Enacted Stigma and HIV Risk Behaviours among Sexual Minority Indigenous Youth in Canada, New Zealand, and the United States.
Enacted stigma has been linked to increased HIV risk behaviours among sexual minority youth, but despite higher rates of HIV and other STIs, there is very little research with Indigenous youth. In this study, secondary analyses of three population-based, school surveys were conducted to explore the associations between HIV risk and enacted stigma among sexual minority Indigenous youth in Canada, the US, and New Zealand. Data were analyzed and interpreted with guidance from Indigenous and sexual minority research team members, Indigenous advisory groups, and community consultations. In all three countries, Indigenous sexual minority youth were more likely to experience enacted stigma (such as bullying, discrimination, exclusion, harassment, or school-based violence) and report increased HIV risk behaviours (such as lack of condom use, multiple sexual partners, pregnancy involvement, and injection drug use) compared to heterosexual peers. Data were analyzed by age, gender, and sexual orientation, and for some groups, higher levels of enacted stigma was associated with higher HIV risk. The findings highlight the need for more research, including identifying protective factors, and developing interventions that focus on promoting resilience, addressing the levels of stigma and homophobic violence in school, and restoring historical traditions of positive status for Indigenous sexual minority people.


Mode-selective photonic lanterns for space-division multiplexing.
We demonstrate a 3x1 fiber-based photonic lantern spatial-multiplexer with mode-selectivity greater than 6 dB and transmission loss of less than 0.3 dB. The total insertion loss of the mode-selective multiplexers when coupled to a graded-index few-mode fiber was < 2 dB. These mode multiplexers showed mode-dependent loss below 0.5 dB. To our knowledge these are the lowest insertion and mode-dependent loss devices, which are also fully compatible with conventional few-mode fiber technology and broadband operation.


Systematic review of the use of data from national childhood obesity surveillance programmes in primary care: a conceptual synthesis.
This study reviewed the use in primary care of national surveillance data for children to determine the data's potential utility to inform policy and practice decisions on how to prevent and treat childhood obesity. We reviewed the 28 countries identified by the World Obesity Federation as having high-quality comparable body mass index data for children. Literature published from any period up to December 2013 was included. Peer review literature was searched using Web of Science (Core Collection, MEDLINE). Grey literature was searched using the Internet by country name, programme name and national health and government websites. We included studies that (i) use national surveillance obesity data in primary care, or (ii) explore practitioner or parent perspectives about the use of such data. The main uses of national surveillance data in primary care were to identify and recruit obese children and their parents to participate in school and general practice-based research and/or interventions, and to inform families of children's measurements. Findings indicate a need for school staff and practitioners to receive additional training and support to sensitively communicate with families. Translation of these findings into policy and practice could help to improve current uses of national child obesity surveillance data in primary care.


Recent findings of halogenated flame retardants (HFR) in the German and Polar environment.
To get an overview about distribution, levels and temporal trends of polybrominated diphenyl ethers (PBDE) and halogenated flame retardants (HFR) of emerging concern, different types of environmental samples archived in the German Environment Specimen Bank as well as fish filet samples from the Arctic (n = 13) and Antarctica (n = 5) were analysed for 43 substances (24 PBDE, 19 HFR) using a multi-column clean-up and GC-API-MS/MS or GC-MS. Sample types were herring gull egg (n = 3), blue mussel (n = 3) and eelpout filet (n = 3) from the German North- and Baltic Sea, bream filet (n = 7), zebra mussel (n = 6) and suspended particulate matter (SPM, n = 7) from German freshwater ecosystems as well as tree leaves (n = 9)/shoots (n = 10), soil (n = 4), earthworm (n = 4) and deer liver (n = 7) as representatives of German terrestrial ecosystems. PBDE and emerging HFR were present in each investigated matrices from Germany and Polar regions showing their widespread distribution. The presence in Arctic and Antarctic fish samples confirms their long-range transport potential. Average concentrations of total emerging HFR were highest in SPM (26 ng g-1 dry weight (dw)), zebra mussel (10 ng g-1 dw) and herring gull egg (2.6 ng g-1 dw). Lowest levels were measured in fish filet samples from Antarctica (0.02 ng g-1 dw). Average total PBDE concentrations were highest in bream filet (154 ng g-1), herring gull egg (61 ng g-1 dw), SPM (21 ng g-1 dw), and zebra mussel 18 (ng g-1) and lowest in deer liver (0.04 ng g-1 dw). The patterns of non-fauna terrestrial samples (leaves, shoots, soil) as well as SPM were dominated by DBDPE and BDE209. Elevated proportions of DPTE and in most cases the absence of DBDPE characterized all fauna samples with the exception of Polar samples. Overall, emerging HFR appeared to be less bioaccumulative than PBDE. Temporal trends were generally decreasing with few exceptions such as DBDPE.


Acute effects of walking with Nordic poles in persons with mild to moderate low-back pain.
Regular walking with or without Nordic poles is effective over time at reducing discomfort in individuals with chronic low back pain (LBP). Nordic pole use increases balance and stability, distributes weight through the arms and torso, and decreases loading of the spine and lower limbs. The purpose of this study was to determine if Nordic poles would reduce perceived acute discomfort while self-paced walking in individuals with LBP. We also examined whether walking with or without poles increased heart rate (HR) and ratings of perceived exertion (RPE) or speed of movement. Subjects included 20 adults (12 males, 8 females; mean age of 45.1±16.3) who were experiencing LBP of at least six months' duration (Oswestry Disability Index (ODI): mean 17 ± 8%, range 6-36% indicating minimal to moderate disability) with no current active flare-up. Participants walked a predetermined dirt-path course (805 m or 0.5 mi) with and without poles in randomized order. Data were analyzed using a 2 X 2 repeated measures ANOVA (Condition X Time), where Condition was poles vs no poles and Time was pre- and post-walk. HR and RPE increased significantly from walking the course, whereas pain did not change. There were also no differences between walking with or without poles for pain (ODI Sec #1: 0.2 points, p=0.324), HR (4 bpm, p=0.522) and RPE (0 points, p=0.759). The mean course time (sec) was slower with poles: 617±87 vs 566±65 (p<0.001). Unexpectedly, there was a noticeable drop in pain following the warm up which was done using poles (0.9 points, p<0.001). Nordic pole use is well tolerated in those with current back pain and can be encouraged, however it cannot be recommended as a superior method of addressing acute symptoms when walking.


