Associations of Community Water Fluoridation with Caries Prevalence and Oral Health Inequality in Children.
This study aimed to confirm the association between the community water fluoridation (CWF) programme and dental caries prevention on permanent teeth, comparing to a control area, neighbouring population without the programme, and verifying whether the programme can reduce the socio-economic inequality related to the oral health of children in Korea. Evaluation surveys were conducted among 6-, 8-, and 11-year-old children living in Okcheon (CWF) and neighbouring Yeongdong (non-CWF, control area) towns in South Korea. Data on monthly family income, caregiver educational level, and Family Affluence Scale scores were evaluated using questionnaires that were distributed to the parents. The effectiveness of CWF in caries reduction was calculated based on the differences in decayed, missing, and filled teeth and decayed, missing, and filled tooth surfaces indices between the two towns. The data were analysed using logistic regression and univariate analysis of variance. Both 8- and 11-year-old children living in the CWF area had lower dental caries prevalence than those living in the non-CWF community. Differences in dental caries prevalence based on educational level were found in the control area but not in the CWF area. Socio-economic factor-related inequality in oral health were observed in the non-CWF community. Additionally, 8- and 11-year-old children living in the CWF area displayed lower dental caries prevalence in the pit-and-fissure and smooth surfaces than those living in the non-CWF community. These results suggest that CWF programmes are effective in the prevention of caries on permanent teeth and can reduce oral health inequalities among children. The implementation of CWF programmes should be sustained to overcome oral health inequalities due to socio-economic factors and improve children's overall oral health.


Chromosome aberration induction is dependent on the spatial distribution of energy deposition through a cell nucleus.
The importance of the spatial distribution of energy deposition through the nucleus in determining the resultant chromosome rearrangements was investigated using fluorescent in situ hybridisation technique following either uniform or partial irradiation of HF19 human fibroblast cells with low-LET 1.5 keV ultrasoft X-rays. Irradiations were performed with and without a copper irradiation mask with a Poisson distribution of micron-sized holes immediately below the irradiation dish and the results are compared with previous results obtained following exposure to a Poisson distribution of alpha particles. For the same radiation quality, the spatial distribution of energy deposition within the nucleus was found to be important in determining the ultimate biological response, with an increased ratio of complex-to-simple aberrations observed for partial compared to uniform irradiation. Comparisons between low-LET ultrasoft X-rays and high-LET alpha particles indicate that the sub-micron clustering of damage along the alpha particle track is more important than just the total number of double-strand breaks produced.


Growth factor, steroid, and steroid antagonist regulation of cyclin gene expression associated with changes in T-47D human breast cancer cell cycle progression.
Cyclins and proto-oncogenes including c-myc have been implicated in eukaryotic cell cycle control. The role of cyclins in steroidal regulation of cell proliferation is unknown, but a role for c-myc has been suggested. This study investigated the relationship between regulation of T-47D breast cancer cell cycle progression, particularly by steroids and their antagonists, and changes in the levels of expression of these genes. Sequential induction of cyclins D1 (early G1 phase), D3, E, A (late G1-early S phase), and B1 (G2 phase) was observed following insulin stimulation of cell cycle progression in serum-free medium. Transient acceleration of G1-phase cells by progestin was also accompanied by rapid induction of cyclin D1, apparent within 2 h. This early induction of cyclin D1 and the ability of delayed administration of antiprogestin to antagonize progestin-induced increases in both cyclin D1 mRNA and the proportion of cells in S phase support a central role for cyclin D1 in mediating the mitogenic response in T-47D cells. Compatible with this hypothesis, antiestrogen treatment reduced the expression of cyclin D1 approximately 8 h before changes in cell cycle phase distribution accompanying growth inhibition. In the absence of progestin, antiprogestin treatment inhibited T-47D cell cycle progression but in contrast did not decrease cyclin D1 expression. Thus, changes in cyclin D1 gene expression are often, but not invariably, associated with changes in the rate of T-47D breast cancer cell cycle progression. However, both antiestrogen and antiprogestin depleted c-myc mRNA by > 80% within 2 h. These data suggest the involvement of both cyclin D1 and c-myc in the steroidal control of breast cancer cell cycle progression.


Postharvest dark skin spots in potato tubers are an oversuberization response to Rhizoctonia solani infection.
Israeli farmers export 250,000 tons of potato tubers annually, ≈40,000 tons of which are harvested early, before skin set. In recent years, there has been an increase in the occurrence of dark skin spots on early-harvested potato tubers ('Nicola') packed in large bags containing peat to retain moisture. The irregular necrotic spots form during storage and overseas transport. Characterization of the conditions required for symptom development indicated that bag temperature after packing is 11 to 13°C and it reaches the target temperature (8°C) only 25 days postharvest. This slow decrease in temperature may promote the establishment of pathogen infection. Isolates from typical lesions were identified as Rhizoctonia spp., and Koch's postulates were completed with 25 isolates by artificial inoculation performed at 13 to 14°C. Phylogenetic analysis, using the internal transcribed spacer sequences (ITS1 and ITS2) of rDNA genes, assigned three isolates to anastomosis group 3 of Rhizoctonia solani. Inoculation of wounded tubers with mycelium of these R. solani isolates resulted in an oversuberization response in the infected area. With isolate Rh17 of R. solani, expression of the suberin biosynthesis-related genes StKCS6 and CYP86A33 increased 6.8- and 3.4-fold, respectively, 24 h postinoculation, followed by a 2.9-fold increase in POP_A, a gene associated with wound-induced suberization, expression 48 h postinoculation, compared with the noninoculated tubers. We suggest that postharvest dark spot disease is an oversuberization response to R. solani of AG-3 infection that occurs prior to tuber skin set.


Quality of life of family carers of persons with young-onset compared to late-onset dementia.
Objectives: To compare quality of life (QOL) of family carers of persons with young- (YOD) to late-onset dementia (LOD).Methods: This was a cross-sectional comparison of 88 carers of persons with YOD and 100 carers of persons with LOD. The Quality of Life - Alzheimer's Disease questionnaire (QOL-AD) was used to measure QOL of both carers and persons with dementia. Depressive symptoms were measured by the Geriatric Depression Scale (GDS) for carers and the Cornell Scale for Depression in Dementia for persons with dementia. Care burden was measured by the Relatives' Stress Scale. Activities of Daily Living (ADL) of the persons with dementia were assessed using the total score from the Lawton & Brody Instrumental-ADL scale and the Physical Self-Maintenance Scale. Multiple linear regression models with interactions between covariates and group (YOD versus LOD) were estimated.Results: The QOL-AD scores of YOD-carers were significantly poorer compared to LOD-carers (mean difference 2.5 (95% CI 0.7; 4.3), p = 0.006). Poorer QOL of carers was associated with more depressive symptoms (mean QOL-AD change -0.5 (-0.6; -0.3), p < 0.001), but with no difference between the two groups. In contrast to LOD, QOL of carers of people with YOD was also significantly associated with symptom duration (p = 0.002), depressive symptoms of the persons with dementia (p = 0.030), ADL (p = 0.001), and carer burden (p = 0.002).Conclusion: YOD-carers reported significantly poorer QOL compared to LOD-carers. QOL was significantly associated with depressive symptoms in carers of both groups.


Drug Synergy Slows Aging and Improves Healthspan through IGF and SREBP Lipid Signaling.
There is growing interest in pharmacological interventions directly targeting the aging process. Pharmacological interventions against aging should be efficacious when started in adults and, ideally, repurpose existing drugs. We show that dramatic lifespan extension can be achieved by targeting multiple, evolutionarily conserved aging pathways and mechanisms using drug combinations. Using this approach in C. elegans, we were able to slow aging and significantly extend healthy lifespan. To identify the mechanism of these drug synergies, we applied transcriptomics and lipidomics analysis. We found that drug interactions involved the TGF-β pathway and recruited genes related with IGF signaling. daf-2, daf-7, and sbp-1 interact upstream of changes in lipid metabolism, resulting in increased monounsaturated fatty acid content and this is required for healthy lifespan extension. These data suggest that combinations of drugs targeting distinct subsets of the aging gene regulatory network can be leveraged to cause synergistic lifespan benefits.


The human vestibular cortex revealed by coordinate-based activation likelihood estimation meta-analysis.
The vestibular system contributes to the control of posture and eye movements and is also involved in various cognitive functions including spatial navigation and memory. These functions are subtended by projections to a vestibular cortex, whose exact location in the human brain is still a matter of debate (Lopez and Blanke, 2011). The vestibular cortex can be defined as the network of all cortical areas receiving inputs from the vestibular system, including areas where vestibular signals influence the processing of other sensory (e.g. somatosensory and visual) and motor signals. Previous neuroimaging studies used caloric vestibular stimulation (CVS), galvanic vestibular stimulation (GVS), and auditory stimulation (clicks and short-tone bursts) to activate the vestibular receptors and localize the vestibular cortex. However, these three methods differ regarding the receptors stimulated (otoliths, semicircular canals) and the concurrent activation of the tactile, thermal, nociceptive and auditory systems. To evaluate the convergence between these methods and provide a statistical analysis of the localization of the human vestibular cortex, we performed an activation likelihood estimation (ALE) meta-analysis of neuroimaging studies using CVS, GVS, and auditory stimuli. We analyzed a total of 352 activation foci reported in 16 studies carried out in a total of 192 healthy participants. The results reveal that the main regions activated by CVS, GVS, or auditory stimuli were located in the Sylvian fissure, insula, retroinsular cortex, fronto-parietal operculum, superior temporal gyrus, and cingulate cortex. Conjunction analysis indicated that regions showing convergence between two stimulation methods were located in the median (short gyrus III) and posterior (long gyrus IV) insula, parietal operculum and retroinsular cortex (Ri). The only area of convergence between all three methods of stimulation was located in Ri. The data indicate that Ri, parietal operculum and posterior insula are vestibular regions where afferents converge from otoliths and semicircular canals, and may thus be involved in the processing of signals informing about body rotations, translations and tilts. Results from the meta-analysis are in agreement with electrophysiological recordings in monkeys showing main vestibular projections in the transitional zone between Ri, the insular granular field (Ig), and SII.


