Branched chain amino acid transaminase 1 (BCAT1) is overexpressed and hypomethylated in patients with non-alcoholic fatty liver disease who experience adverse clinical events: A pilot study.
Although the burden of non-alcoholic fatty liver disease (NAFLD) continues to increase worldwide, genetic factors predicting progression to cirrhosis and decompensation in NAFLD remain poorly understood. We sought to determine whether gene expression profiling was associated with clinical decompensation and death in patients with NAFLD, and to assess whether altered DNA methylation contributes to these changes in gene expression. We performed a retrospective analysis of 86 patients in the Duke NAFLD Clinical Database and Biorepository with biopsy-proven NAFLD whose liver tissue was previously evaluated for gene expression and DNA methylation using array based technologies. We assessed the prospective development of liver and cardiovascular disease related outcomes, including hepatic decompensation as identified by the development of ascites, hepatic encephalopathy, hepatocellular carcinoma, or variceal bleeding as well as stroke and myocardial infarction via medical chart review. Of the 86 patients, 47 had F0-F1 fibrosis and 39 had F3-F4 fibrosis at index liver biopsy. Gene expression probe sets (n = 54,675) were analyzed; 42 genes showed significant differential expression (p<0.05) and a two-fold change in expression between patients with and without any outcome. Two expression probes of the branched chain amino-acid transaminase 1 (BCAT1) gene were upregulated (p = 0.02; fold change 2.1 and 2.2 respectively) in patients with a clinical outcome. Methylation of three of the 34 BCAT1 CpG methylation probes were significantly inversely correlated with BCAT1 expression specific to the probes predictive of clinical deterioration. We found differential gene expression, correlated to changes in DNA methylation, at multiple BCAT1 loci in patients with cardiovascular outcomes and/or hepatic decompensation. BCAT1 catalyzes the transformation of alpha-ketoglutarate to glutamate and has been linked to the presence and severity of NAFLD, possibly through derangements in the balance between glutamate and alpha-ketoglutarate. Given the potential for BCAT1 to identify patients at risk for poor outcomes, and the potential therapeutic implications, these results should be validated in larger prospective studies.


Characterization of the rs2802292 SNP identifies FOXO3A as a modifier locus predicting cancer risk in patients with PJS and PHTS hamartomatous polyposis syndromes.
Hamartomatous polyposis syndromes (HPS) are inherited conditions associated with high cancer risk. They include the Peutz-Jeghers and the PTEN hamartoma tumor syndromes, which are caused by mutations in the LKB1 and PTEN genes, respectively. Estimation of cancer risk is crucial in order to optimize surveillance, but no prognostic markers are currently available for these conditions. Our study relies on a 'signal transduction' hypothesis based on the crosstalk between LKB1/AMPK and PI3K/PTEN/Akt signaling at the level of the tumor suppressor protein FoxO3A. Interestingly, the FOXO3A rs2802292 G-allele was shown to be associated with longevity, reduced risk of aging-related diseases and increased expression of FoxO3A mRNA. We typed rs2802292 in 150 HPS unrelated patients and characterized the expression of FoxO3A by quantitative PCR and immunoblot analysis in human intestinal cell lines. We found a significantly higher risk for malignancies in females and TT genotype carriers compared to patients having at least one G-allele. Subgroup analysis for each HPS syndrome revealed a G-allele-associated beneficial effect on cancer risk occurring mainly in males. Molecular characterization of human intestinal cell lines showed that the G-allele significantly correlated with increased basal expression of FoxO3A mRNA and protein. Our results suggest an inverse correlation between the protective allele (G) copy number and cancer risk, and might be useful to optimize surveillance in HPS patients. Further investigations are needed to confirm our hypothesis and to ascertain whether differences in therapeutic response exist across genotypes.


Experimental demonstration of possible cryptic female choice on male tsetse fly genitalia.
A possible explanation for one of the most general trends in animal evolution - rapid divergent evolution of animal genitalia - is that male genitalia are used as courtship devices that influence cryptic female choice. But experimental demonstrations of stimulatory effects of male genitalia on female reproductive processes have generally been lacking. Previous studies of female reproductive physiology in the tsetse fly Glossina morsitans suggested that stimulation during copulation triggers ovulation and resistance to remating. In this study we altered the form of two male genital structures that squeeze the female's abdomen rhythmically in G. morsitans centralis and induced, as predicted, cryptic female choice against the male: sperm storage decreased, while female remating increased. Further experiments in which we altered the female sensory abilities at the site contacted by these male structures during copulation, and severely altered or eliminated the stimuli the male received from this portion of his genitalia, suggested that the effects of genital alteration on sperm storage were due to changes in tactile stimuli received by the female, rather than altered male behavior. These data support the hypothesis that sexual selection by cryptic female choice has been responsible for the rapid divergent evolution of male genitalia in Glossina; limitations of this support are discussed. It appears that a complex combination of stimuli trigger female ovulation, sperm storage, and remating, and different stimuli affect different processes in G. morsitans, and that the same processes are controlled differently in G. pallidipes. This puzzling diversity in female triggering mechanisms may be due to the action of sexual selection.


Re-examining the role of ABA as the primary long-distance signal produced by water-stressed roots.
The role of ABA as the primary long-distance signal produced by water-stressed roots and transported to stomata continues to be challenged. We have recently reported that expression of ABA biosynthetic genes in roots only increases in the later stage of water stress. Our results support the hypothesis that in early water stress, increased levels of ABA in xylem sap are due to leaf biosynthesis and translocation to roots and from there to xylem. If so, other xylem-borne chemicals may be the primary stress signal(s) inducing ABA biosynthesis in leaves. We found that apart from ABA, sulfate was the only xylem-borne chemical that consistently showed higher concentrations from early to later water stress. We also found increased expression of a sulfate transporter gene in roots from early water stress onwards. Moreover, using bioassays we found an interactive effect of ABA and sulfate in decreasing maize transpiration rate, as compared to ABA alone. While ABA is undoubtedly the key mediator of water stress responses such as stomatal closure, it may not be the primary signal produced by roots perceiving water stress.


gltB gene and regulation of nitrogen metabolism by glutamine synthetase in Escherichia coli.
A mutant (gltB) of Escherichia coli lacking glutamate synthase (GOGAT) was unable to utilize a wide variety of compounds as sole nitrogen source (e.g., arginine, proline, gamma-aminobutyrate, and glycine). Among revertants of these Asm- strains selected on one of these compounds (e.g., arginine, proline, or gamma-aminobutyrate) were those that produce glutamine synthetase (GS) constitutively (GlnC phenotype). These revertants had a pleiotropically restored ability to grow on compounds that are metabolized to glutamate. This suggested that the expression of the genes responsible for the metabolism of these nitrogen sources was regulated by GS. An examination of the regulation of proline oxidase confirmed this hypothesis. The differential sensitivities of GlnC and wild-type strains to low concentrations (0.1 mM) of the glutamine analog L-methionine-DL-sulfoximine supported the conclusion that the synthesis of a glutamine permease was also positively controlled by GS. During the course of this study we found that the reported position of the locus (gltB) for glutamate synthase is incorrect. We have relocated this gene to be 44% linked to the argG locus by P1 transduction. Further mapping has shown that the locus previously called aspB is in reality the gltB locus and that the "suppressor" of the aspB mutation (A. M. Reiner, J. Bacteriol. 97:1431-1436, 1969) is the locus for glutamate dehydrogenase (gdhA).


Poor Metabolic Control in Children and Adolescents With Type 1 Diabetes and Psychiatric Comorbidity.
Type 1 diabetes is associated with an increased risk of psychiatric morbidities. We investigated predictors and diabetes outcomes in a pediatric population with and without psychiatric comorbidities. Data from the Danish Registry of Childhood and Adolescent Diabetes (DanDiabKids) and National Patient Register were collected (1996-2015) for this population-based study. We used Kaplan-Meier plots to investigate whether age at type 1 diabetes onset and average glycated hemoglobin (HbA1c) levels during the first 2 years after onset of type 1 diabetes (excluding HbA1c at debut) were associated with the risk of being diagnosed with a psychiatric disorder. Mixed-effects linear and logistic regression models were used to analyze HbA1c, BMI, severe hypoglycemia (SH), or ketoacidosis as outcomes, with psychiatric comorbidities as explanatory factor. Among 4,725 children and adolescents with type 1 diabetes identified in both registers, 1,035 were diagnosed with at least one psychiatric disorder. High average HbA1c levels during the first 2 years predicted higher risk of psychiatric diagnoses. Patients with psychiatric comorbidity had higher HbA1c levels (0.22% [95% CI 0.15; 0.29]; 2.40 mmol/mol [1.62; 3.18]; P < 0.001) and an increased risk of hospitalization with diabetic ketoacidosis (1.80 [1.18; 2.76]; P = 0.006). We found no associations with BMI or SH. High average HbA1c levels during the first 2 years after onset of type 1 diabetes might indicate later psychiatric comorbidities. Psychiatric comorbidity in children and adolescents with type 1 diabetes increases the risk of poor metabolic outcomes. Early focus on the disease burden might improve outcomes.


Does temporal discounting explain unhealthy behavior? A systematic review and reinforcement learning perspective.
The tendency to make unhealthy choices is hypothesized to be related to an individual's temporal discount rate, the theoretical rate at which they devalue delayed rewards. Furthermore, a particular form of temporal discounting, hyperbolic discounting, has been proposed to explain why unhealthy behavior can occur despite healthy intentions. We examine these two hypotheses in turn. We first systematically review studies which investigate whether discount rates can predict unhealthy behavior. These studies reveal that high discount rates for money (and in some instances food or drug rewards) are associated with several unhealthy behaviors and markers of health status, establishing discounting as a promising predictive measure. We secondly examine whether intention-incongruent unhealthy actions are consistent with hyperbolic discounting. We conclude that intention-incongruent actions are often triggered by environmental cues or changes in motivational state, whose effects are not parameterized by hyperbolic discounting. We propose a framework for understanding these state-based effects in terms of the interplay of two distinct reinforcement learning mechanisms: a "model-based" (or goal-directed) system and a "model-free" (or habitual) system. Under this framework, while discounting of delayed health may contribute to the initiation of unhealthy behavior, with repetition, many unhealthy behaviors become habitual; if health goals then change, habitual behavior can still arise in response to environmental cues. We propose that the burgeoning development of computational models of these processes will permit further identification of health decision-making phenotypes.