Qualitative environmental analysis for industrial districts implantation using geoprocessing techniques.
Industrial districts became important instruments which are used by the Public Power to induce economic decentralization and create new development poles. For this reason the legislative process is an indispensable means to define the priorities in the uses of soil, also to conduct and follow the process of industrial registration. However, the industrial district establishment shall not be analyzed by taking into account just the economic factor, but also the environmental issue of the enterprise. Thus, this research has the objective of determining adequate places for industrial districts implantation, having as a pilot area the city of São Leopoldo, Rio Grande do Sul State, Brazil. A Geographic Information System for execution of spatial analysis and criteria creation on a large volume of environmental information will be used as a tool, which will be guided by the Municipal, State and Federal legislation and a Quickbird satellite image that covers the interest area. The main information used on this research are: altimeter, hydrography, soil use, pedology, geology and infrastructure. The results are visualized in scenarios modeled in accordance with the restrictions imposed upon the information, allowing at the end, to combine all scenarios and create through the multiple criteria method a map that indicates adequate places for implantation of industrial districts.


Digit ratio varies with sex, egg order and strength of mate preference in zebra finches.
The steroid environment encountered by developing vertebrates has important organizational effects on physiology and behaviour that persist throughout an organism's lifetime. Optimal allocation of maternal steroids to zygotes may be difficult to achieve because of the sexually antagonistic effects of steroids; thus, for example, a hormone environment beneficial to a developing male may be much less beneficial to a developing female. Research into the important topic of how mothers might adaptively adjust steroid titres experienced by particular young has been constrained by the difficulty of measuring the steroid environment experienced by the embryo at critical times in development. A potential approach to this problem has been suggested by research on variation in digit ratios in humans, where the ratio of the length of the second and fourth digits reflects the steroid environment experienced by the foetus; notably, digit 4 lengthens in response to androgens. In light of the conservative nature of homeobox genes regulating early development in tetrapods, we questioned whether a sex difference in digit ratio exists in a passerine bird, the zebra finch, Taeniopygia guttata castanotis, and whether observed variation in the ratio is consistent with the previously reported pattern that androgen allocation to zebra finch egg yolk declines across laying order. We established an aviary population of outbred, wild-type zebra finches, and allowed them to breed freely. Hatchlings were marked to correspond to their egg order, and their digit ratios were measured after birds reached adulthood. We found that digit ratio increased across egg order, which is consistent with a pattern of decreasing androgen allocation. Moreover, digit ratios differed between the sexes. We also investigated whether variation in digit ratio among adult females predicted variation in their performance in mate-choice tests. Digit ratio accounted for almost 50% of the variance in strength of female preference for an attractive male trait: specifically, females with higher (presumably less 'androgenized') ratios had stronger preferences for attractive males. Digit ratio may prove to be an extremely useful tool for addressing a wide range of questions about vertebrate differentiation and behaviour.


Highly crystalline films of PCPDTBT with branched side chains by solvent vapor crystallization: influence on opto-electronic properties.
PCPDTBT, a marginally crystallizable polymer, is crystallized into a new crystal structure using solvent-vapor annealing. Highly ordered areas with three different polymer-chain orientations are identified using TEM/ED, GIWAXS, and polarized Raman spectroscopy. The optical and structural properties differ significantly from films prepared by standard device preparation protocols. Bilayer solar cells, however, show similar performance.


Accuracy and stability of national and international somatic cell score evaluations.
Somatic cell score (SCS) evaluations have been published in the United States since 1994 and international evaluations have been available through Interbull since May 2001. The accumulated data provides an opportunity to investigate the accuracy and stability of SCS evaluations. United States domestic evaluations from January 1995 through August 2004, for 21,500 Holstein bulls were considered, over time and sequentially within bull, for changes to the November 2004 evaluation. On average, predicted transmitting ability (PTA) SCS increased (worsened) by 0.002 from earlier evaluations to November 2004. Although bias was small, PTA changes were more than expected based on change in reliability. When looked at sequentially, bulls' earlier evaluations were generally lower (i.e., merit was overestimated) relative to November 2004. Differences were small, and PTA SCS increased steadily with the addition of second-crop daughters. All 524,081 evaluations were considered pairwise providing over 8,000,000 pairs of bulls' evaluations for analysis of PTA differences relative to change in reliability. Agreement of observed and expected SD improved for larger changes in reliability. The November 2004 US and Interbull PTA were matched with US and Interbull PTA from May 2001 (US04, IB04, US01, and IB01, respectively) for 14,652 Holstein bulls. For bulls having only US daughters in IB01, correlations were similar for US01 and IB01 with US04, and IB01 with IB04. Corresponding regressions were all nearly 1.00. For bulls also having nonUS daughters in IB01, correlations with yield deviations calculated for later daughters (used as source of independent data) were higher (0.747 vs. 0.714) for IB01 than for US01. For bulls with added US daughters, correlation with US04 was also higher for IB01 than US01, showing that inclusion of foreign data improved predictive value of SCS evaluations.


Air-breathing adaptation in a marine Devonian lungfish.
Recent discoveries of tetrapod trackways in 395 Myr old tidal zone deposits of Poland (Niedźwiedzki et al. 2010 Nature 463, 43-48 (doi:10.1038/nature.08623)) indicate that vertebrates had already ventured out of the water and might already have developed some air-breathing capacity by the Middle Devonian. Air-breathing in lungfishes is not considered to be a shared specialization with tetrapods, but evolved independently. Air-breathing in lungfishes has been postulated as starting in Middle Devonian times (ca 385 Ma) in freshwater habitats, based on a set of skeletal characters involved in air-breathing in extant lungfishes. New discoveries described herein of the lungfish Rhinodipterus from marine limestones of Australia identifies the node in dipnoan phylogeny where air-breathing begins, and confirms that lungfishes living in marine habitats had also developed specializations to breathe air by the start of the Late Devonian (ca 375 Ma). While invasion of freshwater habitats from the marine realm was previously suggested to be the prime cause of aerial respiration developing in lungfishes, we believe that global decline in oxygen levels during the Middle Devonian combined with higher metabolic costs is a more likely driver of air-breathing ability, which developed in both marine and freshwater lungfishes and tetrapodomorph fishes such as Gogonasus.


