Research; Estados UnidosFil: Alvarado, Alejandro Sanchez. Howard Hughes Medical Institute; Estados Unidos. Stowers Institute for Medical Research; Estados UnidosFil: Ross, Eric. Howard Hughes Medical Institute; Estados Unidos. Stowers Institute for Medical Research; Estados UnidosFil: Lan, Yi. Hong Kong University of Science and Technology; Hong KongFil: Sun, Yanan. Hong Kong University of Science and Technology; Hong KongFil: Castro Vazquez, Alfredo Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Fisiología; ArgentinaFil: Vega, Israel Aníbal. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Fisiología; ArgentinaFil: Heras, Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo; ArgentinaFil: Ituarte, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Van Bocxlaer, Bert. Centre National de la Recherche Scientifique; FranciaFil: Hayes, Kenneth A.. Bernice Pauahi Bishop Museum; Estados UnidosFil: Cowie, Robert H.. University of Hawaii. Pacific Biosciences Research Center; Estados UnidosFil: Zhao, Zhongying. Hong Kong Baptist University; Hong KongFil: Zhang, Yu. Shenzhen University. College of Life Sciences and Oceanography. Shenzhen Key Laboratory of Marine Bioresource and Eco-environmental Science; ArgentinaFil: Qian, Pei-Yuan. Hong Kong University of Science and Technology; Hong KongFil: Qiu, Jian-Wen. Hong Kong Baptist University; Hong Kon

Structure and Photoluminescent Properties of ZnO Encapsulated in Mesoporous Silica SBA-15 Fabricated by Two-Solvent Strategy

The two-solvent method was employed to prepare ZnO encapsulated in mesoporous silica (ZnO/SBA-15). The prepared ZnO/SBA-15 samples have been studied by X-ray diffraction, transmission electron microscope, X-ray photoelectron spectroscopy, nitrogen adsorption–desorption isotherm, and photoluminescence spectroscopy. The ZnO/SBA-15 nanocomposite has the ordered hexagonal mesostructure of SBA-15. ZnO clusters of a high loading are distributed in the channels of SBA-15. Photoluminescence spectra show the UV emission band around 368 nm, the violet emission around 420 nm, and the blue emission around 457 nm. The UV emission is attributed to band-edge emission of ZnO. The violet emission results from the oxygen vacancies on the ZnO–SiO2interface traps. The blue emission is from the oxygen vacancies or interstitial zinc ions of ZnO. The UV emission and blue emission show a blue-shift phenomenon due to quantum-confinement-induced energy gap enhancement of ZnO clusters. The ZnO clusters encapsulated in SBA-15 can be used as light-emitting diodes and ultraviolet nanolasers