The production of wheat - Aegilops sharonensis 1Ssh chromosome substitution lines harboring alien novel high-molecular-weight glutenin subunits.
In our previous work, a novel high-molecular-weight glutenin subunit (HMW-GS) with an extremely large molecular weight from Aegilops sharonensis was identified that may contribute to excellent wheat (Triticum aestivum) processing quality and increased dough strength, and we further generated HMW-GS homozygous lines by crossing. In this study, we crossed the HMW-GS homozygous line 66-17-52 with 'Chinese Spring' Ph1 mutant CS ph1b to induce chromosome recombination between wheat and Ae. sharonensis. SDS-PAGE was used to identify 19 derived F2 lines with the HMW-GSs of Ae sharonensis. The results of non-denaturing fluorescence in situ hybridization (ND-FISH) indicated that lines 6-1 and 6-7 possessed a substitution of both 5D chromosomes by a pair of 1Ssh chromosomes. Further verification by newly developed 1Ssh-specific chromosome markers showed that these two lines amplified the expected fragment. Thus, it was concluded that lines 6-1 and 6-7 are 1Ssh(5D) chromosome substitution lines. The 1Ssh(5D) chromosome substitution lines, possessing alien subunits with satisfactory quality-associated structural features of large repetitive domains and increased number of subunits, may have great potential in strengthening the viscosity and elasticity of dough made from wheat flour. Therefore, these substitution lines can be used for wheat quality improvement and further production of 1Ssh translocation lines.


A copper-catalyzed carbonylative four-component reaction of ethene and aliphatic olefins.
To have a balance between reactivity and selectivity has been a long-standing challenge in multicomponent reactions. In this communication, a carbonylative four-component reaction has been developed. With copper as the catalyst, using ethene including other aliphatic alkenes, alcohols and acetonitrile as the substrates under CO pressure, various desired products were produced in moderate to good yields. The obtained products can be applied in the synthesis of δ-valerolactams. Good functional group tolerance and reaction efficiency can be observed here.


Risk factors of workplace bullying for men and women: the role of the psychosocial and physical work environment.
Workplace bullying has been shown to be a severe social stressor at work, resulting in high costs both for the individuals and organizations concerned. The aim of this study is to analyze risk factors in a large, nationally representative sample of Finnish employees (n = 4,392). The study makes three important contributions to the existing literature on workplace bullying: first, it demonstrates the role of the physical work environment alongside the psychosocial work environment - employees with a poor physical work environment are more likely than others to report having been subjected to or having observed bullying. Second, contrary to common assumptions, the results suggest that performance-based pay is associated with a lower, rather than higher risk of bullying. Third, the findings suggest that there are gender differences in risk factors, thereby constituting a call for more studies on the role of gender when identifying risk factors. Increased knowledge of risk factors is important as it enables us to take more effective measures to decrease the risk of workplace bullying.


Factors associated with medication adherence among patients with schizophrenia in Mekelle, Northern Ethiopia.
Non-adherence to antipsychotic medication has a negative impact on the course of illness resulting in increased risk of relapse, rehospitalization and suicide, and increased costs to healthcare systems. The objective of this study was to investigate factors associated with medication adherence among patients with schizophrenia at Ayder Referral Hospital and Mekelle Hospital in Mekelle, Tigray region, Northern Ethiopia. The study was a cross-sectional survey in which sociodemographic characteristics, drug attitudes, insight and side effects were measured and explored in terms of their relationship with medication adherence. A structured questionnaire as a data collection tool was used. Data were analyzed with the help of SPSS Version 20.0. A total of 393 patients participated, 26.5% were non-adherent to their antipsychotic medication. The factors significantly associated with better adherence were positive treatment attitudes (AOR = 1.40, 95% CI: 1.26, 1.55), fewer side effects (AOR = 0.97, 95% CI: 0.94, 0.99), awareness of illness (AOR = 1.44, 95% CI: 1.12, 1.85) and the ability to relabel symptoms (AOR = 1.57, 95% CI: 1.19, 2.07). However, khat chewers (AOR = 0.24, 95% CI: 0.09, 0.68), being illiterate (AOR = 0.13, 95% CI: 0.03, 0.47) and older age group (AOR = 0.03, 95% CI: 0.01, 0.16) were associated with less medication adherence. A high prevalence of medication non-adherence was found among patients with schizophrenia. Intervention strategies focused on educating the patients to better understand the illness, medications and their potential side effects might be useful in improving adherence to antipsychotic medication treatment.


Structural NMR of protein oligomers using hybrid methods.
Solving structures of native oligomeric protein complexes using traditional high-resolution NMR techniques remains challenging. However, increased utilization of computational platforms, and integration of information from less traditional NMR techniques with data from other complementary biophysical methods, promises to extend the boundary of NMR-applicable targets. This article reviews several of the techniques capable of providing less traditional and complementary structural information. In particular, the use of orientational constraints coming from residual dipolar couplings and residual chemical shift anisotropy offsets are shown to simplify the construction of models for oligomeric complexes, especially in cases of weak homo-dimers. Combining this orientational information with interaction site information supplied by computation, chemical shift perturbation, paramagnetic surface perturbation, cross-saturation and mass spectrometry allows high resolution models of the complexes to be constructed with relative ease. Non-NMR techniques, such as mass spectrometry, EPR and small angle X-ray scattering, are also expected to play increasingly important roles by offering alternative methods of probing the overall shape of the complex. Computational platforms capable of integrating information from multiple sources in the modeling process are also discussed in the article. And finally a new, detailed example on the determination of a chemokine tetramer structure will be used to illustrate how a non-traditional approach to oligomeric structure determination works in practice.


Bibliometric Analysis of Medication Errors and Adverse Drug Events Studies.
Medication errors and adverse drug events are a key concern of the health-care industry. The objectives of this study were to map the intellectual structure of the studies of medication errors and adverse drug events and to investigate the developing path of this literature and interrelationships among the main topics. The Web of Science database was searched for documentation of medication errors and adverse drug events from 1961 to 2013. The most cited articles and references were profiled and analyzed using HistCite software to draw a historiograph and Ucinet software to draw a sociogram. The database search revealed 3343 medication errors and 3342 adverse drug event documents. The most cited articles on medication errors focused on 3 key themes from 1961 to 2013, namely, medication errors in adult inpatients, computerized physician order entry in medication error studies, and medication errors in pediatric inpatients. The developing path for the most cited articles about adverse drug events from 1987 to 2013 was as follows: detection, analysis, effect, and prevention from adult inpatient to pediatric inpatient settings and from hospitalized care to ambulatory care. In addition, social network analysis based on the most cited references revealed a close relationship between medication errors and adverse drug events. The mapping results provide a valuable tool for researchers to access the literature in this field and can be used to help identify the direction of medication errors and adverse drug events research.


Gallbladder cancer incidence among American Indians and Alaska Natives, US, 1999-2004.
Gallbladder cancer (GBC) is rare; however, it disproportionately affects the American Indian and Alaska Natives (AI/AN) population. The purpose of the study was to characterize GBC among AI/AN in the US population. Cases of GBC diagnosed between 1999 and 2004 and collected by state-based cancer registries were included. Registry records were linked with Indian Health Service (IHS) administration records to decrease race misclassification of AI/AN. GBC rates and/or percent distributions for AI/AN and non-Hispanic whites (NHW) were calculated by sex, IHS region, age, and stage for all US counties and IHS Contract Health Service Delivery Area (CHSDA) counties, in which approximately 56% of US AI/AN individuals reside. In CHSDA counties, the GBC incidence rate among AI/AN was 3.3 per 100,000, which was significantly higher than that among NHW (P < .05). Rates varied widely among IHS regions and ranged from 1.5 in the East to 5.5 in Alaska. Rates were higher among AI/AN females than males in all regions, except the Northern Plains. Higher percentages of GBC were diagnosed among AI/AN aged <65 years compared with NHW. GBC was most often diagnosed at the regional stage among AI/AN, whereas GBC was most often diagnosed at regional or distant stages among NHW. To the authors' knowledge to date, this is the most comprehensive study of GBC incidence among AI/AN in the US. The accurate characterization of GBC in this population could help inform the development of interventions aimed at reducing morbidity and mortality from this disease.


Identification of Mycobacterium tuberculosis H37Rv integral membrane proteins by one-dimensional gel electrophoresis and liquid chromatography electrospray ionization tandem mass spectrometry.
Because many membrane-associated proteins represent potential drug targets, diagnostic probes, and components of vaccines, we have chosen to study the membrane proteins of Mycobacterium tuberculosis H37Rv. To remove cytosolic proteins and facilitate access to the integral membrane proteins, membrane fractions of M. tuberculosis H37Rv were intensely washed with 5 M urea and high pH carbonate solution. One-dimensional SDS-PAGE, followed by enzymatic hydrolysis and nanoLC electrospray ionization MS/MS, proved to be the most efficient way to identify the proteins contained within the membrane fraction. Here we report 349 protein identifications in total, validated by at least two tryptic peptide matches and MOWSE scores greater than 75. Of those 349 proteins, 100 are integral membrane proteins with at least one predicted transmembrane alpha helix (excluding the possible signal sequence). 84 M. tuberculosis H37Rv proteins, including 42 integral membrane proteins, are described for the first time.


Prolonging the response movement inhibits the feed-forward motor program in the sustained attention to response task.
Despite widespread use in clinical and experimental contexts, debate continues over whether or not the Sustained Attention to Response Task (SART) successfully measures sustained attention. Altering physical aspects of the response movement required to SART stimuli may help identify whether performance is a better measure of perceptual decoupling, or response strategies and motor inhibition. Participants completed a SART where they had to manually move a mouse cursor to respond to stimuli, and another SART where this extra movement was not required, as in a typical SART. Additionally, stimuli were located at either a close or a far distance away. Commission errors were inversely related to distance in the manual movement condition, as the farther distance led to longer response times which gave participants more time to inhibit prepotent responses and thus prevent commission errors. Self-reported measures of mental demand and fatigue suggested there were no differences in mental demands between the manual and automatic condition; instead the differences were primarily in physical demands. No differences were found for task-unrelated thoughts between the manual and automatic condition. The movement effect combined with participants' subjective reports are evidence for time dependent action stopping, not greater cognitive engagement. These findings support a response strategy perspective as opposed to a perceptual decoupling perspective, and have implications for authors considering using the SART. Applied implications of this research are also discussed.