First Report of Twig Canker on Peach Caused by Phomopsis amygdali in China.
During May and June of 2009, canker and twig dieback were observed with 30 to 40% incidence in trees in one peach orchard in Nanhui of Shanghai (cv. YuLu juicy peach) and one orchard (cv. JingXiu yellow peach) in Jiaxin of Zhejiang Province, China. Cankers were generally centrally positioned on the nodes at the base of shoots with sunken, reddish brown/tan-to-silver symptoms. Blight was also observed on a few shoots (1). Five samples were collected from each orchard and isolations were conducted on potato sucrose agar (PSA). Ten isolates were obtained and all had white mycelia on PSA. Black pycnidia, formed in culture, produced two types of conidia: hyaline, fusiform alpha conidia and hyaline, string-like beta conidia. Alpha conidia varied from 5.0 to 6.3 × 1.5 to 2.5 μm and beta conidia ranged from 20 to 25 × 1.2 to 1.5 μm. Morphological characteristics suggested the identity of the fungal isolates to be Phomopsis amygdali. To confirm pathogenicity, an inoculum suspension was made from one isolate (106 conidia/ml) and was sprayed until runoff onto five twigs with buds. Inoculated twigs were maintained at 26°C and 100% relative humidity in a growth chamber with a 12-h period of fluorescent light daily. Twigs inoculated with sterilized water were included as noninoculated controls. After 4 days, dark brown lesions appeared around buds on inoculated twigs. No symptoms were observed on the control twigs. Constriction cankers were reproduced and P. amygdali was reisolated from the lesions. To confirm the identity of the pathogen, total genomic DNA was extracted with the cetyltrimethylammoniumbromide (CTAB) method from the mycelia of two isolates from YuLu juicy peach and Jinxiu yellow peach (2). PCR was performed with universal primers ITS1 (5'-TCCGTAGGTGAACCTGCGG-3') and ITS4 (5'-TCCTCCGCTTATTGATATGC-3') to amplify a DNA fragment of approximately 550 bp. The PCR products were purified and sequenced in both directions (Sangon Biotech (Shanghai) Co., Ltd., China). The sequences (GenBank Accession Nos. HQ632013 and HQ632014) shared 98.9% identity with each other (MegAlign software; DNASTAR, Madison, WI). A comparison of these two sequences with those in GenBank showed that the sequences had the highest nucleotide similarity (99%) with P. amygdali isolate FAU1052 from peach in the southeastern United States (Accession No. AF102998). To our knowledge, this is the first report of P. amygdali causing twig canker on peach in China and will provide useful information for developing effective control strategies. References: (1) D. F. Farr et al. Mycologia 91:1008, 1999. (2) M. A. Saghai-Maroof et al. Proc. Natl. Acad. Sci. USA. 81:8014, 1984.


Outcomes of aortic arch replacement surgery after previous cardiac surgery.
Aortic arch replacement is a potentially high-risk operation and in the re-operative setting has been found to be a risk factor for poor outcome, yet there is a dearth of published data specifically on this topic. The aim of the study was to review our unit's outcomes in this re-operative setting. Data were collated for all patients who underwent aortic arch replacement surgery after previous cardiac surgery from January 1988 to November 2011. The patients were divided based primarily on elective versus non-elective and also early (≤2005) and late (≥2006) series. Twenty-seven eligible patients (22 male; median age: 53.0 years; elective: 14, non-elective: 13) were identified. There was a mean period of 14.5 years between the first operation and the subsequent aortic arch replacement. The overall 30-day mortality rate was 22.2% - 0% elective and 46.2% non-elective (P = 0.004). Overall permanent neurological dysfunction was 21.7% - 28.6% elective and 11.1% non-elective (P = 0.463). There were 11 early-series patients and 16 late-series patients. For early-series patients, 90.9% were non-elective versus 18.8% in the late-series patients. The 30-day mortality rate was 54.5% early series versus 0% late series. Aortic arch replacement is high risk in the re-operative setting. These risks are even greater for non-elective procedures. This highlights the need for aggressive first-time surgery to reduce re-operative procedures and good long-term follow-up programmes to allow elective procedures if required.


Further characterization and high-resolution mapping of quantitative trait loci for ethanol-induced locomotor activity.
Differential sensitivity to the stimulant effects of ethanol on locomotor activity is determined in part by genetic differences. Among inbred strains of mice, moderate doses of ethanol (1-2 g/kg) stimulate locomotor activity in some strains, e.g., the DBA/2J (D2), but only mildly affect activity in other strains, e.g., C57BL/6J (B6) (Crabbe et al., 1982, 1983; Crabbe, 1986; Dudek and Phillips, 1990; Dudek et al., 1991; Dudek and Tritto, 1994). Quantitative trait loci (QTL) for the acute ethanol (1.5 g/kg) locomotor response has been identified in the BXD recombinant inbred (RI) series (N = 25 strains), a C57BL/6J x DBA/2J (B6D2) F2 intercross (N = 1800), and heterogeneous stock (HS) mice (N = 550). QTLs detected (p < .01) in the RI series were found on chromosomes 1, 2, and 6 and these QTLs were expressed in a time-dependent fashion. The QTLs on chromosomes 1 and 2 were confirmed in the F2 intercross at p < 10(-7) or better. HS mice from G32 to G35 were used to fine-map the chromosome 2 QTL. Compared to the consensus map, the genetic map in the HS animals was expanded 10- to 15-fold. Over the region flanked by D2Mit94 to D2Mit304, three separate QTLs were detected in the HS animals. The data obtained confirm the usefulness of HS mice for the fine-mapping of QTLs to a resolution of 2 cM or less.


Identification of transcriptional signals in Encephalitozoon cuniculi widespread among Microsporidia phylum: support for accurate structural genome annotation.
Microsporidia are obligate intracellular eukaryotic parasites with genomes ranging in size from 2.3 Mbp to more than 20 Mbp. The extremely small (2.9 Mbp) and highly compact (approximately 1 gene/kb) genome of the human parasite Encephalitozoon cuniculi has been fully sequenced. The aim of this study was to characterize noncoding motifs that could be involved in regulation of gene expression in E. cuniculi and to show whether these motifs are conserved among the phylum Microsporidia. To identify such signals, 5' and 3'RACE-PCR experiments were performed on different E. cuniculi mRNAs. This analysis confirmed that transcription overrun occurs in E. cuniculi and may result from stochastic recognition of the AAUAAA polyadenylation signal. Such experiments also showed highly reduced 5'UTR's (<7 nts). Most of the E. cuniculi genes presented a CCC-like motif immediately upstream from the coding start. To characterize other signals involved in differential transcriptional regulation, we then focused our attention on the gene family coding for ribosomal proteins. An AAATTT-like signal was identified upstream from the CCC-like motif. In rare cases the cytosine triplet was shown to be substituted by a GGG-like motif. Comparative genomic studies confirmed that these different signals are also located upstream from genes encoding ribosomal proteins in other microsporidian species including Antonospora locustae, Enterocytozoon bieneusi, Anncaliia algerae (syn. Brachiola algerae) and Nosema ceranae. Based on these results a systematic analysis of the approximately 2000 E. cuniculi coding DNA sequences was then performed and brings to highlight that 364 translation initiation codons (18.29% of total CDSs) had been badly predicted. We identified various signals involved in the maturation of E. cuniculi mRNAs. Presence of such signals, in phylogenetically distant microsporidian species, suggests that a common regulatory mechanism exists among the microsporidia. Furthermore, 5'UTRs being strongly reduced, these signals can be used to ensure the accurate prediction of translation initiation codons for microsporidian genes and to improve microsporidian genome annotation.


Oxidative stress and increased type-IV collagenase levels in bronchoalveolar lavage fluid from newborn babies.
Oxidative stress may increase lung permeability by up-regulation of matrix-metalloproteinase-9 (MMP-9), a type-IV collagenase that can disrupt alveolar basement membranes. We have compared a marker of oxidative stress (protein carbonyl residues) with levels of MMP-9 and its inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), in bronchoalveolar lavage samples from newborn babies. Bronchoalveolar lavage samples (n = 87, two from each time point) were taken in the first 6 postnatal days from 41 ventilated babies: 18 of <29 wk gestation, 10 of 29-36 wk, 9 term with persistent fetal circulation, and 4 term without lung disease. Respiratory disease severity at the time of bronchoalveolar lavage was assessed using the arterial-alveolar oxygen tension ratio. One sample from each time point was used for the measurement of MMP-9 by zymography and TIMP-1 by ELISA. The second sample was used to measure carbonyl group concentrations, also using an ELISA. Correlations were calculated between protein carbonyls, arterial-alveolar oxygen tension ratio, and MMP-9 and TIMP-1 concentrations. Significant correlations were found between carbonyl concentrations and arterial-alveolar oxygen tension ratio (r = -0.325, p = 0.0031, n = 81), MMP-9 (r = 0.331, p < 0.0029, n = 79), and TIMP-1 (r = 0.436, p < 0.0001, n = 87). Worsening respiratory disease in newborn babies is associated with increased carbonyl concentrations in neonatal bronchoalveolar lavage fluid, and these correlated with MMP-9 and TIMP-1 levels. Increased oxidative stress may damage the lung by increasing type-IV collagenase activity, causing disruption of the extracellular matrix.


Eradication of established tumors by vaccination with recombinant Bordetella pertussis adenylate cyclase carrying the human papillomavirus 16 E7 oncoprotein.
High-risk human papillomaviruses (HPV) such as HPV16 are associated with the development of cervical cancer. The HPV16-E6 and HPV16-E7 oncoproteins are expressed throughout the replicative cycle of the virus and are necessary for the onset and maintenance of malignant transformation. Both these tumor-specific antigens are considered as potential targets for specific CTL-mediated immunotherapy. The adenylate cyclase (CyaA) of Bordetella pertussis is able to target dendritic cells through specific interaction with the alpha(M)beta(2) integrin. It has been previously shown that this bacterial protein could be used to deliver CD4(+) and CD8(+) T cell epitopes to the MHC class II and class I presentation pathways to trigger specific Th and CTL responses in vivo, providing protection against subsequent viral or tumoral challenge. Here, we constructed recombinant CyaA containing either the full sequence or various subfragments from the HPV16-E7 protein. We show that, when injected to C57BL/6 mice in absence of any adjuvant, these HPV16-recombinant CyaAs are able to induce specific Th1 and CTL responses. Furthermore, when injected into mice grafted with HPV16-E7-expressing tumor cells (TC-1), one of these recombinant proteins was able to trigger complete tumor regression in 100% of the animals tested. This therapeutic efficacy compared favorably to that of strongly adjuvanted peptide and was marginally affected by prior immunity to CyaA protein. This study represents the first in vivo demonstration of the antitumoral therapeutic activity of recombinant CyaA proteins carrying human tumor-associated antigens and paves the way for the testing of this vector in clinical trials.