Monte Carlo analysis of the terahertz difference frequency generation susceptibility in quantum cascade laser structures.
Based on self-consistent ensemble Monte Carlo simulations coupled to the optical field dynamics, we investigate the giant nonlinear susceptibility giving rise to terahertz difference frequency generation in quantum cascade laser structures. Specifically, the dependence on temperature, bias voltage and frequency is considered. It is shown that the optical nonlinearity is temperature insensitive and covers a broad spectral range, as required for widely tunable room temperature terahertz sources. The obtained results are consistent with available experimental data.


The economic burden of not meeting food recommendations in Canada: The cost of doing nothing.
Few studies have estimated the economic burden of chronic diseases (e.g., type 2 diabetes, cardiovascular diseases, cancers) attributable to unhealthy eating. In this study, we estimated the economic burden of chronic disease attributable to not meeting Canadian food recommendations. We first obtained chronic disease risk estimates for intakes of both protective (1. vegetables; 2. fruit; 3. whole grains; 4. milk; 5. nuts and seeds) and harmful (6. processed meat; 7. red meat; 8. sugar-sweetened beverages) foods from the Global Burden of Disease Study, and food intakes from the 2004 Canadian Community Health Survey 24-hour dietary recalls (n = 33,932 respondents). We then calculated population attributable fractions (PAFs) for all relevant food-chronic disease combinations by age and sex groups. These PAFs were then mathematically combined for each disease for each age and sex group. We then estimated attributable costs by multiplying these combined PAFs with estimated 2014 annual direct health care (hospital, drug, physician) and indirect (human capital approach) costs for each disease. We found that not meeting recommendations for the eight foods was responsible for CAD$13.8 billion/year (direct health care: CAD$5.1 billion, indirect: CAD$8.7 billion). Nuts and seeds and whole grains were the top cost contributors rather than vegetables and fruit. Our findings suggest that unhealthy eating constitutes a tremendous economic burden to Canada that is similar in magnitude to the burden of smoking and larger than that of physical inactivity which were estimated using similar approaches. A status quo in promotion of healthy eating will allow this burden to continue. Interventions to reduce the health and economic burden of unhealthy eating in Canada may be more effective if they are broad in focus and include promotion of nuts and seeds and whole grains along with vegetables and fruit rather than have a narrow focus such as primarily on vegetables and fruit.


Convergence of Campylobacter species: implications for bacterial evolution.
The nature of species boundaries in bacteria remains controversial. In particular, the mechanisms of bacterial speciation and maintenance in the face of frequent genetic exchange are poorly understood. Here, we report patterns of genetic exchange that show two closely related zoonotic pathogenic species, Campylobacter jejuni and Campylobacter coli, are converging as a consequence of recent changes in gene flow. Population expansion into a novel ecological niche generated by human activity is the most probable explanation for the increase in genetic exchange between these species. Bacterial speciation can therefore occur by mechanisms analogous to those seen in metazoans, where genetic diversification and incipient speciation caused by ecological factors have been reported in several genera.


Steroid-free immunosuppression since 1999: 129 pediatric renal transplants with sustained graft and patient benefits.
Despite early promising patient and graft outcomes with steroid-free (SF) immunosuppression in pediatric kidney transplant recipients, data on long-term safety and efficacy results are lacking. We present our single-center experience with 129 consecutive pediatric kidney transplant recipients on SF immunosuppression, with a mean follow-up of 5 years. Outcomes are compared against a matched cohort of 57 concurrent recipients treated with steroid-based (SB) immunosuppression. In the SF group, 87% of kidney recipients with functioning grafts remain corticosteroid-free. Actual intent-to-treat SF (ITT-SF) and still-on-protocol SF patient survivals are 96% and 96%, respectively, actual graft survivals for both groups are 93% and 96%, respectively and actual death-censored graft survivals for both groups are 97% and 99%, respectively. Unprecedented catch-up growth is observed in SF recipients below 12 years of age. Continued low rates of acute rejection, posttransplant diabetes mellitus (PTDM), hypertension and hyperlipidemia are seen in SF patients, with sustained benefits for graft function. In conclusion, extended enrollment and longer experience with SF immunosuppression for renal transplantation in low-risk children confirms protocol safety, continued benefits for growth and graft function, low acute rejection rates and reduced cardiovascular morbidity.


Diversity of effective treatments of panic attacks: what do they have in common?
By comparing efficacious psychological therapies of different kinds, inferences about common effective treatment mechanisms can be made. We selected six therapies for review on the basis of the diversity of their theoretical rationales and evidence for superior efficacy: psychoanalytic psychotherapy, hypercapnic breathing training, hypocapnic breathing training, reprocessing with and without eye-movement desensitization, muscle relaxation, and cognitive behavior therapy. The likely common element of all these therapies is that they reduce the immediate expectancy of a panic attack, disrupting the vicious circle of fearing fear. Modifying expectation is usually regarded as a placebo mechanism in psychotherapy, but may be a specific treatment mechanism for panic. The fact that this is seldom the rationale communicated to the patient creates a moral dilemma: Is it ethical for therapists to mislead patients to help them? Pragmatic justification of a successful practice is a way out of this dilemma. Therapies should be evaluated that deal with expectations directly by promoting positive thinking or by fostering non-expectancy.