Effects of the anabolic steroid stanozolol on cells derived from human bone.
1. In this study, cells derived from explants of human trabecular bone were treated with the anabolic steroid stanozolol in order to determine whether the potential therapeutic effect of this agent might be explained by direct effects on skeletal tissue. 2. Stanozolol at a concentration of 10(-10) mol/l to 10(-6) mol/l consistently stimulated the incorporation of [3H]thymidine into DNA of human bone cells and increased proliferation. 3. Stanozolol had variable effects on the expression of two other markers of the osteoblast phenotype, namely the bone-specific vitamin-K-dependent protein osteocalcin, and the enzyme alkaline phosphatase. Although stanozolol tended to increase the values, this was not seen in all experiments. 4. We conclude that human bone cells respond to stanozolol. The effects of this agent on cell proliferation may be important in understanding the mode of action of this drug in the treatment of osteopenic disorders.


Abiotic synthesis of amino acids and self-crystallization under prebiotic conditions.
Building on previous research on the origin and homochirality of life, this study focuses on analyses profiling important building blocks of life: the natural amino acids. The spark discharge variation of the iconic Miller experiment was performed with a reducing gas mixture of ammonia, methane, water and hydrogen. Amino acid analysis using liquid chromatography coupled with tandem mass spectrometry after pre-column derivatizaiton revealed the generation of several amino acids including those essential for life. Re-crystallization of the synthetic products and enantiomeric ratio analysis were subsequently performed. Results from liquid chromatography coupled with either fluorescent detector or tandem mass spectrometry after pre-column derivatization with chiral reagent revealed spontaneous and effective asymmetric resolution of serine and alanine. This work describes a useful analytical platform for investigation of hypotheses regarding the origin and homochirality of amino acids under prebiotic conditions. The formation of numerous amino acids in the electric discharge experiment and the occurrence of high enantiomeric ratios of amino acids in re-crystallization experiment give valuable implications for future studies in unraveling fundamental questions regarding origins and evolution of life.


Relationship of beta-cell function and autoantibodies to progression and nonprogression of subclinical type 1 diabetes: follow-up of the Seattle Family Study.
A total of 85 islet cell antibody (ICA)+ or insulin autoantibody (IAA)+ relatives of patients with type 1 diabetes have been followed as part of the Seattle Family Study for a mean of 2.8 years. Of the subjects followed, 10 developed diabetes during this time period. The presence of GAD antibodies was strongly associated with the development of diabetes. In contrast, the presence of IAAs did not influence the risk of diabetes among ICA+ GAD+ subjects. When either the initial absolute acute insulin response to glucose (AIRg) or the AIR percentile, which accounts for the individual's insulin sensitivity, was below the 10th percentile of normal subjects, the risk of diabetes approached 50% at 5 years. However, impaired beta-cell function did not influence the risk of diabetes among those who were GAD+. There were 13 subjects with low AIRg and 13 subjects with two or more antibodies who had not progressed to diabetes during the course of the study. Other measurements of beta-cell function or demographic characteristics were not different in this group of nonprogressors compared with those with low AIRg who did not progress to diabetes. We conclude that ICA+ relatives with GAD antibodies or low AIRg have a high risk for development of diabetes, but among ICA+ GAD+ relatives, the addition of IAA or a single determination of AIRg does not enhance the prediction of diabetes. We suggest that prediction of diabetes risk depends on both the type and the number of antibodies present. In addition, there are a group of ICA+ relatives with low AIRg and/or multiple antibodies who have not progressed to diabetes over the course of the study.


Adiponectin: An Indicator for Metabolic Syndrome.
Metabolic syndrome (MetS), a cluster of cardiometabolic risk factors, consider as a manifestation of obesity. However, a proportion of obese patients do not develop MetS. The aim of our study was to determine whether concentration of plasma adiponectin and leptin differ between metabolic unhealthy obese (MUO) patients and comparable age- and sex-matched control groups. In this case-control study, we assigned 51 obese patients with MetS (MUO) in cases group and 102 metabolic healthy obese (MHO) and normal weight metabolic healthy subjects matched for age and gender to cases in control groups. The study was conducted between December 2014 and February 2016 in the Endocrinology Research Center of Tehran University of Medical Sciences, Tehran, Iran. We measured serum adiponectin, leptin, their ratio, and body composition in all subjects. No significant differences were observed between MHO and MUO in term of total fat mass and trunk fat (P>0.05). Compared to MHO and normal weight metabolic healthy subjects, MUO subjects had lower levels of plasma adiponectin (P<0.001) and lower plasma adiponectin to leptin ratio (P<0.001) and a higher level of plasma leptin (P<0.002). A Receiver Operator Characteristic curve was used to identify the ability of adiponectin and leptin level to predict the MetS. The area under the Receiver Operator Characteristic curve was 0.66 (P<0.01), 0.73 (P<0.001) and 0.75 (P<0.001) for leptin, adiponectin, and adiponectin/leptin ratio levels respectively. Our study introduced adiponectin and leptin as indicator of MetS and obesity respectively.


Metabolomic Analysis by Nuclear Magnetic Resonance Spectroscopy as a New Approach to Understanding Inflammation and Monitoring of Pharmacological Therapy in Children and Young Adults With Cystic Fibrosis.
15-F2t-Isoprostane, a reliable biomarker of oxidative stress, has been found elevated in exhaled breath condensate (EBC), a non-invasive technique for sampling of airway secretions, in patients with cystic fibrosis (CF). Azithromycin has antioxidant properties in experimental models of CF, but its effects on oxidative stress in CF patients are largely unknown. Primary objective of this pilot, proof-of-concept, prospective, parallel group, pharmacological study, was investigating the potential antioxidant effects of azithromycin in CF patients as reflected by EBC 15-F2t-isoprostane. Secondary objectives included studying the effect of azithromycin on EBC and serum metabolic profiles, and on serum 15-F2t-isoprostane. In CF patients who were on maintenance treatment with oral vitamin E (200 UI once daily), treatment with oral azithromycin (250 or 500 mg depending on body weight) plus vitamin E (400 UI once daily) (group A) (n = 24) or oral vitamin E alone (400 UI once daily) (group B) (n = 21) was not associated with changes in EBC 15-F2t-isoprostane concentrations compared with baseline values after 8-weeks treatment or 2 weeks after treatment suspension. There was no between-group difference in post-treatment EBC 15-F2t-isoprostane. Likewise, no within- or between-group differences in serum 15-F2t-isoprostane concentrations were observed in either study group. NMR spectroscopy-based metabolomics of EBC shows that suspension of both azithromycin plus vitamin E and vitamin E alone has a striking effect on metabolic profiles in EBC. Between-group comparisons show that EBC metabolite distribution after treatment and 2 weeks after treatment suspension is different. Quantitative differences in ethanol, saturated fatty acids, acetate, acetoin/acetone, and methanol are responsible for these differences. Our study was unable to show antioxidant effect of azithromycin as add-on treatment with doubling the dose of oral vitamin E as reflected by 15-F2t-isoprostane concentrations in EBC. Add-on therapy with azithromycin itself does not induce EBC metabolite changes, but its suspension is associated with EBC metabolic profiles that are different from those observed after vitamin E suspension. The pathophysiological and therapeutic implications of these findings in patients with stable CF are unknown and require further research. Preliminary data suggest that EBC NMR-based metabolomics might be used for assessing the effects of pharmacological treatment suspension in stable CF patients.


OCCURRENCE OF PATHOGENIC CHYTRID FUNGI BATRACHOCHYTRIUM SALAMANDRIVORANS AND BATRACHOCHYTRIUM DENDROBATIDIS IN THE HONG KONG NEWT (PARAMESOTRITON HONGKONGENSIS) AND OTHER WILD AND IMPORTED AMPHIBIANS IN A SUBTROPICAL ASIAN REGION.
One of the major threats for the massive loss in global amphibian diversity is chytridiomycosis, caused by chytrid fungi Batrachochytrium dendrobatidis (Bd) and B. salamandrivorans (Bsal). Following its discovery in 2013, Bsal has emerged as a severe threat to the global survival of urodelans. In 2018, a study reported a high prevalence of Bsal (65.6%) in the Hong Kong newts (Paramesotriton hongkongensis, Near Threatened) of a southern China population adjacent to Hong Kong (HK). Uncertainty regarding the Bsal infection status of P. hongkongensis inhabiting HK raised deep concern over the risk of introducing Bsal from that population. We screened the skin swabs from wild individuals of P. hongkongensis, 15 sympatric amphibian species, and 16 imported amphibian species in HK for chytrids. We found that both Bsal and Bd occur in low prevalences in P. hongkongensis (Bsal 1.7%, 5/293; Bd 0.34%, 1/293), Hong Kong cascade frog, Amolops hongkongensis, family Ranidae (Bsal only, 5.26%, 1/19), and Asian common toad, Duttaphrynus melanostictus, family Bufonidae (Bsal only, 5.88%, 1/17), populations of HK, with infected individuals being asymptomatic, suggesting a potential role of these species as reservoirs of Bsal. Conversely, Bd, but not Bsal, was present on 13.2% (9/68) of imported amphibians, indicating a high chytrid introduction risk posed by international amphibian trade. Long-term surveillance of the presence of Bd and Bsal in wild and captive amphibians would be advisable, and we recommend that import and export of nonnative chytrid carriers should be prevented, especially to those regions with amphibian populations naïve to Bd and Bsal.


Physical activity, dyspnea, and chest pain before and after coronary artery bypass grafting in relation to a history of diabetes.
To describe the limitation of physical activity and symptoms of chest pain and dyspnea before and after coronary artery bypass grafting (CABG) in relation to a history of diabetes. All patients in western Sweden in whom CABG was performed between 1988 and 1991 were asked to complete a questionnaire before 3 months and 2 years after the operation. The questionnaire evaluated limitation of physical activity and symptoms of chest pain and dyspnea. In all, 2,121 patients participated in the evaluation, of whom 13% had a history of diabetes. The overall 2-year mortality was 14% among patients with a history of diabetes and 6% among patients without such a history (P < 0.001). The proportion of patients with a limitation of physical activity caused by chest pain decreased from 76% before CABG to 19% 2 years after in diabetic patients (P < 0.001) and from 79 to 17% in nondiabetic patients (P < 0.001). The proportion of diabetic patients without dyspnea increased from 13% before to 31% 2 years after CABG (P < 0.001). The corresponding figures for nondiabetic patients were 12 and 43% (P < 0.001). Symptoms of angina pectoris were reported in 94% of diabetic patients before CABG versus 35% after 2 years (P < 0.001). Corresponding figures for nondiabetic patients were 93 and 29% (P < 0.001). Aggregate data confirmed differences between diabetic and nondiabetic patients, with more symptoms in the diabetic patients, particularly with regard to dyspnea. Mortality during 2 years of follow up was more than twice as high in diabetic than in nondiabetic patients. Limitation of physical activity, dyspnea, and angina pectoris improved markedly and similarly in diabetic and nondiabetic patients after CABG. Whereas limitation of physical activity and dyspnea was more frequent in diabetic than in nondiabetic patients, the occurrence of angina pectoris was more similar in the two groups.