All About the Ligamentum Teres: From Biomechanical Role to Surgical Reconstruction.
Intriguing anatomists and surgeons for centuries, the exact function and biomechanical significance of the ligamentum teres (LT) remains incompletely understood. The LT, also described as the ligamentum femoris capitis, is an intra-articular extrasynovial ligament extending from the cotyloid fossa of the acetabulum to the fovea on the femoral head. Some studies have described it as a vestigial structure in the adult hip. More recent biomechanical studies, however, along with histological and anatomical studies, have suggested the LT to have an important function in proprioception, nociception, and as a secondary stabilizer of the hip joint. The advent and increased utilization of hip arthroscopy to treat hip pathology over the past two decades has ignited a renewed interest in the role of the LT, as well as techniques and indications for management of pathology. In the constellation of intra-articular pain generators of the hip, LT injuries have historically been difficult to diagnose through physical examination or advanced imaging. Numerous classification systems have been proposed based on arthroscopic appearance, and for most cases, conservative management is adequate. In patients undergoing hip arthroscopy, LT débridement usually suffices, although in cases of persistent pain and severe instability, reconstruction of the ligament may be indicated. Multiple methods for reconstruction have been described, with the greatest variation in the method of acetabular fixation of the graft. Future research should focus on clarifying the role of the LT, appropriate surgical indications for reconstruction, and optimization of graft fixation within the acetabulum.


Relevance of current guidelines for organizing an anticoagulation clinic.
To describe variations in the structure of anticoagulation clinic (ACC) care within the Veterans Health Administration (VA) and to identify structures of care that are associated with better site-level anticoagulation control. Questionnaire correlated with automated clinical data. We characterized 90 VA ACCs using a questionnaire administered by the VA Central Office. Site descriptors included staffing levels, provider training, visit modalities, quality improvement programs, documentation, and care coordination. Patient outcomes were measured by site mean risk-adjusted percentage time in therapeutic range, a measure of anticoagulation control over time. Our study was powered to detect a 3% difference in risk-adjusted percentage time in therapeutic range, a small-to-moderate effect size, between sites with and without a certain characteristic. We observed considerable variation in the structure of ACC care. For example, 48 sites had fewer than 400 patients per provider, 25 sites had 400 to 599 patients per provider, and 17 sites had 600 patients or more per provider. However, none of the site characteristics measured were significantly related to anticoagulation control. We found substantial variation in guideline-targeted organizational and management features of ACC care within the VA. However, no single feature was associated with better anticoagulation control. Current guidelines for organizing an ACC may have limited relevance for improving patient outcomes.


Functionalization/passivation of porous graphitic carbon with di-tert-amylperoxide.
Porous graphitic carbon (PGC) particles were functionalized/passivated in situ in packed beds at elevated temperature with neat di-tert-amylperoxide (DTAP) in a column oven. The performance of these particles for high performance liquid chromatography (HPLC) was assayed before and after this chemistry with the following analytes: benzene, toluene, ethyl benzene, n-propyl benzene, n-butyl benzene, p-xylene, phenol, 4-methylphenol, phenetole, 3,5-xylenol, and anisole. After the first functionalization/passivation, the retention factors, k, of these compounds decreased by about 5% and the number of theoretical plates (N) increased by ca. 15%. These values of k then remained roughly constant after a second functionalization/passivation but a further increase in N was noticed. In addition, after each of the reactions, the peak asymmetries decreased by ca. 15%, for a total of ca. 30%. The columns were then subjected twice to methanol at 100°C for 5h at 1 mL/min. After these stability tests, the values of k remained roughly constant, the number of plates increased, which is favorable, and the asymmetries rose and then declined, where they remained below the initial values for the unfunctionalized columns. Functionalized and unfunctionalized particles were characterized by scanning electron microscopy and BET measurements, which showed no difference between the functionalized and unfunctionalized materials, and X-ray photoelectron spectroscopy and time-of-flight secondary ion mass spectrometry (ToF-SIMS), where ToF-SIMS suggested some chemical differences between the functionalized and unfunctionalized materials. In particular ToF-SIMS suggested that the expected five-carbon fragments from DTAP exist at higher concentrations on DTAP-functionalized PGC. First principle calculations on model graphitic surfaces suggest that the first addition of a DTAP radical to the surface proceeds in an approximately isothermal or slightly favorable fashion, but that subsequent DTAP additions are then increasingly thermodynamically favorable. Thus, this analysis suggests that the direct functionalization/passivation of PGC with DTAP is plausible. Chemometric analyses of the chromatographic and ToF-SIMS data are also presented.


Preparation and evaluation of nanocellulose-gold nanoparticle nanocomposites for SERS applications.
Nanocellulose is of research interest due to its extraordinary optical, thermal, and mechanical properties. The incorporation of guest nanoparticles into nanocellulose substrates enables production of novel nanocomposites with a broad range of applications. In this study, gold nanoparticle/bacterial cellulose (AuNP/BC) nanocomposites were prepared and evaluated for their applicability as surface-enhanced Raman scattering (SERS) substrates. The nanocomposites were prepared by citrate mediated in situ reduction of Au(3+) in the presence of a BC hydrogel at 303 K. Both the size and morphology of the AuNPs were functions of the HAuCl4 and citrate concentrations. At high HAuCl4 concentrations, Au nanoplates form within the nanocomposites and are responsible for high SERS enhancements. At lower HAuCl4 concentrations, uniform nanospheres form and the SERS enhancement is dependent on the nanosphere size. The time-resolved increase in the SERS signal was probed as a function of drying time with SERS 'hot-spots' primarily forming in the final minutes of nanocomposite drying. The application of the AuNP/BC nanocomposites for detection of the SERS active dyes MGITC and R6G as well as the environmental contaminant atrazine is illustrated as is its use under low and high pH conditions. The results indicate the broad applicability of this nanocomposite for analyte detection.


Large-scale proteome investigation in wild relatives (A, B, and D genomes) of wheat.
Large-scale proteomics of three wild relatives of wheat grain (A, B, and D genomes) were analyzed by using multidimensional protein identification technology coupled to liquid chromatography quadruple mass spectrometry. A total of 1568 (peptide match ≥1) and 255 (peptide match ≥2) unique proteins were detected and classified, which represents the most wide-ranging proteomic exploitation to date. The development of standard proteomes exhibiting all of the proteins involved in normal physiology will facilitate the delineation of disease/defense, metabolism, energy metabolism, and protein synthesis. A relative proteome exploration of the expression patterns indicates that proteins are involved in abiotic and biotic stress. Functional category analysis indicates that these differentially expressed proteins are mainly involved in disease/defense (15.38%, 21.26%, and 16.78%), metabolism (8.39%, 12.07%, and 14.09%), energy metabolism (11.19%, 11.49%, and 13.42%), protein synthesis (9.09%, 9.20%, and 8.72%), cell growth and division (9.09%, 4.60%, and 6.04%), cellular organization (4.20%, 5.75%, and 5.37%), development (6.29%, 2.87%, 3.36%), folding and stability (6.29%, 8.62%, and 8.05%), signal transduction (11.19%, 7.47%, and 8.05%), storage protein (4.20%, 1.72%, and 2.01%), transcription (5.59%, 5.17%, and 4.03%), and transport facilitation (1.40%, 1.15%, and 3.36%) in A, B, and D genomes, respectively. Here, we reported genome-specific protein interaction network using Cytoscape software, which provides further insight into the molecular functions and mechanism of biochemical pathways. We provide a promising understanding about the expressed proteins and protein functions. Our approach should be applicable as a marker to assist in breeding or gene transfer for quality and stress research of cultivated wheat.


Breast conservation therapy for invasive lobular carcinoma: the impact of lobular carcinoma in situ in the surgical specimen on local recurrence and axillary node status.
Forty patients undergoing breast-conserving therapy for invasive lobular carcinoma were studied for the volume of lobular carcinoma in situ (LCIS) in the surgical specimen and its relationship to the surgical margins. The pathology of all cases was reviewed for margin status as well as the volume of LCIS in the surgical specimen. Mean follow-up time was 67 months. There were no local recurrences despite the fact that 38 per cent of patients had close or involved margins. There was one cancer-related death. Increasing tumor size and moderate or extensive involvement of the surgical specimen with LCIS were found to be independent predictors of axillary node metastases. The volume of LCIS in the surgical did not appear to have an impact on local recurrence. This paper adds to the growing body of literature suggesting that in patients undergoing breast-conserving therapy, LCIS in the surgical margin does not impact the risk of local recurrence and therefore may not require reexcision for close or involved surgical margins.


Preliminary experience with postmortem computed tomography in military penetrating trauma.
Postmortem examination serves as a tool for confirmation of clinical diagnosis, "quality" assurance, and education. In Israel, mostly because of religious reasons, most families withhold their permission to perform autopsies. To obtain objective information regarding the death of soldiers, the Israel Defense Forces Medical Corps started in September of 1997 to perform postmortem computed tomographic (PMCT) scans. The purpose of our study is to determine what information can be obtained from the PMCT scans. In a period of 16 months, 27 soldiers were killed in low-intensity conflicts and PMCT was obtained in 22 cases. Medical data obtained from the field medical care providers were collected and compared with PMCT results. Several examples of patients whose death was determined at the scene either before any medical intervention or after initiation of resuscitative treatment are shown in our study and compared with the clinical impression of the treating physician. Two examples of autopsy results are compared with PMCT results. Gas was detected in various parts of the circulatory system in many cases. The significance of this finding, described in our study for the first time, needs further investigation. PMCT scanning has limits in detecting superficial injuries and injuries of the extremities and determining the exact route of fragments through body tissues in penetrating military trauma. It also cannot serve as a tool for examining ammunition or the protection provided by various armors. However, it can provide a substantial amount of evidence that, when reviewed with the clinical information obtained from the physician at the scene, can help in assessing the treatment given at the field and point toward the probable cause of death.