Impact of Age and Sex on CD4+ Cell Count Trajectories following Treatment Initiation: An Analysis of the Tanzanian HIV Treatment Database.
New guidelines recommend that all HIV-infected individuals initiate antiretroviral treatment (ART) immediately following diagnosis. This study describes how immune reconstitution varies by gender and age to help identify poorly reconstituting subgroups and inform targeted testing initiatives. Longitudinal data from the outpatient monitoring system of the National AIDS Control Program in Tanzania. An asymptotic nonlinear mixed effects model was fit to post-treatment CD4+ cell count trajectories, allowing for fixed effects of age and sex, and an age by sex interaction. Across 220,544 clinic visits from 32,069 HIV-infected patients, age- and sex-specific average CD4+ cell count at ART initiation ranged from 83-136 cells/mm3, long term asymptotic CD4+ cell count ranged from 301-389 cells/mm3, and time to half of maximal CD4+ reconstitution ranged from 3.57-5.68 months. CD4+ cell count at ART initiation and asymptotic CD4+ cell count were 1.28 (95% CI: 1.18-1.40) and 1.25 (95% CI: 1.20-1.31) times higher, respectively, for females compared to males in the youngest age group (19-29 years). Older patients started treatment at higher CD4+ counts but experienced slower CD4+ recovery than younger adults. Treatment initiation at greater CD4+ cell counts was correlated with greater asymptotic CD4+ cell counts within all sex and age groups. Older adults should initiate care early in disease progression because total immune reconstitution potential and rate of reconstitution appears to decrease with age. Targeted HIV testing and care linkage remains crucial for patient populations who tend to initiate treatment at lower CD4+ cell counts, including males and younger adults.


Impact of electromagnetic fields on in vitro toxicity of silver and graphene nanoparticles.
The correlation between shape and concentration of silver nanoparticles (AgNPs), their cytotoxicity and formation of reactive oxygen species (ROS) in the presence of electromagnetic fields (EMFs) has been investigated. In addition, the bio-effects caused by the combination of EMFs and graphene nanoparticles (GrNPs) have been also assessed. The AgNPs of three shapes (triangular, spherical and colloidal) and GrNPs were added in high concentrations to the culture of human fibroblasts and exposed to EMF of three different frequencies: 900, 2400 and 7500 MHz. The results demonstrated the dependence of the EMF-induced cytotoxicity on the shape and concentration of AgNPs. The maximal cell killing effect was observed at 900 MHz frequency for NPs of all shapes and concentrations. The highest temperature elevation was observed for GrNPs solution irradiated by EMF of 900 MHz frequency. The exposure to EMF led to significant increase of ROS formation in triangular and colloidal AgNPs solutions. However, no impact of EMF on ROS production was detected for spherical AgNPs. GrNPs demonstrated ROS-protective activity that was dependent on their concentration. Our findings indicate the feasibility to control cytotoxicity of AgNPs by means of EMFs. The effect EMF on the biological activity of AgNPs and GrNPs is reported here for the first time.


Auditory event-related responses to diphthongs in different attention conditions.
The modulation of auditory event-related potentials (ERP) by attention generally results in larger amplitudes when stimuli are attended. We measured the P1-N1-P2 acoustic change complex elicited with synthetic overt (second formant, F2Δ=1000Hz) and subtle (F2Δ=100Hz) diphthongs, while subjects (i) attended to the auditory stimuli, (ii) ignored the auditory stimuli and watched a film, and (iii) diverted their attention to a visual discrimination task. Responses elicited by diphthongs where F2 values rose and fell were found to be different and this precluded their combined analysis. Multivariate analysis of ERP components from the rising F2 changes showed main effects of attention on P2 amplitude and latency, and N1-P2 amplitude. P2 amplitude decreased by 40% between the attend and ignore conditions, and by 60% between the attend and divert conditions. The effect of diphthong magnitude was significant for components from a broader temporal window which included P1 latency and N1 amplitude. N1 latency did not vary between attention conditions, a finding that may be related to stimulation with a continuous vowel. These data show that a discernible P1-N1-P2 response can be observed to subtle vowel quality transitions, even when the attention of a subject is diverted to an unrelated visual task.


Supplementation of ascorbic acid and alpha-tocopherol is useful to preventing bone loss linked to oxidative stress in elderly.
To determine the effect of ascorbic acid and alpha-tocopherol on oxidative stress and bone mineral density (BMD) in elderly people. A double-blind, controlled clinical assay was carried out in a sample of 90 elderly subjects divided into three age-paired random groups with 30 subjects in each group. Group Tx0 received placebo, group Tx1 received 500 mg of ascorbic acid and 400 IU of alpha-tocopherol, whereas group Tx2 received 1,000 mg of ascorbic acid and 400 IU of alpha-tocopherol, for a 12-month period. We measured thiobarbituric acid reactive substances (TBARS), total antioxidant status (TAS), superoxide dismutase (SOD), and glutation peroxidase (GPx); BMD was obtained on DXA of hip and spine before and after the 12-month treatment period with supplementation of vitamins C and E. We found a positive correlation between hip-BMD and SOD (r = 0.298, p < 0.05) and GPx (r = 0.214, p < 0.05). Also, a significantly lower decrease of LPO (p < 0.05) was observed as linked with hip bone loss in the Tx2 group than in the Tx0 group. Our findings suggest that that administration of 1,000 mg of ascorbic acid together with 400 IU of alpha-tocopherol could be useful in preventing or aiding in the treatment of age-related osteoporosis.


Disruption of kinesin II function using a dominant negative-acting transgene in Xenopus laevis rods results in photoreceptor degeneration.
Kinesin II is a motor protein that moves on microtubules and whose importance in ciliary and flagellar transport has been well documented. In the current study, the role of kinesin II in rod photoreceptors was examined by expressing a dominant negative-acting transgene that disrupts kinesin II function in Xenopus laevis rods of transgenic tadpoles. A previously characterized dominant negative-acting kinesin II transgene tagged with enhanced green fluorescent protein (EGFP) driven by the Xenopus rod opsin promoter was used to make Xenopus transgenic tadpoles to disrupt kinesin II function specifically in rod photoreceptors. Transgenic tadpole retinas were examined to ascertain transgene expression pattern and morphologic phenotype. Rod-to-cone ratios were determined in experimental and control retinas. Visualized by its EGFP tag, the kinesin II transgene was expressed in rods in a mosaic pattern in the retina. Subcellular localization of transgenic kinesin II was similar to that of endogenous kinesin II subunit photoreceptor expression-that is, it was localized to the connecting cilium, inner segment, and synapse. However, in kinesin II transgene-expressing animals, fluorescence was transient. Ocular fluorescence was lost 6 days after its first detection. The disappearance of fluorescence was due to degeneration of rods expressing the transgene. Retinas of 7- to 9-day old kinesin II transgenic tadpoles had significantly fewer rods than did control retinas. The observation that rod degeneration is produced by expression of a dominant negative-acting kinesin II transgene in Xenopus rods is consistent with previous studies in mice, suggesting that kinesin II function is required for photoreceptor survival.