Seq-Well: A Sample-Efficient, Portable Picowell Platform for Massively Parallel Single-Cell RNA Sequencing.
Seq-Well is a low-cost picowell platform that can be used to simultaneously profile the transcriptomes of thousands of cells from diverse, low input clinical samples. In Seq-Well, uniquely barcoded mRNA capture beads and cells are co-confined in picowells that are sealed using a semipermeable membrane, enabling efficient cell lysis and mRNA capture. The beads are subsequently removed and processed in parallel for sequencing, with each transcript's cell of origin determined via the unique barcodes. Due to its simplicity and portability, Seq-Well can be performed almost anywhere.


A methodological approach for assessing the uptake of core outcome sets using ClinicalTrials.gov: findings from a review of randomised controlled trials of rheumatoid arthritis.
Objective To assess the uptake of the rheumatoid arthritis core outcome set using a new assessment method of calculating uptake from data in clinical trial registry entries.Design Review of randomised trials.Setting ClinicalTrials.gov.Subjects 273 randomised trials of drug interventions for the treatment of rheumatoid arthritis and registered in ClinicalTrials.gov between 2002 and 2016. Full publications were identified for completed studies from information in the trial registry or from an internet search using Google and the citation database Web of Science.Main outcome measure The percentage of trials reporting or planning to measure the rheumatoid arthritis core outcome set calculated from the information presented in the trial registry and compared with the percentage reporting the rheumatoid arthritis core outcome set in the resulting trial publications.Results The full rheumatoid arthritis core outcome set was reported in 81% (116/143) of trials identified on the registry as completed (or terminated) for which results were found in either the published literature or the registry. For trials identified on the registry as completed (or terminated), using information only available in the registry gives an estimate for uptake of 77% (145/189).Conclusions The uptake of the rheumatoid arthritis core outcome set in clinical trials has continued to increase over time. Using the information on outcomes listed for completed or terminated studies in a trial registry provides a reasonable estimate of the uptake of a core outcome set and is a more efficient and up-to-date approach than examining the outcomes in published trial reports. The method proposed may provide an efficient approach for an up-to-date assessment of the uptake of the 300 core outcome sets already published.


Sociodemographic factors associated with multiple cardiovascular risk factors among Malaysian adults.
To determine the prevalence and sociodemographic correlates of multiple risk factors for cardiovascular disease (CVD) among Malaysian adults. We analysed data on 1044 men and 1528 women, aged 24-64 years, participants in the Non Communicable Disease Surveillance 2005/2006, a nationally representative, population-based, cross-sectional study. Prevalence of obesity, high blood pressure, dyslipidaemia, hyperglycemia, physical inactivity, smoking, risky drinking, low vegetable and fruit intake were determined and multivariable logistic regression was used to identify sociodemographic factors associated with having ≥3 of these cardiovascular disease risk factors. The response rate was 84.6% (2572/3040). Overall, 68.4% (95% CI: 63.2, 73.1) had at least three risk factors. Among men, older age and Indian ethnicity were independently associated with having ≥3 CVD risk factors; while among women, older age, low education, and housewives were more likely to have ≥3 CVD risk factors. The prevalence of cardiovascular risk factors clustering among Malaysian adults is high, raising concerns that cardiovascular disease incidence will rise steeply in the near future if no immediate preventive measures are taken. The current national health education and promotion programmes pertaining to modifiable risk factors can be further improved by taking into account the sociodemographic variation in CVD risk factors clustering.


Prevalence and risk of violence against children with disabilities: a systematic review and meta-analysis of observational studies.
Globally, at least 93 million children have moderate or severe disability. Children with disabilities are thought to have a substantially greater risk of being victims of violence than are their non-disabled peers. Establishment of reliable estimates of the scale of the problem is an essential first step in the development of effective prevention programmes. We therefore undertook a systematic review and meta-analysis to synthesise evidence for the prevalence and risk of violence against children with disabilities. For this systematic review and meta-analysis, we searched 12 electronic databases to identify cross-sectional, case-control, or cohort studies reported between Jan 1, 1990, and Aug 17, 2010, with estimates of prevalence of violence against children (aged ≤18 years) with disabilities or their risk of being victims of violence compared with children without disabilities. 17 studies were selected from 10,663 references. Reports of 16 studies provided data suitable for meta-analysis of prevalence and 11 for risk. Pooled prevalence estimates were 26·7% (95% CI 13·8-42·1) for combined violence measures, 20·4% (13·4-28·5) for physical violence, and 13·7% (9·2-18·9) for sexual violence. Odds ratios for pooled risk estimates were 3·68 (2·56-5·29) for combined violence measures, 3·56 (2·80-4·52) for physical violence, and 2·88 (2·24-3·69) for sexual violence. Huge heterogeneity was identified across most estimates (I(2)>75%). Variations were not consistently explained with meta-regression analysis of the characteristics of the studies. The results of this systematic review confirm that children with disabilities are more likely to be victims of violence than are their peers who are not disabled. However, the continued scarcity of robust evidence, due to a lack of well designed research studies, poor standards of measurement of disability and violence, and insufficient assessment of whether violence precedes the development of disability, leaves gaps in knowledge that need to be addressed. WHO Department of Violence and Injury Prevention and Disability.


Temporal and stochastic control of Staphylococcus aureus biofilm development.
Biofilm communities contain distinct microniches that result in metabolic heterogeneity and variability in gene expression. Previously, these niches were visualized within Staphylococcus aureus biofilms by observing differential expression of the cid and lrg operons during tower formation. In the present study, we examined early biofilm development and identified two new stages (designated "multiplication" and "exodus") that were associated with changes in matrix composition and a distinct reorganization of the cells as the biofilm matured. The initial attachment and multiplication stages were shown to be protease sensitive but independent of most cell surface-associated proteins. Interestingly, after 6 h of growth, an exodus of the biofilm population that followed the transition of the biofilm to DNase I sensitivity was demonstrated. Furthermore, disruption of the gene encoding staphylococcal nuclease (nuc) abrogated this exodus event, causing hyperproliferation of the biofilm and disrupting normal tower development. Immediately prior to the exodus event, S. aureus cells carrying a nuc::gfp promoter fusion demonstrated Sae-dependent expression but only in an apparently random subpopulation of cells. In contrast to the existing model for tower development in S. aureus, the results of this study suggest the presence of a Sae-controlled nuclease-mediated exodus of biofilm cells that is required for the development of tower structures. Furthermore, these studies indicate that the differential expression of nuc during biofilm development is subject to stochastic regulatory mechanisms that are independent of the formation of metabolic microniches. Importance: In this study, we provide a novel view of four early stages of biofilm formation by the human pathogen Staphylococcus aureus. We identified an initial nucleoprotein matrix during biofilm development that is DNase I insensitive until a critical point when a nuclease-mediated exodus of the population is induced prior to tower formation. Unlike the previously described dispersal of cells that occurs after tower development, we found that the mechanism controlling this exodus event is dependent on the Sae regulatory system and independent of Agr. In addition, we revealed that the gene encoding the secreted staphylococcal nuclease was expressed in only a subpopulation of cells, consistent with a model in which biofilms exhibit multicellular characteristics, including the presence of specialized cells and a division of labor that imparts functional consequences to the remainder of the population.


Optimal times above MICs of ceftibuten and cefaclor in experimental intra-abdominal infections.
The duration of time that serum drug levels remain above the MIC (time above the MIC) for the pathogen has been shown to be the most significant parameter determining the efficacies of beta-lactam antibiotics. In the described study, we investigated the optimal time above the MIC of ceftibuten and cefaclor using a nonneutropenic mouse model of intra-abdominal infections caused by Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, and Streptococcus pneumoniae. The abilities of the drugs to protect mice against the organisms were determined in mouse protection tests, and the doses were fractionated to produce various dosing regimens with different times above the MIC. All drug-organism combinations showed a significant correlation (r > 0.9) between drug efficacy and the time above the MIC. Also, with ceftibuten treatment, the different dosing regimens that produced equal times above the MIC resulted in the same efficacy, whereas with cefaclor, an apparent dose-dependent effect was observed. These results showed that for a 100% recovery from K. pneumoniae and E. coli infections, the optimal times above the MIC with ceftibuten treatment were 2.2 and 1.6 h, respectively. Relatively high doses of both antibiotics were required to ensure recovery from S. pneumoniae infections. In vitro time-kill studies demonstrated that cefaclor exhibits a marked inoculum effect against the pathogens, and there was a concentration-dependent killing at a large inoculum size. On the other hand, ceftibuten showed no inoculum effect. It is suggested that optimization of both dose and time above the MIC appears to be necessary for the treatment of S. aureus infections with cefaclor, and this may apply to other beta-lactams tht exhibit marked inoculum effects.