Evidence for task-dependent memory dysfunction in the aged monkey.
Experimentally naive adult (9-11 years old) and aged (approximately 22-26 years old) female rhesus monkeys were evaluated on 3 neuropsychological tests of memory function. Aged monkeys were impaired in a delayed response test of visuospatial memory when the retention interval of the task was increased from 0 to 10 sec. These animals performed as well as younger subjects, however, at very short delays (0 and 1 sec), when the memory demands of the task were minimal. The same subjects were then trained in a delayed nonmatching to sample (DNMS) test of visual object recognition memory. Although they required significantly more training than the younger subjects to learn the nonmatching principle of the task, aged animals were only minimally impaired when recognition memory was tested at retention intervals ranging from 10 sec to 22 hr. In contrast to their relatively intact performance on the object recognition task, aged monkeys were dramatically impaired in a second version of DNMS that required subjects to remember the temporal order in which objects were presented. These findings support the view that certain memory functions are differentially susceptible to age-dependent deterioration. Since neuropsychological studies in young subjects demonstrate that different brain regions make relatively specific contributions to learning and memory, the task-dependent deficits observed in the aged monkey are important for determining which neural structures mediate age-dependent cognitive dysfunction. According to this perspective, aged monkeys were impaired on tasks known to be sensitive to prefrontal cortical damage, but the same animals performed well on a DNMS procedure that subjects with medial temporal lobe damage fail. These results suggest that prefrontal cortical dysfunction may mediate prominent aspects of age-dependent cognitive impairment in the monkey.


TCB2, a new anti-human interleukin-2 antibody, facilitates heterodimeric IL-2 receptor signaling and improves anti-tumor immunity.
IL-2 is a pleiotropic cytokine that plays an essential role in the survival, expansion, and function of CD8 T cells, regulatory T cells (Tregs), and natural killer (NK) cells. Previous studies showed that binding IL-2 with an anti-IL-2 monoclonal antibody (mAb) with a particular specificity could block its interaction with IL-2Rα, which is mainly expressed on Tregs. This selectivity can enhance the anti-tumor effects of IL-2 by activating CD8 T and NK cells, while disfavoring Treg stimulation. Based on this, we newly developed a series of anti-human IL-2 (hIL-2) mAbs (TCB1-3) that selectively stimulate CD8 T and NK cells without overtly activating Tregs. Among them, the hIL-2/TCB2 complex (hIL-2/TCB2c) exerted the best efficacy by inducing a prodigious expansion of host memory phenotype (MP) CD8 T (60-fold) and NK cells (18-fold) with less efficient Treg proliferation (5-fold). As a result, there was an average eightfold increase in the ratio of MP CD8 to Tregs. Accordingly, hIL-2/TCB2c strongly inhibited the growth of B16F10, MC38, and CT26 tumors. More remarkably, hIL-2/TCB2c showed synergy with checkpoint inhibitors such as anti-CTLA-4 or PD1 antibodies, and resulted in almost complete regression of implanted tumors and resistance to secondary tumor challenge. For direct clinical use, we generated a humanized form of TCB2 that had equal immunostimulatory and anti-tumor efficacy as a murine one. Collectively, these results show that TCB2 can provide a potent immunotherapeutic modality either alone or together with checkpoint inhibitors in cancer patients.


Age-related changes of shape and flow dynamics in healthy adult aortas: A 4D flow MRI study.
Abnormal flow dynamics play an early and causative role in pathologic changes of the ascending aorta. To identify: 1) the changes in flow, shape, and size that occur in the ascending aorta with normal human ageing and 2) the influence of these factors on aortic flow dynamics. Retrospective. In all, 247 subjects (age range 19-86 years, mean 49 ± 17.7, 169 males) free of aortic or aortic valve pathology were included in this study. Subjects were stratified by youngest (18-33 years; n = 64), highest (>60 years, n = 67), and the middle two quartiles (34-60 years, n = 116). Subjects underwent a cardiac MRI (3T) exam including 4D-flow MRI of the aorta. Aortic curvature, arch shape, ascending aortic angle, ascending aortic diameter, and the stroke volume normalized by the aortic volume (nSV) were measured. Velocity, vorticity, and helicity were quantified across the thoracic aorta. Univariate and multivariate regressions were used to quantify continuous relationships between variables. Aortic diameter, ascending aortic angle, shape, and curvature all increased across age while nSV decreased (all P < 0.0001). Systolic vorticity in the mid arch decreased by 50% across the age range (P < 0.0001), while peak helicity decreased by 80% (P < 0.0001). Curvature tightly governs optimal flow in the youngest quartile, with an effect size 1.5 to 4 times larger than other parameters in the descending aorta, but had a minimal influence with advancing age. In the upper quartile of age, flow dynamics were almost completely determined by nSV, exerting an effect size on velocity and vorticity >10 times that of diameter and other shape factors. Aortic shape influences flow dynamics in younger subjects. Flow conditions become increasingly disturbed with advancing age, and in these conditions nSV has a more dominant effect on flow patterns than shape factors. 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:90-100.


Relation between soluble ST2, growth differentiation factor-15, and high-sensitivity troponin I and incident atrial fibrillation.
We investigated whether circulating concentrations of soluble ST2, growth differentiation factor-15 (GDF-15), and high-sensitivity troponin I (hsTnI) are associated with incident atrial fibrillation (AF) and whether these biomarkers improve current risk prediction models including AF risk factors, B-type natriuretic peptide (BNP), and C-reactive protein (CRP). We studied the relation between soluble ST2, GDF-15, and hsTnI and development of AF in Framingham Heart Study participants without prevalent AF. We used Cox proportional hazard regression analysis to examine the relation of incident AF during a 10-year follow-up period with each biomarker. We adjusted for standard AF clinical risk factors, BNP, and CRP. The mean age of the 3,217 participants was 59 ± 10 years, and 54% were women. During a 10-year follow-up, 242 participants developed AF. In age- and sex-adjusted models, GDF-15 and hsTnI were associated with risk of incident AF; however, after including the AF risk factors and BNP and CRP, only hsTnI was significantly associated with AF (hazard ratio per 1 SD of loge hsTnI, 1.12, 95% CI 1.00-1.26, P = .045). The c statistic of the base model including AF risk factors, BNP, and CRP was 0.803 (95% CI 0.777-0.830) and did not improve by adding individual or all 3 biomarkers. None of the discrimination and reclassification statistics were significant compared with the base model. In a community-based cohort, circulating hsTnI concentrations were associated with incident AF. None of the novel biomarkers evaluated improved AF risk discrimination or reclassification beyond standard clinical AF risk factors and biomarkers.


Alisertib in Combination With Weekly Paclitaxel in Patients With Advanced Breast Cancer or Recurrent Ovarian Cancer: A Randomized Clinical Trial.
There is an unmet medical need for the treatment of recurrent ovarian cancer, and new approaches are needed to improve progression-free survival (PFS) and overall survival. This phase 1/2 study evaluated the activity of alisertib in combination with weekly paclitaxel in patients with breast (phase 1) and ovarian cancer (phase 1 and phase 2). An open-label phase 1 and randomized phase 2 clinical trial conducted from April 16, 2010, for phase 1 and March 28, 2012, to August 12, 2013, for phase 2 was conducted at 33 sites (United States, France, and Poland). Data are reported from a cutoff date of August 12, 2014, with a median duration of follow-up of 7.2 months in the alisertib plus paclitaxel arm and 4.6 months in the paclitaxel arm. A total of 191 women with advanced breast (phase 1 only) or recurrent ovarian cancer were enrolled, including 142 patients randomized to alisertib plus paclitaxel (n = 73) or paclitaxel alone (n = 69) in the phase 2 study. Patients were randomized 1:1 stratified by platinum-free interval (refractory, 0-6 months, 6-12 months) and prior weekly taxane treatment (yes, no) to receive alisertib 40 mg twice per day orally and 3 days on and 4 days off for 3 weeks, plus paclitaxel (60 mg/m2 intravenously, days 1, 8, and 15), or weekly paclitaxel 80 mg/m2 intravenously in 28-day cycles. Primary endpoint was PFS; primary efficacy analysis and safety analysis used modified intention to treat (mITT) population (all randomized patients who received ≥1 dose of study drug). The median age for the 191 patients enrolled in phase 1 was 59 (range, 29-75) years. The median age for the 142 patients enrolled in phase 2 was 63 (range, 30-81) years for patients receiving alisertib plus paclitaxel and 61 (range, 41-81) years for patients receiving paclitaxel. At data cutoff, 107 (75%) patients had a documented PFS event; 52 (71%) in the alisertib plus paclitaxel arm, and 55 (80%) in the paclitaxel arm. Median PFS was 6.7 months with alisertib plus paclitaxel vs 4.7 months with paclitaxel (HR, 0.75; 80% CI, 0.58-0.96; P = .14; 2-sided P value cutoff = .20 to be considered worthy of further investigation). Drug-related grade 3 or higher adverse events were reported in 63 (86%) vs 14 (20%) patients in the alisertib plus paclitaxel and paclitaxel arms, including 56 (77%) vs 7 (10%) neutropenia, 18 (25%) vs 0 stomatitis, and 10 (14%) vs 2 (3%) anemia; 54 (74%) vs 17 (25%) had adverse events leading to dose reductions. Two patients died during the study (1 in each arm); neither death was considered related to study drug. The primary endpoint, PFS, significantly favored alisertib plus paclitaxel over paclitaxel alone. Further investigation is warranted. ClinicalTrials.gov identifier: NCT01091428.