A common-path interferometer for time-resolved and shot-noise-limited detection of single nanoparticles.
We give a detailed description of a novel method for timeresolved experiments on single non-luminescent nanoparticles. The method is based on the combination of pump-probe spectroscopy and a commonpath interferometer. In our interferometer, probe and reference arms are separated in time and polarization by a birefringent crystal. The interferometer, fully described by an analytical model, allows us to separately detect the real and imaginary contributions to the signal. We demonstrate the possibilities of the setup by time-resolved detection of single gold nanoparticles as small as 10 nm in diameter, and of acoustic oscillations of particles larger than 40 nm in diameter.


Complete Genome Sequencing of Leptospira interrogans Isolates from Malaysia Reveals Massive Genome Rearrangement but High Conservation of Virulence-Associated Genes.
The ability of Leptospirae to persist in environments and animal hosts but to cause clinically highly variable disease in humans has made leptospirosis the most common zoonotic disease. Considering the paucity of data on variation in complete genomes of human pathogenic Leptospirae, we have used a combination of Single Molecule Real-Time (SMRT) and Illumina sequencing to obtain complete genome sequences of six human clinical L. interrogans isolates from Malaysia. All six contained the larger (4.28-4.56 Mb) and smaller (0.34-0.395 Mb) chromosome typical of human pathogenic Leptospirae and 0-7 plasmids. Only 24% of the plasmid sequences could be matched to databases. We identified a chromosomal core genome of 3318 coding sequences and strain-specific accessory genomes of 49-179 coding sequences. These sequences enabled detailed genomic strain typing (Genome BLAST Distance Phylogeny, DNA-DNA hybridization, and multi locus sequence typing) and phylogenetic classification (whole-genome SNP genotyping). Even though there was some shared synteny and collinearity across the six genomes, there was evidence of major genome rearrangement, likely driven by horizontal gene transfer and homologous recombination. Mobile genetic elements were identified in all strains in highly varying numbers, including in the rfb locus, which defines serogroups and contributes to immune escape and pathogenesis. On the other hand, there was high conservation of virulence-associated genes including those relating to sialic acid, alginate, and lipid A biosynthesis. These findings suggest (i) that the antigenic variation, adaption to various host environments, and broad spectrum of virulence of L. interrogans are in part due to a high degree of genomic plasticity and (ii) that human pathogenic strains maintain a core set of genes required for virulence.


Local and regional spread of chikungunya fever in the Americas.
Chikungunya fever (CHIKV), a viral disease transmitted by mosquitoes, is currently affecting several areas in the Caribbean. The vector is found in the Americas from southern Florida to Brazil, and the Caribbean is a highly connected region in terms of population movements. There is therefore a significant risk for the epidemic to quickly expand to a wide area in the Americas. Here, we describe the spread of CHIKV in the first three areas to report cases and between areas in the region. Local transmission of CHIKV in the Caribbean is very effective, the mean number of cases generated by a human case ranging from two to four. There is a strong spatial signature in the regional epidemic, with the risk of transmission between areas estimated to be inversely proportional to the distance rather than driven by air transportation. So far, this simple distance-based model has successfully predicted observed patterns of spread. The spatial structure allows ranking areas according to their risk of invasion. This characterisation may help national and international agencies to optimise resource allocation for monitoring and control and encourage areas with elevated risks to act.


Baseline characteristics, analysis plan and report on feasibility for the Prevention Of Decline in Cognition After Stroke Trial (PODCAST).
A common complication after stroke is development of cognitive impairment and dementia. However, effective strategies for reducing the risk of developing these problems remain undefined. Potential strategies include intensive lowering of blood pressure (BP) and/or lipids. This paper summarises the baseline characteristics, statistical analysis plan and feasibility of a randomised control trial of blood pressure and lipid lowering in patients post-stroke with the primary objective of reducing cognitive impairment and dementia. The Prevention Of Decline in Cognition After Stroke Trial (PODCAST) was a multi-centre prospective randomised open-label blinded-endpoint controlled partial-factorial internal pilot trial running in secondary and primary care. Participants without dementia were enrolled 3-7 months post ischaemic stroke or spontaneous intracerebral haemorrhage, and randomised to intensive versus guideline BP lowering (target systolic BP <125 mmHg versus <140 mmHg); patients with ischaemic stroke were also randomised to intensive or guideline lipid lowering (target LDL cholesterol <1.4 mmol/L versus <3 mmol/L). The primary outcome was the Addenbrooke's Cognitive Examination-Revised; a key secondary outcome was to assess feasibility of performing a large trial of one or both interventions. Data are number (%) or mean (standard deviation). The trial was planned to last for 8 years with follow-up between 1 and 8 years. The plan for reporting the main results is included as Additional file 2. 83 patients (of a planned 600) were recruited from 19 UK sites between 7 October 2010 and 31 January 2014. Delays, due to difficulties in the provision of excess treatment costs and to complexity of follow-up, led to few centres taking part and a much lower recruitment rate than planned. Patient characteristics at baseline were: age 74 (SD 7) years, male 64 (77 %), index stroke ischaemic 77 (93 %), stroke onset to randomisation 4.5 [SD 1.3] months, Addenbrooke's Cognitive Examination-Revised 86 (of 100, SD 8), Montreal Cognitive Assessment 24 (of 30, SD 3), BP 147/82 (SD 19/11) mmHg, total cholesterol 4.0 (SD 0.8) mmol/L and LDL cholesterol 2.0 (SD 0.7) mmol/L, modified Rankin Scale 1.1 (SD 0.8). Limited recruitment suggests that a large trial is not feasible using the current protocol. The effects of the interventions on BP, lipids, and cognition will be reported in the main publication. ISRCTN85562386 registered on 23 September 2009.