Military Career Adaptability Questionnaire in China: Development and Validation.
To develop the Military Career Adaptability Questionnaire (MCAQ) in China and to test its reliability and validity. In study 1, an open-ended questionnaire survey was conducted among 200 military personnel. Based on the empirical construction by military personnel of various branches, the dimensions of the MCAQ were constructed, and a preliminary questionnaire was prepared. In study 2, the questionnaire survey was conducted in 1,578 participants enrolled through stratified cluster sampling. They were randomly divided into two groups (n = 789). Sample 1 was used for item analysis and exploratory factor analysis, and sample 2 was used for confirmatory factor analysis and internal consistency testing. In sample 1, the participants were selected to test the test-retest reliability of the questionnaire at a 4 weeks interval. In sample 2, participants were selected to test criterion validity using the Psychological Capital Questionnaire and the Job Satisfaction Questionnaire. According to study 1, we obtained an initial 23-item MCAQ containing five dimensions (organization and fusion ability, communication ability, learning development ability, emotion regulation ability, and career transformation ability). After the exploratory factor analysis in study 2, 21 items contributing 72.17% of the total variance remained. Via the subsequent confirmatory factor analysis, the model was confirmed to have good fit indices [chi-square/degree of freedom (X 2/df) = 3.11, goodness of fit index (GFI) = 0.90, normed fit index (NFI) = 0.91, incremental fit index (IFI) = 0.94, tucker lewis index (TLI) = 0.93, comparative fit index (CFI) = 0.94, standardized root mean square residual (SRMR) = 0.07]. These five factors were significantly correlated with the total score of the MCAQ (r = 0.73-0.79, p < 0.01). The Cronbach α coefficient of the questionnaire was 0.92; the Cronbach α coefficients of the five factors were 0.89, 0.83, 0.88, 0.84, and 0.79, respectively, the test-retest reliability of the questionnaire was 0.93. The MCAQ developed in this study has a clear five-factor structure and good reliability and validity. It can be used to assess the career adaptability of military personnel to provide a theoretical basis for military vocational psychological education.


Exploring the association of legalisation status of cannabis with problematic cannabis use and impulsivity in the USA.
There has been an increased trend towards the legalisation of medicinal and recreational cannabis use worldwide. This has been controversial as the long-term effects of frequent cannabis use on the brain are still poorly understood. In this study, we investigated whether the legal status of cannabis in the United States of America (USA) is associated with problematic cannabis use and impulsivity in 329 frequent cannabis users. The data were collected in 2015 and were analysed in 2017. Ethical approval for this study was obtained from Monash University in 2015. The results indicated that participants' problematic cannabis use and impulsivity was not different whether they resided in states where cannabis is legal for medical and/or recreational use or prohibited. The present study is a cross-sectional design, making it difficult to infer causality and establish whether cannabis use is a cause, consequence, or correlate of altered impulsivity. Our study supports the notion that frequent cannabis use is associated with impulsive behaviours, whilst, conversely, we did not find an association between US state legalisation and problematic cannabis use or impulsivity.


The Influence of Impeller Geometries on Hemolysis in Bearingless Centrifugal Pumps.
Goal: The importance of the main impeller design parameters in bearingless centrifugal pumps with respect to hemolysis for cardiopulmonary bypass (CPB) and extracorporeal membrane oxygenation (ECMO) applications are studied in this work. Methods: Impeller prototypes were designed based on theoretical principles. They were manufactured and their hydraulic and hemolytic performance were analyzed experimentally. The cell compatibility is benchmarked against commercially available centrifugal blood pumps BPX-80 (Medtronic) and FloPump 32 (International Biophysics Corporation). Results: The developed prototypes outperform the BPX-80 and FloPump 32 with regard to hemocompatibility by more than a factor of 4.5. The implemented pump features reduced overall and priming volumes. A significant improvement of the cell compatibility is achieved by increasing the radial gap between the impeller and the pump head. The blade should be sufficiently high and a blade outlet angle of 90° provides favorable performance. No correlation between the hydraulic and hemolytic performance is observed. Conclusions: This work identified the most important geometrical parameters of the impeller for blood pumps with respect to cell compatibility. This provides valuable design guidelines for improving existing pumps.


Cytotoxicity and genotoxicity caused by yttrium oxide nanoparticles in HEK293 cells.
The increased use of engineered nanoparticles (NPs) has caused new concerns about the potential exposure to biological systems and the potential risk that these materials may pose on human health. Here, we examined the effects of exposure to different concentrations (0-50 μg/mL) and incubation times (10 hours, 24 hours, or 48 hours) of yttrium oxide (Y2O3) NPs on human embryonic kidney (HEK293) cells. Changes in cellular morphology, cell viability, cell membrane integrity, reactive oxygen species levels, mitochondrial membrane potential, cell death (apoptosis and necrosis), and the DNA damage after NP exposure were compared to the effects seen following incubation with paraquat, a known toxicant. The 24-hour inhibitory concentration 50 (IC50) of Y2O3 NPs (41 ± 5 nm in size) in the HEK293 cells was found to be 108 μg/mL. Incubation with Y2O3 NPs (12.25-50 μg/mL) increased the ratio of Bax/Bcl-2, caspase-3 expression and promoted apoptotic- and necrotic-mediated cell death in both a concentration and a time-dependent manner. Decreases in cell survivability were associated with elevations in cellular reactive oxygen species levels, increased mitochondrial membrane permeability, and evidence of DNA damage, which were consistent with the possibility that mitochondria impairment may play an important role in the cytotoxic response. These data demonstrate that the Y2O3 NP exposure is associated with increased cellular apoptosis and necrosis in cultured HEK293 cells.


Concussion Increases Odds of Sustaining a Lower Extremity Musculoskeletal Injury After Return to Play Among Collegiate Athletes.
Previous studies have identified abnormalities in brain and motor functioning after concussion that persist well beyond observed clinical recovery. Recent work suggests subtle deficits in neurocognition may impair neuromuscular control and thus potentially increase risk of lower extremity musculoskeletal injury after concussion. To determine the odds of sustaining an acute lower extremity musculoskeletal injury during the 90-day period after return to play from concussion in a cohort of National Collegiate Athletic Association (NCAA) Division I collegiate athletes. Cohort study; Level of evidence, 3. Included in this study were 87 cases of concussion among 75 athletes (58 men; 17 women) participating in NCAA Division I football, soccer, hockey, softball, basketball, wrestling, or volleyball at a single institution from 2011 to 2014. The 90-day period after return to play for each case of concussion was reviewed for acute noncontact lower extremity musculoskeletal injury. Each 90-day period after return to play was matched to the same 90-day period in up to 3 controls. Control athletes without a history of concussion in the previous year were matched to concussed athletes by sport team/sex, games played, and position. A total of 182 control (136 men; 46 women) 90-day periods were reviewed for acute injury. Conditional logistic regression was used to assess the association between concussion and subsequent risk of acute lower extremity musculoskeletal injury. The incidence of acute lower extremity musculoskeletal injury was higher among recently concussed athletes (15/87; 17%) compared with matched controls (17/182; 9%). The odds of sustaining an acute lower extremity musculoskeletal injury during the 90-day period after return to play were 2.48 times higher in concussed athletes than controls during the same 90-day period (odds ratio, 2.48; 95% CI, 1.04-5.91; P = .04). Concussed athletes have increased odds of sustaining an acute lower extremity musculoskeletal injury after return to play than their nonconcussed teammates. The study results suggest further investigation of neurocognitive and motor control deficits may be warranted beyond the acute injury phase to decrease risk for subsequent injury.


The effect of nicotine dependence and withdrawal symptoms on use of nicotine replacement therapy: Secondary analysis of a randomized controlled trial in primary care.
Nicotine replacement therapy (NRT) is effective for smoking cessation, but the optimal method of using NRT to maximize benefit is unclear. We examined whether nicotine dependence was associated with consumption of NRT, whether this was mediated by withdrawal symptoms, and the impact of these factors on cessation, in a population advised to use as much NRT as needed. Secondary analysis of data from an open label, parallel group randomized controlled trial. Participants (n = 539) attended a smoking cessation clinic in primary care and remained engaged with treatment for at least one week following a quit attempt. Baseline dependence was measured by the Fagerström Test for Cigarette Dependence (FTCD), with tobacco exposure assessed via an exhaled carbon monoxide test. At one week after quit day, mean daily consumption of NRT was measured for all participants; withdrawal (Mood and Physical Symptoms Scale (MPSS)) was also assessed in the subsample who reported being completely abstinent to that point (n = 279). Abstinence was biochemically assessed at four weeks for all participants as the principal smoking cessation outcome. Each point higher on the FTCD was associated with 0.83 mg/day more NRT consumption, controlling for tobacco exposure. This relationship was diminished when withdrawal was controlled for, and withdrawal was associated with NRT consumption, with each point higher on the MPSS associated with a 0.12 mg/day increase. Increased consumption of NRT directly predicted subsequent smoking cessation. Higher dependence appears to lead to greater withdrawal, which appears to drive greater use of NRT. This effect may partly offset lower abstinence rates in people with higher dependence. Advice to use sufficient NRT to suppress withdrawal may increase abstinence rates.


Revision thoracic slide tracheoplasty: Outcomes following unsuccessful tracheal reconstruction.
Over the past decade, thoracic slide tracheoplasty (TST) has become the principal operation in the management of congenital tracheal stenosis. The purpose of this report was to describe our experience with revision TST following unsuccessful prior tracheal reconstruction. Retrospective analysis at an academic children's hospital. Patients undergoing TST on cardiopulmonary bypass between January 2005 and May 2014 were reviewed. Patients with a history of prior airway surgery were extracted for further analysis. Preoperative patient variables and postoperative outcomes were evaluated and compared between patients undergoing revision slide tracheoplasty (RTST) and a control group of 26 matched patients undergoing primary surgery TST. Twenty-six revision patients (25 referrals, one primary patient) of 162 patients reviewed over the study period met inclusion criteria. Twenty-three patients had a history of complete tracheal rings, and three patients had cartilaginous deficiency. A total of 41 airway reconstruction procedures had been performed prior to RTST. When compared to primary TST, patients undergoing RTST required fewer cardiac procedures intraoperatively, and fewer mean ventilator hours (P = .01) postoperatively. There was no significant difference in the median length of stay, requirement of >48 hours ventilation, or postoperative complications between groups. There was one nonsurgical postoperative mortality following RTST. Despite some differences in the postoperative management when compared to nonrevision cases, revision TST can be successfully performed after prior tracheal reconstruction with good postoperative outcomes. 4. Laryngoscope, 128:2181-2186, 2018.