Dapagliflozin compared with other oral anti-diabetes treatments when added to metformin monotherapy: a systematic review and network meta-analysis.
Indirect evidence from randomized controlled trials (RCTs) was used to estimate the effect of dapagliflozin, a new agent with a novel mechanism of action (SGLT-2 inhibition), relative to other anti-diabetes therapies after 1 year of treatment. A systematic literature review and Bayesian network meta-analysis (NMA) of RCTs involving anti-diabetes treatments added to metformin were conducted. RCTs enrolling subjects with type 2 diabetes inadequately controlled on metformin monotherapy were included. Comparators included dipeptidyl peptidase-4 (DPP-4) inhibitors, thiazolidinediones (TZDs), sulphonylureas, glucagon-like peptide-1 (GLP-1) analogues and dapagliflozin. Outcomes of interest were mean change from baseline HbA1c, weight and systolic blood pressure, and incidence of hypoglycaemia. From 4270 abstracts, six RCTs were included in the primary analysis; no RCTs involving GLP-1 analogues met primary inclusion criteria. All RCTs were actively controlled with sulphonylureas. The mean change in HbA1c from baseline was similar across comparators. The treatment effect (95% credible interval) of dapagliflozin on HbA1c was -0.08% (-0.25, 0.10) relative to DPP-4 inhibitors, -0.02% (-0.24, 0.21) relative to TZDs and 0.00% (-0.16, 0.16) relative to sulphonylureas. Non-sulphonylureas showed significantly lower risk of hypoglycaemia relative to sulphonylureas. Dapagliflozin had a significant effect on weight change: the relative difference was -2.74 kg (-5.35, -0.10) compared with DPP-4 inhibitors, and -4.67 kg (-7.03, -2.35) compared with sulphonylureas. Systolic blood pressure was not meta-analysed due to infrequent reporting. Compared with DPP-4 inhibitors, TZDs and sulphonylureas, dapagliflozin offers similar HbA1c control after 1 year, with similar or reduced risk of hypoglycaemia and the additional benefit of weight loss, when added to metformin.


Integration of somatosensory and motor-related information in the auditory system.
An ability to integrate information provided by different sensory modalities is a fundamental feature of neurons in many brain areas. Because visual and auditory inputs often originate from the same external object, which may be located some distance away from the observer, the synthesis of these cues can improve localization accuracy and speed up behavioral responses. By contrast, multisensory interactions occurring close to the body typically involve a combination of tactile stimuli with other sensory modalities. Moreover, most activities involving active touch generate sound, indicating that stimuli in these modalities are frequently experienced together. In this review, we examine the basis for determining sound-source distance and the contribution of auditory inputs to the neural encoding of space around the body. We then consider the perceptual consequences of combining auditory and tactile inputs in humans and discuss recent evidence from animal studies demonstrating how cortical and subcortical areas work together to mediate communication between these senses. This research has shown that somatosensory inputs interface with and modulate sound processing at multiple levels of the auditory pathway, from the cochlear nucleus in the brainstem to the cortex. Circuits involving inputs from the primary somatosensory cortex to the auditory midbrain have been identified that mediate suppressive effects of whisker stimulation on auditory thalamocortical processing, providing a possible basis for prioritizing the processing of tactile cues from nearby objects. Close links also exist between audition and movement, and auditory responses are typically suppressed by locomotion and other actions. These movement-related signals are thought to cancel out self-generated sounds, but they may also affect auditory responses via the associated somatosensory stimulation or as a result of changes in brain state. Together, these studies highlight the importance of considering both multisensory context and movement-related activity in order to understand how the auditory cortex operates during natural behaviors, paving the way for future work to investigate auditory-somatosensory interactions in more ecological situations.


Governing health data across changing contexts: A focus group study of citizen's views in England, Iceland, and Sweden.
The governance structures associated with health data are evolving in response to advances in digital technologies that enable new ways of capturing, using, and sharing different types of data. Increasingly, health data moves between different contexts such as from healthcare to research, or to commerce and marketing. Crossing these contextual boundaries has the potential to violate societal expectations about the appropriate use of health data and diminish public trust. Understanding citizens' views on the acceptability of and preferences for data use in different contexts is essential for developing information governance policies in these new contexts. Focus group design presenting data sharing scenarios in England, Iceland, and Sweden. Seventy-one participants were recruited. Participants supported the need for data to help understand the observable world, improve medical research, the quality of public services, and to benefit society. However, participants consistently identified the lack of information, transparency and control as barriers to trusting organisations to use data in a way that they considered appropriate. There was considerable support for fair and transparent data sharing practices where all parties benefitted. Data governance policy should involve all stakeholders' perspectives on an ongoing basis, to inform and implement changes to health data sharing practices that accord with stakeholder views. The Findings showed that (1) data should be used for ethical purposes even when there was commercial interest; (2) data subjects and/or public institutions that provide and share data should also receive benefits from the sharing of data; (3) third parties use of data requires greater transparency and accountability than currently exists, (4) there should be greater information provided to empower data subjects.


An Investigation of the Relationship Between Emergency Medicine Trainee Burnout and Clinical Performance in a High-fidelity Simulation Environment.
Burnout is prevalent among emergency medicine (EM) physicians, with physicians experiencing burnout more likely to report committing medical errors or delivering suboptimal care. The relationship between physician burnout and identifiable differences in clinical care, however, remains unclear. We examined if EM trainee burnout was associated with differences in clinical performance using high-fidelity simulation as a proxy for patient care. In this cross-sectional study across six institutions, we measured trainee performance over four simulation scenarios based on recognized EM milestones. For each scenario a faculty rater assessed whether the trainee performed predefined critical actions specific to each case. A summation of performed actions across all cases resulted in a cumulative task (CT) score (range = 0-85). Raters also assigned an impression score on a 10-point scale (0 = poor; 10 = outstanding) assessing the trainee's overall performance after each scenario, with the mean of the scores resulting in an overall impression (OI) score. After the simulation assessment, we measured trainees' burnout via the Maslach Burnout Inventory through a confidential, electronic survey. Trainee depression, quality of life (QOL) and daytime sleepiness were also evaluated. Survey results were compared to simulation scores using analysis of variance and covariance. Fifty-eight of 89 (65.2%) eligible participants completed the survey and simulation assessment. Thirty-one of 58 (53.4%, 95% CI = 40.2% to 66.7%) trainees reported burnout. In trainees with burnout compared to those without, mean CT scores (73.4 vs. 75.2, 95% CI of difference = 0.06 to 3.51) and OI scores (6.4 vs 6.8, 95% CI of difference = 0.03 to 0.79) were negatively associated with burnout after controlling for training program. In contrast, QOL were positively associated with CT [F(1,48) = 4.796, p = 0.033] and OI [F(1,48) = 4.561, p = 0.038] scores. There were no significant associations between simulation performance and depression or daytime sleepiness. Emergency medicine trainees with burnout received lower cumulative performance scores over four high-fidelity simulation scenarios than trainees without burnout.


Oxygen isotope variations at the margin of a CAI records circulation within the solar nebula.
Micrometer-scale analyses of a calcium-, aluminum-rich inclusion (CAI) and the characteristic mineral bands mantling the CAI reveal that the outer parts of this primitive object have a large range of oxygen isotope compositions. The variations are systematic; the relative abundance of (16)O first decreases toward the CAI margin, approaching a planetary-like isotopic composition, then shifts to extremely (16)O-rich compositions through the surrounding rim. The variability implies that CAIs probably formed from several oxygen reservoirs. The observations support early and short-lived fluctuations of the environment in which CAIs formed, either because of transport of the CAIs themselves to distinct regions of the solar nebula or because of varying gas composition near the proto-Sun.


Efficacy of screening mammography. A meta-analysis.
To determine the efficacy of screening mammography by age, number of mammographic views per screen, screening interval, and duration of follow-up. Literature review and meta-analysis. DATA IDENTIFICATION AND ANALYSIS: Literature search of English-language studies reported from January 1966 to October 31, 1993, using MEDLINE, manual literature review, and consultation with experts. A total of 13 studies were selected, and their results were combined using meta-analytic techniques based on the assumption of fixed effects. The overall summary relative risk (RR) estimate for breast cancer mortality for women aged 50 to 74 years undergoing screening mammography compared with those who did not was 0.74 (95% confidence interval [CI], 0.66 to 0.83). The magnitude of the benefit in this age group was similar regardless of number of mammographic views per screen, screening interval, or duration of follow-up. In contrast, none of the summary RR estimates for women aged 40 to 49 years was significantly less than 1.0, irrespective of screening intervention or duration of follow-up. The overall summary RR estimate in women aged 40 to 49 years was 0.93 (95% CI, 0.76 to 1.13); the summary RR estimate for those studies that used two-view mammography was 0.87 (95% CI, 0.68 to 1.12) compared with 1.02 (95% CI, 0.73 to 1.44) for those studies that used one-view mammography, and for those studies with 7 to 9 years of follow-up, the summary RR estimate was 1.02 (95% CI, 0.82 to 1.27) compared with 0.83 (95% CI, 0.65 to 1.06) for those studies with 10 to 12 years of follow-up. Screening mammography significantly reduces breast cancer mortality in women aged 50 to 74 years after 7 to 9 years of follow-up, regardless of screening interval or number of mammographic views per screen. There is no reduction in breast cancer mortality in women aged 40 to 49 years after 7 to 9 years of follow-up. Screening mammography may be effective in reducing breast cancer mortality in women aged 40 to 49 years after 10 to 12 years of follow-up, but the same benefit could probably be achieved by beginning screening at menopause or 50 years of age.


Angiotensin I-converting enzyme gene polymorphism enhances the effect of hypercholesterolemia on the risk of coronary heart disease in a general Japanese population: the hisayama study.
The angiotensin I-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism has been reported to be implicated in susceptibility to coronary heart disease (CHD). However, this association remains inconclusive. The purpose of this study was to clarify the association between the I/D polymorphism of the ACE gene and the development of CHD in a Japanese general population and investigate whether the effects of traditional risk factors on the risk of CHD are heterogeneous among ACE genotypes. The subjects included 2,125 community-dwelling individuals 40 years of age or older without cardiovascular disease for whom genetic information was available. All patients were prospectively followed for 19 years, and the association between the ACE polymorphism and the incidence of CHD was examined based on the interactions with traditional risk factors, such as hypercholesterolemia, hypertension, diabetes and smoking. A total of 161 CHD events occurred during the follow-up period. The age- and sex-adjusted incidence of CHD was not significantly different among the genotypes (5.8, 5.2, and 6.9 per 1,000person-years for genotypes II, ID and DD, respectively). In a stratified analysis, however, the ACE DD genotype was found to significantly accelerate the risk of developing CHD by hypercholesterolemia (hazard ratio [HR]=4.50, 95% confidence interval=2.02-10.04 for hypercholesterolemia with the DD genotype; HR=1.48, 95% CI=1.04-2.12 for hypercholesterolemia with the ID+II genotype; P for interaction=0.01), even after adjusting for other confounding factors, whereas no such associations were observed for hypertension, diabetes or smoking. The current findings suggest that the ACE DD genotype enhances the effect of hypercholesterolemia on the development of CHD in the general Japanese population.