The hypoxia-inducible factor-1 alpha is a negative factor for tumor therapy.
Tumor hypoxia negatively regulates cell growth and causes a more malignant phenotype by increasing the expression of genes encoding angiogenic, metabolic and metastatic factors. Of clinical importance, insufficient tumor oxygenation affects the efficiency of chemotherapy and radiotherapy by poorly understood mechanisms. The hypoxia-inducible factor (HIF)-1 is a master transcriptional activator of oxygen-regulated genes and HIF-1 is constitutively upregulated in several tumor types. HIF-1 might thus be implicated in tumor therapy resistance. We found that transformed mouse embryonic fibroblasts deficient for HIF-1alpha are more susceptible to the treatment with carboplatin, etoposide and ionizing radiation than wild-type cells. Increased cell death in HIF-1alpha-deficient cells was because of apoptosis and did not involve p53 induction. Tumor chemotherapy of experimental fibrosarcoma in immunocompromised mice with carboplatin and etoposide confirmed the enhanced susceptibility of HIF-1alpha-deficient cells. Agents that did not cause DNA double-strand breaks, such as DNA-synthesis inhibitors or a DNA single-strand break-causing agent equally impaired cell growth, independent of the HIF-1alpha genotype. Functional repair of a fragmented reporter gene was decreased in HIF-1alpha-deficient cells. Thus, hypoxia-independent basal HIF-1alpha expression in tumor cells, as known from untransformed embryonic stem cells, is sufficient to induce target gene expression, probably including DNA double-strand break repair enzymes.


Hepatic coagulopathy-intricacies and challenges; a cross-sectional descriptive study of 110 patients from a superspecialty institute in North India with review of literature.
Hemostatic defect in chronic liver disease (CLD) is complex involving opposing factors of primary hemostasis, coagulation, and fibrinolysis. The concept of causal relationship between abnormal tests and clinical bleeding is unclear. This study was undertaken to evaluate and correlate clinical bleeding and the commonly used laboratory tests for hemostasis in CLD patients including the subgroup of acute on chronic liver failure (ACLF) patients and test the reproducibility of international normalized ratio (INR) using different reagents. This was a cross-sectional descriptive study wherein clinical records and laboratory data from 110 patients (95 CLD, 15 ACLF) over a 6-month period were analysed. Variceal bleeding (33.3%) was the commonest followed by mucosal/skin bleeds (5.4%). Thrombocytopenia seen in 70.9% patients was mostly mild (48.2%) to moderate (14.5%). Prothrombin time (PT) prolongation was seen in 81.8% with significant variation in PT/INR using different reagents. Adverse outcome in the form of disseminated intravascular coagulation, septic shock or death was seen in 13.6% patients (eight ACLF and seven CLD). There was no correlation of bleeding with prolonged PT/INR, decreased platelet count and adverse clinical outcome. However, individually, there was significant but weak correlation between variceal bleeding and lower platelet count and superficial bleeding and prolonged PT. Correction of PT/INR post-fresh frozen plasma was significant but platelet count postplatelet concentrate transfusion was not. ACLF patients compared with CLD patients had greater PT prolongation and adverse outcome but no increase in bleeding. Routine tests, although globally deranged inadequately reflect haemostatic imbalance in CLD and poorly predict bleeding risk.


Primary care physicians' perceptions of diabetes treatment protocols.
Primary care physicians' perceptions of diabetes treatment protocols (DTPs) in the management of type 2 diabetes mellitus (T2DM) were examined at the individual and organizational levels. A 27-item electronic survey was administered to primary care physicians from an integrated multispecialty health care system in Texas. Information was collected on various aspects of DTPs, including attitudes toward these protocols, perceived barriers, and knowledge, as well as utilization of diabetes self-management programs. Besides quality of care, the primary care physicians surveyed generally had mixed feelings regarding DTPs' ability to contribute positively to other aspects of health care; in addition, only a small percentage were familiar with some currently available self-management programs. Given that implementation of DTPs depends on primary care physicians, we should address physicians' attitudes and perceptions toward DTPs so as to increase utilization of these helpful protocols.


Modality-specific nutrition support in ESRD: weighing the evidence.
Protein-calorie malnutrition affects a large fraction of patients with end-stage renal disease (ESRD) and contributes significantly to the high rates of mortality and morbidity observed in this population. Observational studies of specific interventions, including intradialytic parenteral nutrition (IDPN), suggest that aggressive nutrition support may be of some benefit to some patients with ESRD. Due in part to lack of data derived from prospective, randomized clinical trials, and to the large expense associated with these therapies, Medicare and other payers have strongly discouraged the prescription of IDPN and other intermittent, dialysis-specific methods of nutrition support, such as intraperitoneal nutrition (IPN). The "burden of proof" has been placed on the dialysis community. In response, we must continue to emphasize the importance of securing nutritional health for all patients on or anticipating renal replacement therapy. Intradialytic parenteral nutrition should be reserved for patients who are taking in sufficient calories yet are unable to tolerate oral or enteral protein-rich foods or formulas designed to meet daily protein requirements (> or = 1.5 g/kg in some patients). Intradialytic parenteral nutrition should not be prescribed in place of total parenteral nutrition (TPN) if the latter is truly needed. Creative methods of nutrition support, including the use of dietary supplements at dialysis (intradialytic oral or enteral nutrition), should be explored. Prospective clinical trials investigating the effects of nutrition support on survival, hospitalization rates, health-related quality of life, and functional status, are urgently needed.


Placental Vesicles Carry Active Endothelial Nitric Oxide Synthase and Their Activity is Reduced in Preeclampsia.
Preeclampsia, a multisystem hypertensive disorder of pregnancy, is associated with increased systemic vascular resistance. Placentae from patients with preeclampsia have reduced levels of endothelial nitric oxide synthase (eNOS) and, thus, less nitric oxide (NO). Syncytiotrophoblast extracellular vesicles (STBEV), comprising microvesicles (STBMV) and exosomes, carry signals from the syncytiotrophoblast to the mother. We hypothesized that STBEV-bound eNOS (STBEV-eNOS), capable of producing NO, are released into the maternal circulation. Dual-lobe ex vivo placental perfusion and differential centrifugation was used to isolate STBEV from preeclampsia (n=8) and normal pregnancies (NP; n=11). Plasma samples of gestational age-matched preeclampsia and NP (n=6) were used to isolate circulating STBMV. STBEV expressed placental alkaline phosphatase, confirming placental origin. STBEV coexpressed eNOS, but not inducible nitric oxide synthase, confirmed using Western blot, flow cytometry, and immunodepletion. STBEV-eNOS produced NO, which was significantly inhibited by N G-nitro-l-arginine methyl ester (eNOS inhibitor; P<0.05) but not by N-(3-(aminomethyl) bezyl) acetamidine) (inducible nitric oxide synthase inhibitor). STBEV-eNOS catalytic activity was confirmed by visualizing eNOS dimerization. STBEV-eNOS was more abundant in uterine vein compared with peripheral blood, indicating placental origin. STBEV isolated from preeclampsia-perfused placentae had lower levels of STBEV-eNOS (STBMV; P<0.05) and overall lower NO activity (STBMV, not significant; syncytiotrophoblast extracellular exosomes, P<0.05) compared with those from NP. Circulating plasma STBMV from preeclampsia women had lower STBEV-eNOS expression compared with that from NP women (P<0.01). This is the first observation of functional eNOS expressed on STBEV from NP and preeclampsia placentae, as well as in plasma. The lower STBEV-eNOS NO production seen in preeclampsia may contribute to the decreased NO bioavailability in this disease.