Hepatic SR-BI, not endothelial lipase, expression determines biliary cholesterol secretion in mice.
High density lipoprotein cholesterol is thought to represent a preferred source of sterols secreted into bile following hepatic uptake by scavenger receptor class B type I (SR-BI). The present study aimed to determine the metabolic effects of an endothelial lipase (EL)-mediated stimulation of HDL cholesterol uptake on liver lipid metabolism and biliary cholesterol secretion in wild-type, SR-BI knockout, and SR-BI overexpressing mice. In each model, injection of an EL expressing adenovirus decreased plasma HDL cholesterol (P < 0.001) whereas hepatic cholesterol content increased (P < 0.05), translating into decreased expression of sterol-regulatory element binding protein 2 (SREBP2) and its target genes HMG-CoA reductase and LDL receptor (each P < 0.01). Biliary cholesterol secretion was dependent on hepatic SR-BI expression, being decreased in SR-BI knockouts (P < 0.001) and increased following hepatic SR-BI overexpression (P < 0.001). However, in each model, biliary secretion of cholesterol, bile acids, and phospholipids as well as fecal bile acid and neutral sterol content, remained unchanged in response to EL overexpression. Importantly, hepatic ABCG5/G8 expression did not correlate with biliary cholesterol secretion rates under these conditions. These results demonstrate that an acute decrease of plasma HDL cholesterol levels by overexpressing EL increases hepatic cholesterol content but leaves biliary sterol secretion unaltered. Instead, biliary cholesterol secretion rates are related to the hepatic expression level of SR-BI. These data stress the importance of SR-BI for biliary cholesterol secretion and might have relevance for concepts of reverse cholesterol transport.


The novel subset of CD14+/CD16+ blood monocytes exhibits features of tissue macrophages.
The CD14+/CD16+ cells account for about 10% of all blood monocytes. They are characterized by a low level expression of the CD14 molecule and a high level expression of the CD16 (Fc gamma R III) molecule. Polymerase chain reaction analysis of mRNA prevalence in CD14+/CD16+ cells (compared to the regular CD14++ blood monocytes) demonstrates low levels of CD14 transcripts and high levels of CD16 transcripts, suggestive of a transcriptional control for both of these proteins. Analysis of additional cell surface molecules in three-color immunofluorescence reveals that CD14+/CD16+ cells express the Fc gamma R II in all, and Fc gamma R I and ICAM-1 in some donors. Furthermore, class II antigens are expressed at fourfold higher levels, while both, CD11b and CD33 cell surface proteins, are decreased by a factor of two. Transcript levels were reduced in CD14+/CD16+ cells for all three cell surface molecules. Since these phenotypic markers of the CD14+/CD16+ blood monocytes are reminiscent of tissue macrophages, we performed a comparative analysis with alveolar macrophages (AM). These cells are similar to the CD14+/CD16+ monocytes in that they show low levels of CD14 and strong expression of CD16. Furthermore, similar to the CD14+/CD16+ cells, the AM also exhibit higher levels of class II and lower levels of CD11b and CD33 when compared to the regular CD14++ blood monocytes. In vitro induction of maturation of blood monocytes by 5 day culture of peripheral blood mononuclear cells in 10% human serum will result in decreased CD14 and increased CD16 cell surface expression on the monocyte derived macrophages. At the same time, these cells acquire increased levels of class II and decreased levels of CD11b and CD33. Taken together, these data show that CD14+/CD16+ monocytes, while still in circulation, have acquired features in common with mature tissue macrophages.


Effect of codeine phosphate, Lomotil, and Isogel on iileostomy function.
The effect on ileostomy function of codeine phosphate, Lomotil, or Isogel was tested in 20 subjects at home living a normal life, studied over two three-day periods on and off treatment. Codeine phosphate 60 mg three times daily was associated with a reduction in the mean total weight of ileostomy output and the ileostomy outputs of water, sodium, and potassium (p < 0.05). The proportion of faecal solids increased on codeine and the effluent appeared thicker but the output of faecal solids remained unchanged. Mean faecal fat increased on codeine. The transit rate from mouth to stoma was slower in four of the five subjects on codeine and a further two subjects withdrew from the trial with temporary intestinal obstruction while on the drug. Lomotil two tablets three times daily was associated with a small and statistically not quite significant fall in the mean total weight of ileostomy output and the ileostomy output of water. Sodium and potassium outputs in the effluent fell on Lomotil (p < 0.05) but the other parameters remained unchanged. Isogel 15 ml three times daily was associated with an increase in the mean total weight of ileostomy output and the ileostomy outputs of water, sodium, potassium, and faecal solids (p < 0.01). Although the effluent looked more viscid on Isogel, the proportion of faecal solids was unchanged. These results suggest that codeine phosphate has a beneficial effect on ileostomy function, reducing the loss of water and electrolytes, while Lomotil has a similar but less effective action in the dosage tested. By contrast, Isogel increases the ileostomy loss of water and electrolytes and will aggravate their depletion in patients with excessive fluid effluents. The increase in faecal fat associated with taking codeine phosphate suggests that it should be stopped before collecting specimens for faecal fat estimations.


Function and recruitment of mucosal regulatory T cells in human chronic Helicobacter pylori infection and gastric adenocarcinoma.
CD4(+)CD25(high) FOXP3-expressing regulatory T cells (Treg) can suppress immune responses to infections and tumors, thereby promoting microbial persistence and tumor progression. However, little is known about the phenotype and function of human mucosal Treg. Therefore, we analyzed the suppressive activity and homing phenotype of Treg in gastric mucosa of Helicobacter pylori-infected gastric adenocarcinoma patients. We found increased numbers of CD4(+)FOXP3(+) Treg in the tumor compared to tumor-free gastric mucosa. Gastric Treg cells were able to suppress H. pylori-induced T cell proliferation and IFN-gamma production. Furthermore, gastric Treg expressed increased levels of l-selectin and CCR4, compared to non-Treg cells, suggesting that these receptors contribute to Treg recruitment. The presence of functional antigen-specific Treg in H. pylori-infected gastric mucosa supports an important role for these cells in suppression of mucosal effector T cell responses, which probably contribute to bacterial persistence and possibly also to gastric tumor progression.


Inhibition of the c-fms proto-oncogene autocrine loop and tumor phenotype in glucocorticoid stimulated human breast carcinoma cells.
The c-fms proto-oncogene encoded CSF-1 receptor and its ligand represent a feedback loop, which in a paracrine manner, is well known to promote spread of breast cancers. The role of the autocrine feedback loop in promotion of breast tumor behavior, in particular in vitro, is less well understood. The physiologic stimulation of c-fms expression by glucocorticoids (GCs) in vitro and in vivo magnifies the tumor promoting effect seen in these cells from activated c-fms signaling by CSF-1. Targeted molecular therapy against c-fms could therefore abrogate both complementary feedback loops. Using breast cancer cells endogenously co-expressing receptor and ligand, we used complementary approaches to inhibit c-fms expression and function within this autocrine pathway in the context of GC stimulation. Silencing RNA (shRNA), antisense oligonucleotide therapy (AON), and inhibition of c-fms signaling, were all used to quantitate inhibition of GC-stimulated adhesion, motility, and invasion of human breast cancer cells in vitro. shRNA to c-fms downregulated GC-stimulated c-fms mRNA by fourfold over controls, correlating with over twofold reduction in cellular invasiveness. AON therapy was also able to inhibit GC stimulation of c-fms mRNA, and resulted in threefold less invasiveness and 1.5 to 2-fold reductions in adhesion and motility. Finally, the small-molecule c-fms inhibitor Ki20227 was able to decrease in a dose-response manner, breast cancer cell invasion by up to fourfold. Inhibition of this receptor/ligand pair may have clinical utility in inhibition of the autocrine as well as the known paracrine interactions in breast cancer, thus further supporting use of targeted therapies in this disease.


Incapacitation and just deserts as motives for punishment.
What motivates a person's desire to punish actors who commit intentional, counternormative harms? Two possible answers are a just deserts motive or a desire to incarcerate the actor so that he cannot be a further danger to society. Research participants in two experiments assigned punishments to actors whose offenses were varied with respect to the moral seriousness of the offense and the likelihood that the perpetrator would commit similar future offenses. Respondents increased the punishment as the seriousness of the offense increased, but their sentences were not affected by variations in the likelihood of committing future offenses, suggesting that just deserts was the primary sentencing motive. Only in a case in which a brain tumor was identified as the cause of an actor's violent action, a case that does not fit the standard prototype of a crime intentionally committed, did respondents show a desire to incarcerate the actor in order to prevent future harms rather than assigning a just deserts based punishment.


The determination of the structure of Saturn's F ring by nearby moonlets.
Saturn's narrow F ring exhibits several unusual features that vary on timescales of hours to years. These include transient clumps, a central core surrounded by a multistranded structure and a regular series of longitudinal channels associated with Prometheus, one of the ring's two 'shepherding' satellites. Several smaller moonlets and clumps have been detected in the ring's immediate vicinity, and a population of embedded objects has been inferred. Here we report direct evidence of moonlets embedded in the ring's bright core, and show that most of the F ring's morphology results from the continual gravitational and collisional effects of small satellites, often combined with the perturbing effect of Prometheus. The F-ring region is perhaps the only location in the Solar System where large-scale collisional processes are occurring on an almost daily basis.


Anticholinergic Burden and Safety Outcomes in Older Patients with Chronic Hepatitis C: A Retrospective Cohort Study.
Older patients with chronic hepatitis C infection starting direct-acting antivirals (DAAs) are frequently prescribed multiple medications that may be categorized as inappropriate. Anticholinergic burden has been shown to be a predictor of adverse health and functional outcomes. Different scales are available to calculate anticholinergic burden. The aim of this study was to determine the prevalence of anticholinergic medication among older patients treated with DAAs and the risk factors associated using the Anticholinergic Cognitive Burden (ACB) scale, the Anticholinergic Risk Scale (ARS) and the Anticholinergic Drug Scale (ADS) and analyze the resulting safety consequences. Observational, retrospective cohort study of consecutive patients ≥65 years old receiving DAAs and taking concomitant medication. This study was conducted in accordance with the Strengthening the Reporting of observational studies in Epidemiology Statement. 236 patients were included. The average age was 71.7 years, 73.3% cirrhotic, and 47% patients took ≥5 medicines. According to the ACB, ARS and ADS scales, 35.2% (n = 83), 10.6% (n = 25) and 34.3% (n = 81) of the patients were treated with anticholinergic medication. Two hundred-and-six (86%) patients presented any adverse events (AEs) during therapy. ARS scale showed a significant relationship between presence of anticholinergic medication and AEs. A large number of patients suffered anticholinergic events, with more events per patient in patients taking anticholinergic drugs. Older hepatitis C chronic patients are exposed to potentially inappropriate polypharmacy and anticholinergic risk, according to the ACB, ARS and ADS scales. The three scales showed different results. Only the ARS scale was associated with AEs, but the rate of anticholinergic effects per patient was significantly higher in patients with anticholinergic drugs, regardless of the scale used. Consider quality of pharmacotherapy when starting DAA with a multidisciplinary approach could improve health outcomes.