Sex differences in human brain morphometry and metabolism: an in vivo quantitative magnetic resonance imaging and positron emission tomography study on the effect of aging.
There are significant age and sex effects in cognitive ability and brain disease. However, sex differences in aging of human brain areas associated with nonreproductive behavior have not been extensively studied. We hypothesized that there would be significant sex differences in aging of brain areas that subserve speech, visuospatial, and memory function. We investigated sex differences in the effect of aging on human brain morphometry by means of volumetric magnetic resonance imaging and on regional cerebral metabolism for glucose by positron emission tomography. In the magnetic resonance imaging study, we examined 69 healthy right-handed subjects (34 women and 35 men), divided into young (age range, 20 to 35 years) and old (60 to 85 years) groups. In the positron emission tomography study, we investigated 120 healthy right-handed subjects (65 women and 55 men) aged 21 to 91 years. In the magnetic resonance imaging study, age-related volume loss was significantly greater in men than women in whole brain and frontal and temporal lobes, whereas it was greater in women than men in hippocampus and parietal lobes. In the positron emission tomography study, significant sex differences existed in the effect of age on regional brain metabolism, and asymmetry of metabolism, in the temporal and parietal lobes, Broca's area, thalamus, and hippocampus. We found significant sex differences in aging of brain areas that are essential to higher cognitive functioning. Thus, our findings may explain some of the age-sex differences in human cognition and response to brain injury and disease.


Evaluating quality in adolescent mental health services: a systematic review.
To evaluate the quality of adolescent mental health service provision globally, according to the WHO Global Standards of adolescent mental health literacy, appropriate package of services and provider competencies. Systematic review of 5 databases, and screening of eligible articles, from 1 January 2008 to 31 December 2020. We focused on quantitative and mixed-method studies that evaluated adolescent mental health literacy, appropriate package of services and provider competencies in mental health services, and that targeted depression, anxiety and post-traumatic stress disorder among adolescents (10-19 years). This included adolescents exposed to interventions or strategies within mental health services. Study quality was assessed using the National Institutes for Health Study Quality Assessment Tools. Data were extracted and grouped based on WHO quality Standards. Of the 20 104 studies identified, 20 articles were included. The majority of studies came from high-income countries, with one from a low-income country. Most of the studies did not conceptualise quality. Results found that an online decision aid was evaluated to increase adolescent mental health literacy. Studies that targeted an appropriate package of services evaluated the quality of engagement between the therapist and adolescent, patient-centred communication, mental health service use, linkages to mental health services, health facility culture and intensive community treatment. Provider competencies focused on studies that evaluated confidence in managing and referring adolescents, collaboration between health facility levels, evidence-based practices and technology use. There is limited evidence on quality measures in adolescent mental health services (as conforms to the WHO Global Standards), pointing to a global evidence gap for adolescent mental health services. There are several challenges to overcome, including a need to develop consensus on quality and methods to measure quality in mental health settings. CRD42020161318.


Aortic rupture and aorto-pulmonary fistulation in the Friesian horse: characterisation of the clinical and gross post mortem findings in 24 cases.
In horses, aortic sinus of Valsalva aneurysms or tears in the aortic root are well-recognised conditions in breeding stallions, often leading to sudden death. A more uncommon form of aortic rupture, located proximal to the ligamentum arteriosum has been reported in 3 Friesian horses. The purpose of this study was to phenotypically characterise aortic rupture and aorto-pulmonary fistulation in Friesian horses in terms of clinical and post mortem data based on 24 cases. Friesian horses that were diagnosed with aortic rupture and aorto-pulmonary fistulation over a period of 13 years (1997-2010) at the Department of Equine Sciences of Utrecht University (n = 15) and Wolvega Equine Hospital (n = 9), were included in this study. Case history, results of clinical examination and gross post mortem findings were screened and analysed. Some cases were found dead without prior symptoms, but in several cases signs such as recurrent colic, peripheral oedema and sustained tachycardia were present for several weeks prior to cardiac failure. Clinical examination during hospitalisation revealed increased rectal temperature, peripheral oedema and increased jugular pulse with a bounding arterial pulse. In the majority of horses an aortic rupture of the aortic arch near the ligamentum arteriosum, concurrent with a circumferential cuff of perivascular haemorrhage and aorto-pulmonary fistulation, was found at post mortem examination. Aorto-pulmonary fistulation in conjunction with aortic rupture is more common in Friesians than previously estimated. In some cases findings demonstrate a progressive pathology rather than acute cardiac failure and sudden death. An appropriate approach is necessary during post mortem examination of the heart in order not to overlook the diagnosis. Equine practitioners should realise that in Friesian horses presented with a history of recurrent false colic, coughing, sustained tachycardia and/or peripheral oedema, aortic rupture and aorto-pulmonary fistulation should be included in the differential diagnosis.


Relative antithrombotic and antihemostatic effects of protein C activator versus low-molecular-weight heparin in primates.
The anticoagulant and anti-inflammatory enzyme, activated protein C (APC), naturally controls thrombosis without affecting hemostasis. We therefore evaluated whether the integrity of primary hemostasis was preserved during limited pharmacological antithrombotic protein C activator (PCA) treatment in baboons. The double-mutant thrombin (Trp215Ala/Glu217Ala) with less than 1% procoagulant activity was used as a relatively selective PCA and compared with systemic anticoagulation by APC and low-molecular-weight heparin (LMWH) at doses that inhibited fibrin deposition on thrombogenic segments of arteriovenous shunts. As expected, both systemic anticoagulants, APC (0.028 or 0.222 mg/kg for 70 minutes) and LMWH (0.325 to 2.6 mg/kg for 70 minutes), were antithrombotic and prolonged the template bleeding time. In contrast, PCA at doses (0.0021 to 0.0083 mg/kg for 70 minutes) that had antithrombotic effects comparable with LMWH did not demonstrably impair primary hemostasis. PCA bound to platelets and leukocytes, and accumulated in thrombi. APC infusion at higher circulating APC levels was less antithrombotic than PCA infusion at lower circulating APC levels. The observed dissociation of antithrombotic and antihemostatic effects during PCA infusion thus appeared to emulate the physiological regulation of intravascular blood coagulation (thrombosis) by the endogenous protein C system. Our data suggest that limited pharmacological protein C activation might exhibit considerable thrombosis specificity.


Quality of infant care in primary health services in Southern and Northeastern Brazil.
To assess the quality of the health care provided to children aged under one year old performed by primary health services in the South and Northeast regions of Brazil. This is a cross-sectional, population-based study carried out in 2010 with 7,915 children aged from one to four years, whose homes are located in the areas of health service coverage. We described the prevalence of procedures and guidelines, such as weight and height measurement, vaccination, newborn blood spot screening, evaluation of umbilical cord, instruction on breastfeeding and introduction of new food, and their respective 95% confidence intervals. The differences were analyzed using the chi-square test of heterogeneity and linear trend. We considered the main outcome of high-quality infant care if the child had received all recommended procedures and guidelines in the first year of life. For this analysis, we used the Poisson regression considering hierarchical model. There was low prevalence for the instruction on breastfeeding in the first week of life (58.8%, 95%CI 57.5-60.0) and on the introduction of new food in the fourth month care. The prevalence of high-quality in childcare was 42.0% (95%CI 40.5-43.5). The adjusted analysis according to hierarchical model indicated greater probability of this outcome in the Northeast region (PR = 1.17, 95%CI 1.09-1.26), in smaller municipalities (PR = 1.17, 95%CI 1.03-1.33), and in municipalities with 50,000 and 99,000 inhabitants (PR = 1.20, 95%CI 1.09-1.34). The Northeast region has higher-quality infant care services, which can be explained by the consolidation of the Family Health Strategy in that region.


A feasibility study incorporating a pilot randomised controlled trial of oral feeding plus pre-treatment gastrostomy tube versus oral feeding plus as-needed nasogastric tube feeding in patients undergoing chemoradiation for head and neck cancer (TUBE trial): study protocol.
There are 7000 new cases of head and neck squamous cell cancers (HNSCC) treated by the NHS each year. Stage III and IV HNSCC can be treated non-surgically by radio therapy (RT) or chemoradiation therapy (CRT). CRT can affect eating and drinking through a range of side effects with 90 % of patients undergoing this treatment requiring nutritional support via gastrostomy (G) or nasogastric (NG) tube feeding. Long-term dysphagia following CRT is a primary concern for patients. The effect of enteral feeding routes on swallowing function is not well understood, and the two feeding methods have, to date, not been compared to assess which leads to a better patient outcome. The purpose of this study is to explore the feasibility of conducting a randomised controlled trial (RCT) comparing these two options with particular emphasis on patient willingness to be randomised and clinician willingness to approach eligible patients. This is a mixed methods multicentre study to establish the feasibility of a randomised controlled trial comparing oral feeding plus pre-treatment gastrostomy versus oral feeding plus as required nasogastric tube feeding in patients with HNSCC. A total of 60 participants will be randomised to the two arms of the study (1:1 ratio). The primary outcome of feasibility is a composite of recruitment (willingness to randomise and be randomised) and retention. A qualitative process evaluation investigating patient, family and friends and staff experiences of trial participation will also be conducted alongside an economic modelling exercise to synthesise available evidence and provide estimates of cost-effectiveness and value of information. Participants will be assessed at baseline (pre-randomisation), during CRT weekly, 3 months and 6 months. Clinicians are in equipoise over the enteral feeding options for patients being treated with CRT. Swallowing outcomes have been identified as a top priority for patients following treatment and this trial would inform a future larger scale RCT in this area to inform best practice. ISRCTN48569216.


Fresh isolates from children with severe Plasmodium falciparum malaria bind to multiple receptors.
The sequestration of Plasmodium falciparum-infected erythrocytes (pRBC) away from the peripheral circulation is a property of all field isolates. Here we have examined the pRBC of 111 fresh clinical isolates from children with malaria for a number of adhesive features in order to study their possible coexpression and association with severity of disease. A large number of adhesion assays were performed studying rosetting, giant rosetting, and binding to CD36, intercellular adhesion molecule 1, platelet endothelial cell adhesion molecule 1, thrombospondin, heparin, blood group A, and immunoglobulins. Suspension assays were performed at the actual parasitemia of the isolate, while all the static adhesion assays were carried out at an equal adjusted parasitemia. The ability to bind to multiple receptors, as well as the ability to form rosettes and giant rosettes, was found to be more frequent among isolates from children with severe versus mild malaria (P = 0.0015). Rosettes and giant rosettes were more frequent for children with severe malaria, and the cell aggregates were larger and tighter, than for those with mild disease (P = 0.0023). Binding of immunoglobulins (97% of isolates) and of heparin (81% of isolates) to infected erythrocytes was common, and binding to heparin and blood group A was associated with severity of disease (P = 0.011 and P = 0.031, respectively). These results support the idea that isolates that bind to multiple receptors are involved in the causation of severe malaria and that several receptor-ligand interactions work synergistically in bringing about severe disease.