Race and region have independent and synergistic effects on dietary intakes in black and white women.
Few studies have examined the effects of race and region on dietary intakes and the evidence on racial and regional disparities among women is limited. We aimed to examine whether race and region were associated with nutrient intakes among black and white women living in the Stroke Belt, Stroke Buckle, and Other regions in the United States. We hypothesized that significant differences would be observed among population sub-groups and that the effects of race on dietary intakes would vary across regions. This study included dietary data from 12,105 women from the Reasons for Geographic and Racial Differences in Stroke study (United States). Dietary data were collected using the Block 98 food frequency questionnaire. Blacks consumed 1.05% lower energy from saturated fat (95% CI: -0.95, -1.16), and intakes were also lower in the Buckle (β = -0.20; 95% CI: -0.08, -0.32) and Belt (β = -0.35; 95% CI: -0.24, -0.46) compared to the Other regions. Within each region, sodium, potassium, and magnesium intakes were all lower among black women compared to white women (P <0.05 for all); intakes were significantly lower among blacks living in the Belt and Buckle compared to those in the Other regions. Significant interactions between race and region were detected for trans fat, calcium, and cholesterol (P <0.05 for all), where black women in the Other regions consumed the lowest dietary cholesterol and calcium while black women in the Belt consumed the lowest trans fat. Race and region were significantly associated with nutrient intakes in a large study of black and non-Hispanic white women in the United States. Intakes of trans fat, calcium, and cholesterol among black and white women differed across regions. Race and region thus interact to impact dietary intakes, and their effects may be mediated by such factors as the broader food environment and food availability as well as food customs and culture. Race, region, and their correlates should therefore be considered together when examining diet and disease associations and planning dietary advice for population sub-groups.


Pro-aromatic and anti-aromatic π-conjugated molecules: an irresistible wish to be diradicals.
Aromaticity is an important concept to understand the stability and physical properties of π-conjugated molecules. Recent studies on pro-aromatic and anti-aromatic molecules revealed their irresistible tendency to become diradicals in the ground state. Diradical character thus becomes another very important concept and it is fundamentally correlated to the physical (optical, electronic and magnetic) properties and chemical reactivity of most of the organic optoelectronic materials. Molecules with distinctive diradical character show unique properties which are very different from those of traditional closed-shell π-conjugated systems, and thus they have many potential applications in organic electronics, spintronics, non-linear optics and energy storage. This critical review first introduces the fundamental electronic structure of Kekulé diradicals within the concepts of anti-aromaticity and pro-aromaticity in the context of Hückel aromaticity and diradical character. Then recent research studies on various stable/persistent diradicaloids based on pro-aromatic and anti-aromatic compounds are summarized and discussed with regard to their synthetic chemistry, physical properties, structure-property relationships and potential material applications. A summary and personal perspective is given at the end.


OGP functionalized phenylalanine-based poly(ester urea) for enhancing osteoinductive potential of human mesenchymal stem cells.
Amino acid-based poly(ester urea)s (PEU) are high modulus, resorbable polymers with many potential uses, including the surgical repair of bone defects. In vitro and in vivo studies have previously shown that phenylalanine-based PEUs have nontoxic hydrolytic byproducts and tunable degradation times. Phenylalanine PEUs (poly(1-PHE-6)) have been further modified by tethering osteogenic growth peptide (OGP) to tyrosine-based monomer subunits. These OGP-tethered PEUs have been fabricated into porous scaffolds and cultured in vitro to examine their effect on differentiation of human mesenchymal stem cells (hMSCs) toward the osteogenic lineage. The influence of tethered OGP on the hMSC proliferation and differentiation profile was measured using immunohistochemistry, biochemistry, and quantitative real time polymerase chain reaction (qRT-PCR). In vitro data indicated an enhanced expression of BSP by 130-160% for hMSCs on OGP-tethered scaffolds compared to controls. By 4 weeks, there was a significant drop (60-85% decrease) in BSP expression on OGP-functionalized scaffolds, which is characteristic of osteogenic differentiation. ALP and OSC expression was significantly enhanced for OGP-functionalized scaffolds by week 4, with values reaching 145% and 300% greater, respectively, compared to nonfunctionalized controls. In vivo subcutaneous implantation of poly(1-PHE-6) scaffolds revealed significant tissue-scaffold integration, as well as the promotion of both osteogenesis and angiogenesis.


Diagnostic validity of self-reported measures of sleep bruxism using an ambulatory single-channel EMG device.
Self-reported measures have been widely used to indicate the presence of possible and probable sleep bruxism (SB) in both research and clinical situations. However, few studies have attempted to assess the diagnostic validity of this approach. The aim of this study was to estimate the diagnostic validity of self-reported measures of SB using an ambulatory single-channel electromyographic (EMG) device. A total of 115 participants were enrolled and examined by standardized Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) including two questions related to SB: self-reported SB and morning-jaw symptoms. An ambulatory single-channel EMG device (GrindCare3™, Medotech A/S) was used for measuring jaw-muscle EMG activity during sleep for seven consecutive nights. Cut-off values for different measures of EMG activity (average, maximum and minimum) and the coefficient of variation (CV) were selected to divide participants into two groups, with higher or lower EMG activity or CV values. The sensitivity and specificity for each question and combination of them were calculated. Self-reported SB had the highest sensitivity (compared with morning-jaw symptoms) for all measures of EMG activity and CV, although the values were low to modest (average: 76.0%, maximum: 76.9%, minimum: 77.3%, CV: 61.0%). The specificity was low for both the questions related to the different measures of EMG activity and CV (35.1-52.4%). This study indicated that the diagnostic validity of self-reported measures of SB was low to modest using an ambulatory EMG device assessment as a reference. Using only self-reported measures for the assessment of SB may not have a high validity, which should be taken into consideration in the clinical evaluation of patients.