Within-species divergence in the seminal fluid proteome and its effect on male and female reproduction in a beetle.
Male seminal fluid proteins (SFPs), transferred to females during mating, are important reproductive proteins that have multifarious effects on female reproductive physiology and that often show remarkably rapid and divergent evolution. Inferences regarding natural selection on SFPs are based primarily on interspecific comparative studies, and our understanding of natural within-species variation in SFPs and whether this relates to reproductive phenotypes is very limited. Here, we introduce an empirical strategy to study intraspecific variation in and selection upon the seminal fluid proteome. We then apply this in a study of 15 distinct populations of the seed beetle Callosobruchus maculatus. Phenotypic assays of these populations showed significant differences in reproductive phenotypes (male success in sperm competition and male ability to stimulate female fecundity). A quantitative proteomic study of replicated samples of male accessory glands revealed a large number of potential SFPs, of which ≥127 were found to be transferred to females at mating. Moreover, population divergence in relative SFP abundance across populations was large and remarkably multidimensional. Most importantly, variation in male SFP abundance across populations was associated with male sperm competition success and male ability to stimulate female egg production. Our study provides the first direct evidence for postmating sexual selection on standing intraspecific variation in SFP abundance and the pattern of divergence across populations in the seminal fluid proteome match the pattern predicted by the postmating sexual selection paradigm for SFP evolution. Our findings provide novel support for the hypothesis that sexual selection on SFPs is an important engine of incipient speciation.


Nurses' and personal care assistants' role in improving the relocation of older people into nursing homes.
This article presents findings from a study that explored nurses' and personal care assistants' role in improving the relocation of older people into a nursing home. Suggestions for improving the relocation process for older people moving into a nursing home have been the outcomes of studies that have interviewed residents and their families. However, the views of nurses and personal care assistants working in nursing homes have not been previously explored. An exploratory, descriptive qualitative research design. Individual interviews were conducted with 20 care staff (seven registered nurses, five enrolled nurses and eight personal care assistants) employed at four nursing homes. Using thematic analysis, two key themes were identified: 'What it's like for them' - highlighted staffs' awareness of the advantages, disadvantages and meaning of relocation, and focused on staffing and nursing care; other services provided and the environment. The second theme - 'We can make it better', revealed suggestions for improving the relocation process, and included spending time with new residents and the importance of a person-centred approach to care. Care staff have an important role in improving the relocation process of older people into a nursing home, as well as contributing to the discussion on this important clinical topic. Challenging care staff to acknowledge the importance of their role in helping older people settle into a nursing home is a key requirement of nursing practice in aged care. Nursing practice guidelines, with a focus on person-centred care, on how to manage the relocation process for an older person and their family are required for this aspect of nursing home care. Education of staff on relocation policies and procedures is essential to ensure that residents and their families are supported through this process.


The benefit-to-risk profile of melagatran is superior to that of hirudin in a rabbit arterial thrombosis prevention and bleeding model.
Although hirudin is better than heparin at preventing recurrent ischemia in patients with unstable angina, hirudin produces more bleeding. The purpose of this study was to use a rabbit arterial thrombosis prevention and ear bleeding model to determine whether for equivalent efficacy, melagatran, a synthetic direct thrombin inhibitor, is safer than hirudin. A combination of balloon injury and stasis was used to induce thrombosis in the distal aorta, and patency and blood flow were continuously monitored with ultrasonic flow probes. Rabbits were randomized to melagatran (in total doses of 78-313 nmol kg(-1)), hirudin (in total doses of 18-107 nmol kg(-1)), or saline over 90 min. To assess safety, blood loss from standardized ear incisions was measured. Both melagatran and hirudin produced dose-dependent increases in patency and blood flow. At doses that maintained the highest levels of patency, however, melagatran produced 2-3-fold less bleeding than hirudin. Thus, at maximally effective doses, melagatran causes less bleeding than hirudin in this model. These findings raise the possibility that some direct thrombin inhibitors are safer than others.


Control of proteoglycan synthesis. Studies on the activation of synthesis observed during culture of articular cartilages.
When slices of adult rabbit articular cartilage were incubated in culture medium, the rate of incorporation of [35S]sulphate or [3H]acetate into glycosaminoglycans increased 4-8 fold during the first 5 days of incubation. Similar changes in biosynthetic activity were observed during culture of adult bovine cartilage. The activation of synthesis was not serum-dependent, but appeared to be a result of the depletion of tissue proteoglycan that occurs under these incubation conditions [Sandy, Brown & Lowther (1978) Biochim. Biophys. Acta 543, 536--544]. Thus, although complete activation was observed in serum-free medium, it was not observed if the cartilage was cultured inside dialysis tubing or in medium containing added proteoglycan subunit. The average molecular size of the proteoglycans synthesized by activated tissue was slightly larger than normal, as determined by chromatography on Sepharose CL-2B, and the average molecular size of the glycosaminoglycans synthesized by activated tissue was markedly increased over the normal. The increase in chain size was accompanied by an increase in the proportion of the chains degraded by chondroitinase ABC; these results are consistent with the preferential synthesis by activated chondrocytes of chondroitin sulphate-rich proteoglycans. The increase in glycosaminoglycan chain size was observed whether the chains were formed on endogenous core protein or on exogenous benzyl-beta-D-zyloside. An approximate 4-fold activation in culture of glycosaminoglycan synthesis on protein core was accompanied by a 1.54-fold increase in the rate of incorporation of [3H]serine into the chondroitin sulphate-linkage region of the proteoglycans. A 2.8-fold activation in culture of glycosaminoglycan synthesis on benzyl-beta-D-zyloside was accompanied by a 1.7-fold increase in the rate of incorporation of [3H]benzyl-beta-D-zyloside into glycosaminoglycans. The activation of glycosaminoglycan synthesis was, however, accompanied by no detectable change in the activity of xylosyltransferase (EC 220.127.116.11) in cell-free extracts. These results are discussed in relation to current ideas on the control of proteoglycan synthesis in cartilage.


Placental mammal diversification and the Cretaceous-Tertiary boundary.
Competing hypotheses for the timing of the placental mammal radiation focus on whether extant placental orders originated and diversified before or after the Cretaceous-Tertiary (KT) boundary. Molecular studies that have addressed this issue suffer from single calibration points, unwarranted assumptions about the molecular clock, andor taxon sampling that lacks representatives of all placental orders. We investigated this problem using the largest available molecular data set for placental mammals, which includes segments of 19 nuclear and three mitochondrial genes for representatives of all extant placental orders. We used the ThorneKishino method, which permits simultaneous constraints from the fossil record and allows rates of molecular evolution to vary on different branches of a phylogenetic tree. Analyses that used different sets of fossil constraints, different priors for the base of Placentalia, and different data partitions all support interordinal divergences in the Cretaceous followed by intraordinal diversification mostly after the KT boundary. Four placental orders show intraordinal diversification that predates the KT boundary, but only by an average of 10 million years. In contrast to some molecular studies that date the rat-mouse split as old as 46 million years, our results show improved agreement with the fossil record and place this split at 16-23 million years. To test the hypothesis that molecular estimates of Cretaceous divergence times are an artifact of increased body size subsequent to the KT boundary, we also performed analyses with a "KT body size" taxon set. In these analyses, interordinal splits remained in the Cretaceous.


Expression profiles and prognostic significance of RNA N6-methyladenosine-related genes in patients with hepatocellular carcinoma: evidence from independent datasets.
Background: N6-methyladenosine (m6A) is the most prevalent modification of mammalian RNA. Emerging evidence suggest that m6A has critical roles in multiple biological activities, but little is known about its roles in cancer pathogenesis. Herein, we report the expression profiles and prognostic relevance of twelve m6A-related genes in hepatocellular carcinoma (HCC) by analyzing four independent datasets. Materials and methods: RNA levels of twelve m6A-related genes were detected in samples of 162 HCC patients who underwent curative resection (the Guangdong General Hospital dataset). We additionally analyzed the expression profiles of m6A-related genes in The Cancer Genome Atlas liver HCC dataset and two Gene Expression Omnibus datasets (GSE14520, GSE63898). Prognostic value of genes was evaluated by Kaplan-Meier curves of overall survival (OS) with the log-rank test and multivariate Cox regression analysis. Gene set enrichment analysis (GSEA) was conducted to identify associated KEGG pathways. Results: Five genes (METTL3, YTHDF1, YTHDF2, YTHDF3, and EIF3) showed consistent upregulation in all four datasets. Abnormal expressions of either METTL3 or YTHDF1 but not the other ten genes were associated with OS. Protein expression of METTL3 and YTHDF1 were confirmed in HCC tissues by immunohistochemical staining. Multivariate Cox regression analysis confirmed the independent predictive value of both METTL3 and YTHDF1 on OS. We further divided patients into three groups based on the median expression values of METTL3 and YTHDF1. In all datasets, the low METTL3/low YTHDF1 group showed a consistent better prognosis than other groups. GSEA revealed that both METTL3 and YTHDF1 regulate HCC cell cycle, RNA splicing, DNA replication, base excision repair, and RNA degradation. Conclusion: Both METTL3 and YTHDF1 were upregulated in HCC, and they were independent poor prognostic factors. Combination of METTL3 and YTHDF1 can be regarded as the biological marker that reflect malignant degree and evaluate prognosis in HCC.


EPODE approach for childhood obesity prevention: methods, progress and international development.
Childhood obesity is a complex issue and needs multi-stakeholder involvement at all levels to foster healthier lifestyles in a sustainable way. 'Ensemble Prévenons l'Obésité Des Enfants' (EPODE, Together Let's Prevent Childhood Obesity) is a large-scale, coordinated, capacity-building approach for communities to implement effective and sustainable strategies to prevent childhood obesity. This paper describes EPODE methodology and its objective of preventing childhood obesity. At a central level, a coordination team, using social marketing and organizational techniques, trains and coaches a local project manager nominated in each EPODE community by the local authorities. The local project manager is also provided with tools to mobilize local stakeholders through a local steering committee and local networks. The added value of the methodology is to mobilize stakeholders at all levels across the public and the private sectors. Its critical components include political commitment, sustainable resources, support services and a strong scientific input--drawing on the evidence-base--together with evaluation of the programme. Since 2004, EPODE methodology has been implemented in more than 500 communities in six countries. Community-based interventions are integral to childhood obesity prevention. EPODE provides a valuable model to address this challenge.