Full-scale comparison of N2O emissions from SBR N/DN operation versus one-stage deammonification MBBR treating reject water - and optimization with pH set-point.
To be able to fulfill the Paris agreement regarding anthropogenic greenhouse gases, all potential emissions must be mitigated. Wastewater treatment plants should aim to eliminate emissions of the most potent greenhouse gas, nitrous oxide (N2O). In this study, these emissions were measured at a full-scale reject water treatment tank during two different operation modes: nitrification/denitrification (N/DN) operating as a sequencing batch reactor (SBR), and deammonification (nitritation/anammox) as a moving bed biofilm reactor (MBBR). The treatment process emitted significantly less nitrous oxide in deammonification mode 0.14-0.7%, compared to 10% of total nitrogen in N/DN mode. The decrease can be linked to the changed feeding strategy, the lower concentrations of nitrite, a lower load of ammonia oxidized, a shorter aeration time, the absence of non-optimized ethanol dosage or periodic lack of oxygen as well as the introduction of biofilm. Further, evaluation was done how the operational pH set point influenced the emissions in deammonification mode. Lower concentrations of nitrous oxide were measured in water phase at higher pH (7.5-7.6) than at lower pH (6.6-7.1). This is believed to be mainly because of the lower aeration ratio and increased complete denitrification at the higher pH set point.


Overcoming procrastination: one-year follow-up and predictors of change in a randomized controlled trial of Internet-based cognitive behavior therapy.
Procrastination is a common self-regulatory failure that can have a negative impact on well-being and performance. However, few clinical trials have been conducted, and no follow-up has ever been performed. The current study therefore aimed to provide evidence for the long-term benefits and investigate predictors of a positive treatment outcome among patients receiving Internet-based cognitive behavior therapy (ICBT). A total of 150 self-recruited participants were randomized to guided or unguided ICBT. Self-report measures of procrastination, depression, anxiety, and quality of life were distributed at pre-treatment assessment, post-treatment assessment, and one-year follow-up. Mixed effects models were used to investigate the long-term gains, and multiple linear regression for predictors of a positive treatment outcome, using the change score on the Irrational Procrastination Scale as the dependent variable. Intention-to-treat was implemented for all statistical analyses. Large within-group effect sizes for guided and unguided ICBT, Cohen's d = .97-1.64, were found for self-report measures of procrastination, together with d = .56-.66 for depression and anxiety. Gains were maintained, and, in some cases, improved at follow-up. Guided and unguided ICBT did not differ from each other, mean differences -.31-1.17, 95% CIs [-2.59-3.22], and none of the predictors were associated with a better result, bs -1.45-1.61, 95% CIs [-3.14-4.26]. In sum, ICBT could be useful and beneficial in relation to managing procrastination, yielding great benefits up to one year after the treatment period has ended, with comparable results between guided and unguided ICBT.


Program assessment through outcomes analysis: efficacy of a comprehensive supportive care team for end-of-life care.
Addressing end-of-life care issues is difficult in our death-denying society, particularly in the hospital environment, which is characterized by a proliferation of life-sustaining therapy. A hospital model for end-of-life care has been in practice at an urban university hospital since late 1985. Outcomes analysis at the micro-level permitted a demonstration of the practice's effectiveness over time.


Surface-sensitive conductivity measurement using a micro multi-point probe approach.
An instrument for microscale electrical transport measurements in ultra-high vacuum is presented. The setup is constructed around collinear lithographically-created multi-point probes with a contact spacing down to 500 nm. Most commonly, twelve-point probes are used. These probes are approached to the surface via piezoelectric positioners. Standard four-point resistance measurements can be performed using any combination of contacts out of the twelve available. Current/voltage measurements are taken semi-automatically for a variety of the possible contact configurations, effectively emulating measurements with an equidistant four-point probe for a wide range of contact spacings. In this way, it is possible to distinguish between bulk-like and surface-like conduction. The paper describes the design of the instrument and the approach to data and error analysis. Application examples are given for epitaxial graphene on SiC and degenerately doped Bi₂Se₃.


A cell-cycle-dependent DNA polymerase activity that replicates intact DNA in chromatin.
An insoluble DNA polymerase activity that replicates the intact chromatin template at 85% of the rate found in vivo has been partially characterized. HeLa cells, encapsulated in agarose microbeads, are lysed using an isotonic salt concentration: the resulting encapsulated nuclei contain polymerase associated with a nucleoskeleton and the unbroken template. This preparation can be manipulated freely without aggregation or breaking the DNA and yet is accessible to enzymes and other probes. The major activity, which is sensitive to aphidicolin, is found only in S-phase nuclei and replicates DNA semi-conservatively, forming intermediates that are ligated efficiently into larger products.


Auditory preferences of young children with and without hearing loss for meaningful auditory-visual compound stimuli.
Experiment 1 examined modality preferences in children and adults with normal hearing to combined auditory-visual stimuli. Experiment 2 compared modality preferences in children using cochlear implants participating in an auditory emphasized therapy approach to the children with normal hearing from Experiment 1. A second objective in both experiments was to evaluate the role of familiarity in these preferences. Participants were exposed to randomized blocks of photographs and sounds of ten familiar and ten unfamiliar animals in auditory-only, visual-only and auditory-visual trials. Results indicated an overall auditory preference in children, regardless of hearing status, and a visual preference in adults. Familiarity only affected modality preferences in adults who showed a strong visual preference to unfamiliar stimuli only. The similar degree of auditory responses in children with hearing loss to those from children with normal hearing is an original finding and lends support to an auditory emphasis for habilitation. Readers will be able to (1) Describe the pattern of modality preferences reported in young children without hearing loss; (2) Recognize that differences in communication mode may affect modality preferences in young children with hearing loss; and (3) Understand the role of familiarity in modality preferences in children with and without hearing loss.


Novel roles for KLF1 in erythropoiesis revealed by mRNA-seq.
KLF1 (formerly known as EKLF) regulates the development of erythroid cells from bi-potent progenitor cells via the transcriptional activation of a diverse set of genes. Mice lacking Klf1 die in utero prior to E15 from severe anemia due to the inadequate expression of genes controlling hemoglobin production, cell membrane and cytoskeletal integrity, and the cell cycle. We have recently described the full repertoire of KLF1 binding sites in vivo by performing KLF1 ChIP-seq in primary erythroid tissue (E14.5 fetal liver). Here we describe the KLF1-dependent erythroid transcriptome by comparing mRNA-seq from Klf1(+/+) and Klf1(-/-) erythroid tissue. This has revealed novel target genes not previously obtainable by traditional microarray technology, and provided novel insights into the function of KLF1 as a transcriptional activator. We define a cis-regulatory module bound by KLF1, GATA1, TAL1, and EP300 that coordinates a core set of erythroid genes. We also describe a novel set of erythroid-specific promoters that drive high-level expression of otherwise ubiquitously expressed genes in erythroid cells. Our study has identified two novel lncRNAs that are dynamically expressed during erythroid differentiation, and discovered a role for KLF1 in directing apoptotic gene expression to drive the terminal stages of erythroid maturation.


Comparison of Atherosclerotic Calcification in Major Vessel Beds on the Risk of All-Cause and Cause-Specific Mortality: The Rotterdam Study.
Atherosclerosis is a major contributor to global morbidity and mortality. Although atherosclerosis is a systemic disease, its burden varies considerably across vessel beds, which may translate into differences in mortality risk. From 2003 to 2006, a sample of 2408 elderly participants (mean age, 69.6±6.7 years; 52.4% female) from the population-based Rotterdam Study underwent computed tomography to quantify atherosclerotic calcification in the coronary arteries, aortic arch, extracranial, and intracranial internal carotid arteries. Mortality follow-up was complete until January 1, 2012. We investigated associations of calcification in each vessel bed with mortality using Cox regression, adjusting for age, sex, and cardiovascular risk factors. Next, all vessel beds were included into 1 model to investigate independency of associations. Finally, we investigated the predictive value of calcification beyond the predictors included in the Pooled Cohort equations. During 15 775 person-years of follow-up, 283 participants died. Larger calcification volumes in all vessels were related to higher risks of all-cause mortality, cardiovascular, and noncardiovascular mortality, independent of cardiovascular risk factors. Most prominent associations were found for aortic arch calcification and cardiovascular mortality (age- and sex-adjusted hazard ratio per 1-SD increase 2.72 [95% confidence interval, 1.85-4.02]), independent of calcification elsewhere (hazard ratio, 1.75 (95% confidence interval, 1.13-2.72]). Calcification in any vessel improved prediction for all 3 outcomes. Atherosclerotic load in major vessel beds is associated with an increased risk of death. In particular, aortic arch calcification volume yields unique information with regard to mortality in addition to atherosclerosis in other vessel beds.


Probiotics Modulate a Novel Amphibian Skin Defense Peptide That Is Antifungal and Facilitates Growth of Antifungal Bacteria.
Probiotics can ameliorate diseases of humans and wildlife, but the mechanisms remain unclear. Host responses to interventions that change their microbiota are largely uncharacterized. We applied a consortium of four natural antifungal bacteria to the skin of endangered Sierra Nevada yellow-legged frogs, Rana sierrae, before experimental exposure to the pathogenic fungus Batrachochytrium dendrobatidis (Bd). The probiotic microbes did not persist, nor did they protect hosts, and skin peptide sampling indicated immune modulation. We characterized a novel skin defense peptide brevinin-1Ma (FLPILAGLAANLVPKLICSITKKC) that was downregulated by the probiotic treatment. Brevinin-1Ma was tested against a range of amphibian skin cultures and found to inhibit growth of fungal pathogens Bd and B. salamandrivorans, but enhanced the growth of probiotic bacteria including Janthinobacterium lividum, Chryseobacterium ureilyticum, Serratia grimesii, and Pseudomonas sp. While commonly thought of as antimicrobial peptides, here brevinin-1Ma showed promicrobial function, facilitating microbial growth. Thus, skin exposure to probiotic bacterial cultures induced a shift in skin defense peptide profiles that appeared to act as an immune response functioning to regulate the microbiome. In addition to direct microbial antagonism, probiotic-host interactions may be a critical mechanism affecting disease resistance.