A systematic review and meta-analysis of the management of visceral artery aneurysms.
The evidence supporting management decisions of visceral artery aneurysms (VAAs) is sparse. Practice guidelines are needed to help patients and surgeons choose between endovascular and open surgery approaches. We searched MEDLINE, EMBASE, Cochrane databases, and Scopus for studies of patients with VAAs. Studies were selected and appraised by pairs of independent reviewers. Meta-analysis was performed when appropriate. We included 80 observational studies that were mostly noncomparative. Data were available for 2845 aneurysms, comprising 1279 renal artery, 775 splenic artery, 359 hepatic artery, 226 pancreaticoduodenal and gastroduodenal arteries, 95 superior mesenteric artery, 87 celiac artery, 15 jejunal, ileal and colic arteries, and 9 gastric and gastroepiploic arteries. Differences in mortality between open and endovascular approaches were not statistically significant. The endovascular approach was used more often by surgeons. The endovascular approach was associated with shorter hospital stay and lower rates of cardiovascular complications but higher rates of reintervention. Postembolization syndrome rates ranged from 9% (renal) to 38% (splenic). Coil migration ranged from 8% (splenic) to 29% (renal). Otherwise, access site complication were low (<5%). Pseudoaneurysms tended to have higher mortality and reintervention rates. This systematic review provides event rates for outcomes important to patients with VAAs. Despite the low certainty warranted by the evidence, these rates along, with surgical expertise and anatomic feasibility, can help patients and surgeons in shared-decision making.


The influence of glide path preparation on the failure rate of WaveOne reciprocating instruments.
The aim of this study was to determine the influence of two different glide path preparation methods on the fracture rate of the Primary 25/08 WaveOne reciprocating instrument. Preparation times for different glide path methods and total time for root canal preparation, with and without prior glide path preparation, were also calculated. ISO 15, 0.02 taper Endo-Training-Blocks (n = 300) were selected and randomly divided into three main groups (n = 100): Group 1: no glide path (control); Group 2: glide path preparation with stainless-steel hand files; and Group 3: glide path preparation with rotary PathFiles. The time taken to prepare each glide path was recorded. The specimens in each main group were then randomly assigned into five subgroups (n=20). New Primary 25/08 WaveOne files were used for canal preparation in each subgroup. The outcome was measured by recording how many simulated canals could be shaped with one WaveOne reciprocating file in each subgroup before instrument breakage occurred. The average time it took to prepare each of the simulated canals was calculated and recorded. The data were collected and statistically analysed using the ANOVA / Bonferroni test. Glide path preparation with PathFiles was significantly faster than with hand files (P<0.001). After the glide path preparation had been performed with PathFiles, a greater number of simulated canals could be prepared before failure of the WaveOne file (P<0.001). Root canal preparation time was significantly shorter (P<0.001) when an initial glide path had been prepared with PathFiles.


Factors predicting the response to growth hormone (GH) therapy in prepubertal children with GH deficiency.
To identify factors influencing the response to GH therapy, we used a multiple regression model to analyze data from 632 naive prepubertal children with GH deficiency (GHD). There were 523 children with idiopathic and 109 children with organic GHD. They were treated with the same preparation of biosynthetic methionyl GH (somatrem, Protropin) for at least 1 yr. In children with idiopathic GHD, six variables predicted 40% of the response to treatment. They were (listed in relative importance, all P < 0.0001): age, log maximum GH, weight adjusted for height, dosing schedule, dose, and midparental height. Three variables, pretreatment growth rate, log maximum GH, and age, predicted 20% of the GH response in children with organic GHD. When data for all children were analyzed using analysis of covariance, children with idiopathic GHD grew better than those with organic GHD (mean +/- SD, 9.2 +/- 2.4 vs. 8.8 +/- 2.6 cm/yr; P < 0.0001). The children (both organic and idiopathic GHD) who did not respond well to treatment were younger and thinner than those who did. Early diagnosis and initiation of therapy should be beneficial to ultimate height attainment. The best response to GH therapy should be in young children with severe idiopathic GHD who receive daily weight-adjusted doses. The use of GH daily in higher doses would be expected to be most beneficial in older children with acquired and/or less severe GHD or in children who are underweight for height.


Heterogeneity in Danish lung choirs and their singing leaders: delivery, approach, and experiences: a survey-based study.
Singing is considered a beneficial leisure time intervention for people with respiratory diseases, and lung choirs have gained increasing attention. However, there is no available guideline on preferred methodology, and hence, outcomes, delivery, and benefits are unclear. The present study investigated for the first time ever emerged delivery, approach, and experiences in Danish lung choirs and their singing leaders, hypothesising the array to be heterogeneous, without disease-specific approach, and a challenging field to navigate for the singing leaders. An online survey comprising 25 questions was performed individually, May 2017, in Denmark. Current singing leaders of Danish lung choirs, identified by hand searches on the internet. In total, 33 singing leaders in formal and informal settings were identified and 20 (67%) responded. Distribution in content, delivery, and approach; level of disease-specific knowledge and modification; experience of challenges and benefits. Quantitative variables were counted, and an inductive content analysis approach was used for the qualitative study component. The lung choirs were heterogeneous concerning setting, duration, and content. The approach was traditional without disease-specific content or physical activity. Most singing leaders held various academic degrees in music, but lacked skills in lung diseases. However, they experienced lung choirs as a highly meaningful activity, and reported that participants benefited both musically, psychosocially, and physically. Singing leaders were enthusiastic regarding potentials in the 'arts-and-health' cross-field and experienced an expansion of their role and overall purpose, professionally as well as personally. However, they also experienced insecurity, inadequacy, and isolation, and requested methodological guidelines, formal support, and peer network. Danish lung choirs are led without any disease-specific guideline or methodological approach. Further studies are needed to develop and distribute a preferred methodological approach. This study is linked to clinical trial number NCT03280355 and was performed prior to data collection and results of the clinical trial.


Disruption of methylarginine metabolism impairs vascular homeostasis.
Asymmetric dimethylarginine (ADMA) and monomethyl arginine (L-NMMA) are endogenously produced amino acids that inhibit all three isoforms of nitric oxide synthase (NOS). ADMA accumulates in various disease states, including renal failure, diabetes and pulmonary hypertension, and its concentration in plasma is strongly predictive of premature cardiovascular disease and death. Both L-NMMA and ADMA are eliminated largely through active metabolism by dimethylarginine dimethylaminohydrolase (DDAH) and thus DDAH dysfunction may be a crucial unifying feature of increased cardiovascular risk. However, despite considerable interest in this pathway and in the role of ADMA as a cardiovascular risk factor, there is little evidence to support a causal role of ADMA in pathophysiology. Here we reveal the structure of human DDAH-1 and probe the function of DDAH-1 both by deleting the DDAH1 gene in mice and by using DDAH-specific inhibitors which, as we demonstrate by crystallography, bind to the active site of human DDAH-1. We show that loss of DDAH-1 activity leads to accumulation of ADMA and reduction in NO signaling. This in turn causes vascular pathophysiology, including endothelial dysfunction, increased systemic vascular resistance and elevated systemic and pulmonary blood pressure. Our results also suggest that DDAH inhibition could be harnessed therapeutically to reduce the vascular collapse associated with sepsis.


A Reconsideration of the Self-Compassion Scale's Total Score: Self-Compassion versus Self-Criticism.
The Self-Compassion Scale (SCS) is currently the only self-report instrument to measure self-compassion. The SCS is widely used despite the limited evidence for the scale's psychometric properties, with validation studies commonly performed in college students. The current study examined the factor structure, reliability, and construct validity of the SCS in a large representative sample from the community. The study was conducted in 1,736 persons, of whom 1,643 were included in the analyses. Besides the SCS, data was collected on positive and negative indicators of psychological functioning, as well as on rumination and neuroticism. Analyses included confirmatory factor analyses (CFA), exploratory factor analyses (EFA), and correlations. CFA showed that the SCS's proposed six-factor structure could not be replicated. EFA suggested a two-factor solution, formed by the positively and negatively formulated items respectively. Internal consistency was good for the two identified factors. The negative factor (i.e., sum score of the negatively formulated items) correlated moderately to strongly to negative affect, depressive symptoms, perceived stress, as well as to rumination and neuroticism. Compared to this negative factor, the positive factor (i.e., sum score of the positively formulated items) correlated weaker to these indicators, and relatively more strongly to positive affect. Results from this study do not justify the common use of the SCS total score as an overall indicator of self-compassion, and provide support for the idea, as also assumed by others, that it is important to make a distinction between self-compassion and self-criticism.


SPINK1 protein expression and prostate cancer progression.
SPINK1 overexpression has been described in prostate cancer and is linked with poor prognosis in many cancers. The objective of this study was to characterize the association between SPINK1 overexpression and prostate cancer-specific survival. The study included 879 participants in the U.S. Physicians' Health Study and Health Professionals Follow-Up Study, diagnosed with prostate cancer (1983-2004) and treated by radical prostatectomy. Protein tumor expression of SPINK1 was evaluated by immunohistochemistry on tumor tissue microarrays. Seventy-four of 879 (8%) prostate cancer tumors were SPINK1 positive. Immunohistochemical data were available for PTEN, p-Akt, pS6, stathmin, androgen receptor (AR), and ERG (as a measure of the TMPRSS2:ERG translocation). Compared with SPINK1-negative tumors, SPINK1-positive tumors showed higher PTEN and stathmin expression, and lower expression of AR (P < 0.01). SPINK1 overexpression was seen in 47 of 427 (11%) ERG-negative samples and in 19 of 427 (4%) ERG-positive cases (P = 0.0003). We found no significant associations between SPINK1 status and Gleason grade or tumor stage. There was no association between SPINK1 expression and biochemical recurrence (P = 0.56). Moreover, there was no association between SPINK1 expression and prostate cancer mortality (there were 75 lethal cases of prostate cancer during a mean of 13.5 years follow-up; HR = 0.71; 95% confidence interval, 0.29-1.76). Our results suggest that SPINK1 protein expression may not be a predictor of recurrence or lethal prostate cancer amongst men treated by radical prostatectomy. SPINK1 and ERG protein expression do not seem to be entirely mutually exclusive, as some previous studies have suggested.