There Are No Differences in Short- to Mid-term Survivorship Among Total Hip-bearing Surface Options: A Network Meta-analysis.
Total hip arthroplasty (THA) is increasingly being performed in patients with long life expectancies and active lifestyles. Newer implant bearing surfaces, with superior wear characteristics, often are used in this cohort with the goal of improving longevity of the prosthesis, but comparisons across the numerous available bearing surfaces are limited, so the surgeon and patient may have difficulty deciding which implants to use. The purpose of this study was to answer the following question: Is there a short- to mid-term survivorship difference between common THA bearings used in patients younger than age 65 years? We conducted a systematic review to identify randomized clinical trials (RCTs) published after 2000 that reported survivorship of ceramic-on-ceramic (CoC), ceramic-on-highly crosslinked polyethylene (CoPxl), or metal-on-highly crosslinked polyethylene (MoPxl) bearings. To qualify for our review, RCTs had to have a minimum 2-year followup and study patients were required to have an average age younger than 65 years. Direct-comparison meta-analysis and network meta-analysis were performed to combine direct and indirect evidence. Direct-comparison meta-analysis found no differences among the bearing surfaces in terms of the risk of revision; this approach demonstrated a risk ratio for revision of 0.65 (95% confidence interval [CI], 0.19-2.23; p = 0.50) between CoC and CoPxl and a risk ratio for revision of 0.40 (95% CI, 0.06-2.63; p = 0.34) between CoC and MoPxl. Network meta-analysis (with post hoc modification) likewise found no differences in survivorship across the three implant types, demonstrating the following probabilities of most effective implant with 95% credible intervals (CrI): CoC = 64.6% (0%-100%); CoPxl = 24.9% (0%-100%); and MoPxl = 9.9% (0%-100%). The CrIs ranged from 0% to 100% for all three bearing surfaces. Direct-comparison meta-analysis allowed for pooling of five RCTs, including 779 THAs, whereas network meta-analysis (before post hoc analysis) enabled pooling of 18 RCTs, including 2599 THAs. Current published evidence does not support survivorship differences among commonly used bearing surfaces in patients younger than age 65 years undergoing THA at short- to mid-term followup. Long-term RCT data will be needed to determine if a survivorship benefit is realized in younger, more active patients over time. Level I, therapeutic study.


Analysis of fiber optic gyroscope vibration error based on improved local mean decomposition and kernel principal component analysis.
The fiber optic gyroscope (FOG), one version of an all solid-state rotation sensor, has been widely used in navigation and position applications. However, the elastic-optic effect of fiber will introduce a non-negligible error in the output of FOG in a vibration and shock environment. To overcome the limitations of mechanism structure improvement methods and the traditional nonlinear analysis approaches, a hybrid algorithm of an optimized local mean decomposition-kernel principal component analysis (OLMD-KPCA) method is proposed in this paper. The vibration signal features of higher frequency components are analyzed by OLMD and their energy is calculated to take shape as the input vector of KPCA. In addition, the output data of three axis gyroscopes in an inertial measurement unit (IMU) under vibration experiment are used to validate the effectiveness and generalization ability of the proposed approach. When compared to the wavelet transform (WT), experimental results demonstrate that the OLMD-KPCA method greatly reduces the vibration noise in the FOG output. Besides, the Allan variance analysis results indicate the error coefficients could be decreased by one order of magnitude and the algorithm stability of OLMD-KPCA is proven by another two sets of data under different vibration conditions.


Novel technique for mode selection in a multimode fiber laser.
A simple technique for transverse mode selection in a large-mode-area (multimode) fiber laser is described. The technique exploits the different spectral responses of feedback elements based on a fiber Bragg grating and a volume Bragg grating to achieve wavelength-dependent mode filtering. This approach has been applied to a cladding-pumped thulium-doped fiber laser with a multimode core to achieve a single-spatial-mode output beam with a beam propagation factor (M2) of 1.05 at 1923 nm. Without mode selection the free-running fiber laser has a multimode output beam with an M2 parameter of 3.3. Selective excitation of higher order modes is also possible via the technique and preliminary results for laser oscillation on the LP11 mode are also discussed along with the prospects for scaling to higher power levels.


Transcriptomic profiling permits the identification of pollutant sources and effects in ambient water samples.
Contaminant exposure is one possible contributor to population declines of endangered fish species in the Sacramento-San Joaquin Estuary, California, including the endangered delta smelt (Hypomesus transpacificus). Herein we investigated transcriptional responses in larval delta smelt resulting from exposure to water samples collected at the Department of Water Resources Field Station at Hood, a site of concern, situated upstream of known delta smelt habitat and spawning sites and downstream of the Sacramento Regional Wastewater Treatment Plant (SRWTP). Microarray assessments indicate impacts on energy metabolism, DNA repair mechanisms and RNA processing, the immune system, development and muscle function. Transcription responses of fish exposed to water samples from Hood were compared with exposures to 9% effluent samples from SRWTP, water from the Sacramento River at Garcia Bend (SRGB), upstream of the effluent discharge, and SRGB water spiked with 2mg/L total ammonium (9% effluent equivalent). Results indicate that transcriptomic profiles from Hood are similar to 9% SRWTP effluent and ammonium spiked SRGB water, but significantly different from SRGB. SRGB samples however were also significantly different from laboratory controls, suggesting that SRWTP effluent is not solely responsible for the responses determined at Hood, that ammonium exposure likely enhances the effect of multiple-contaminant exposures, and that the observed mortality at Hood is due to the combination of both effluent discharge and contaminants arising from upstream of the tested sites.


Sleep at high altitude: guesses and facts.
Lowlanders commonly report a poor sleep quality during the first few nights after arriving at high altitude. Polysomnographic studies reveal that reductions in slow wave sleep are the most consistent altitude-induced changes in sleep structure identified by visual scoring. Quantitative spectral analyses of the sleep electroencephalogram have confirmed an altitude-related reduction in the low-frequency power (0.8-4.6 Hz). Although some studies suggest an increase in arousals from sleep at high altitude, this is not a consistent finding. Whether sleep instability at high altitude is triggered by periodic breathing or vice versa is still uncertain. Overnight changes in slow wave-derived encephalographic measures of neuronal synchronization in healthy subjects were less pronounced at moderately high (2,590 m) compared with low altitude (490 m), and this was associated with a decline in sleep-related memory consolidation. Correspondingly, exacerbation of breathing and sleep disturbances experienced by lowlanders with obstructive sleep apnea during a stay at 2,590 m was associated with poor performance in driving simulator tests. These findings suggest that altitude-related alterations in sleep may adversely affect daytime performance. Despite recent advances in our understanding of sleep at altitude, further research is required to better establish the role of gender and age in alterations of sleep at different altitudes, to determine the influence of acclimatization and of altitude-related illness, and to uncover the characteristics of sleep in highlanders that may serve as a study paradigm of sleep in patients exposed to chronic hypoxia due to cardiorespiratory disease.


Evaluation of maternal practices, efficacy, and cost-effectiveness of alternative antimalarial regimens for use in pregnancy: chloroquine and sulfadoxine-pyrimethamine.
With the knowledge that an efficacious antimalarial administered to pregnant women would markedly reduce placental malaria and its associated risk of low birth weight (LBW), investigations were conducted to identify an antimalarial regimen practical for nationwide implementation through the antenatal clinic (ANC) system. Maternal practices, including ANC utilization and malaria treatment and prevention during pregnancy were evaluated as part of a national malaria knowledge, attitudes, and practices survey. A second study was conducted to evaluate the efficacy and cost of selected alternative antimalarial regimens. Women in their first or second pregnancy were placed on chloroquine (CQ) treatment (25 mg/kg) followed by weekly CQ (300 mg) (CQ/CQ); sulfadoxine-pyrimethamine (SP) treatment followed by CQ (300 mg weekly) (SP/CQ); or SP treatment during the second trimester and repeated at the beginning of the third trimester (SP/SP). With 87% of women attending ANC two or more times during pregnancy, most pregnant women in Malawi could be reached with an antimalarial intervention. Among 159 women in their first or second pregnancy receiving CQ/CQ, SP/CQ, and SP/SP, placental malaria parasitemia rates were 32%, 26%, and 9%, respectively (P = 0.006, by chi-square test). The SP/SP regimen was also markedly more cost-effective in preventing infant deaths, costing $75 per infant death prevented, compared with $481 for SP/CQ and $542 for CQ/CQ. These investigations suggest that a regimen consisting of two treatment doses of SP during pregnancy is an efficacious and cost-effective intervention to prevent placental malaria, and LBW-associated mortality, that can be delivered to pregnant women through ANCs in settings similar to those found in rural Malawi.


A Systematic Review of Safety Reporting in Acute Spinal Cord Injury Clinical Trials: Challenges and Recommendations.
Accurate safety information in published clinical trials guides the assessment of risk-benefit, as well as the design of future clinical trials. Comprehensive reporting of adverse events, toxicity, and discontinuations from acute spinal cord injury clinical trials is an essential step in this process. Here, we sought to assess the degree of "satisfactoriness" of reporting in past clinical trials in spinal cord injury. A review of citations from MEDLINE and EMBASE identified eligible clinical trials in acute (within 30 days) spinal cord injury. English language studies, published between 1980 and 2020, with sensory, motor, or autonomic neurological assessments as the primary outcome measure were eligible for inclusion. Criteria were then established to qualify the safety reporting as satisfactory (i.e., distinguished severe/life-threatening events), partially satisfactory, or unsatisfactory (i.e., only mentioned in general statements, or reported but without distinguishing severe events). A total of 40 trials were included. Satisfactory reporting for clinical adverse events was observed in 30% of trials; partially satisfactory was achieved by 10% of the trials, and the remaining 60% were unsatisfactory. The majority of trials were determined to be unsatisfactory for the reporting of laboratory-defined toxicity (82.5%); only 17.5% were satisfactory. Discontinuations were satisfactorily reported for the majority of trials (80%), with the remaining partially satisfactory (5%) or unsatisfactory (15%). Reporting of safety in clinical trials for acute spinal cord injury is suboptimal. Due to the complexities of acute spinal cord injury (e.g., polytrauma, multiple systems affected), tailored and specific standards for tracking adverse events and safety reporting should be established.