The risk factors and impact on survival of feeding tube placement in nursing home residents with severe cognitive impairment.
The provision of artificial enteral nutrition to an aged person with severe cognitive impairment is a complex dilemma in the long-term care setting. To determine the risk factors and impact on survival of feeding tubes in nursing home residents with advanced cognitive impairment. We conducted a cohort study with 24-month follow-up using Minimum Data Set resident assessments on 1386 nursing home residents older than 65 years with recent progression to severe cognitive impairment in the state of Washington. Residents within this population who underwent feeding tube placement were identified. Clinical characteristics and survival for a period of 24 months were compared for residents who were and were not tube fed. Among the residents with recent progression to severe cognitive impairment, 9.7% underwent placement of a feeding tube. Factors independently associated with feeding tube placement included age younger than 87 years (odds ratio [OR], 1.85; 95% confidence interval [CI], 1.25-2.78), aspiration (OR, 5.46; 95% CI, 2.66-11.20), swallowing problems (OR, 3.00; 95% CI, 1.81-4.97), pressure ulcer (OR, 1.64; 95% CI, 1.23-2.95), stroke (OR, 2.12; 95% CI, 1.17-2.62), less baseline functional impairment (OR, 2.07; 95% CI, 1.27-3.36), no do-not-resuscitate order (OR, 3.03; 95% CI, 1.92-4.85), and no dementia (OR, 2.17; 95% CI, 1.43-3.22). Survival did not differ between groups of residents with and without feeding tubes even after adjusting for independent risk factors for feeding tube placement. There are specific risk factors associated with feeding tube placement in nursing home residents with severe cognitive impairment. However, there is no survival benefit compared with similar residents who are not tube fed. These prognostic data are important for health care providers, families, and patients making decisions regarding enteral nutritional support in long-term care.


The role of personal characteristics in the relationship between health and psychological distress among kidney transplant recipients.
Although kidney transplantation improves overall quality of life and physical functioning, improvements of psychological distress are often modest. However, apparent stressors such as comorbidity are only weakly associated with psychological distress and their impact differs considerably between patients. Wilson and Cleary proposed a theoretical model to explain these relationships. This model has been supported by research, but has never been applied in a population of kidney transplant recipients. Findings of the current study are based on a cross-sectional study carried out in 2008 in the northern Netherlands. An elaborated version of Wilson and Cleary's model specifying hypothesized relationships of objective health, functional status, subjective health, personal characteristics and psychological distress was evaluated with structural equation modelling. After elimination of non-significant paths the final model provided a good fit for the data, X(2) (2)=4.23, p=0.12; RMSEA=0.047, CI(RMSEA) (0; 0.11); ECVI=0.060, ECVI(sat)=0.059. Results suggest that objective health has an indirect effect on psychological distress, in size comparable to the effects exerted by functional status and subjective health. Personal characteristics are the strongest determinant of psychological distress, but are directly and indirectly affected by objective health. Results indicate that poor health might cause psychological distress by increasing coping demands while simultaneously decreasing coping resources.


Asymmetric cycloaddition reactions catalysed by diarylprolinol silyl ethers.
Cycloaddition reactions are among the most important tools for the construction of cyclic compounds in organic synthesis, since these reactions are vital to access natural products and biologically active compounds. Organocatalysis plays an increasingly pivotal role in these reactions, often allowing several stereocenters to be selectively created and integrated in the target molecule. Among the large number of efficient types of organocatalysts available, the diarylprolinol silyl ethers have been established as one of the most frequently used in aminocatalysis allowing for novel activation modes and reaction concepts. In this review, we will focus on the different activation modes made available by the diarylprolinol silyl ether system with the aim of highlighting their applicability in asymmetric cycloadditions for the assembly of complex molecular architectures.


Using long-read sequencing to detect imprinted DNA methylation.
Systematic variation in the methylation of cytosines at CpG sites plays a critical role in early development of humans and other mammals. Of particular interest are regions of differential methylation between parental alleles, as these often dictate monoallelic gene expression, resulting in parent of origin specific control of the embryonic transcriptome and subsequent development, in a phenomenon known as genomic imprinting. Using long-read nanopore sequencing we show that, with an average genomic coverage of ∼10, it is possible to determine both the level of methylation of CpG sites and the haplotype from which each read arises. The long-read property is exploited to characterize, using novel methods, both methylation and haplotype for reads that have reduced basecalling precision compared to Sanger sequencing. We validate the analysis both through comparison of nanopore-derived methylation patterns with those from Reduced Representation Bisulfite Sequencing data and through comparison with previously reported data. Our analysis successfully identifies known imprinting control regions (ICRs) as well as some novel differentially methylated regions which, due to their proximity to hitherto unknown monoallelically expressed genes, may represent new ICRs.


The self-reported learning style preferences of female Macmillan clinical nurse specialists.
Individuals typically adopt and prefer one or two learning styles and therefore, by default, remaining learning styles are underutilised. Insight into learning style preferences confers interpersonal benefits to both learners and teachers. Enlightened learners and teachers can identify their dominant learning styles and potentially strengthen underutilised ones. Findings from a retrospective study commissioned by Macmillan Cancer Relief that investigated learning style preferences of 137 female Macmillan Clinical Nurse Specialists (CNSs) showed that the majority (73.7%) displayed a strong-very strong preference for one or two learning styles. Mean scores across four learning styles were highest for the reflector learning style (mu=14.85+/-3.16) followed by theorist (mu=12.2+/-2.87), pragmatist (mu=11.5 (2.85) and activist (mu=7.95+/-3.11). An understanding of individual learning style preferences, particularly the strengthening of those that are underutilised is said to cultivate both flexible and resourceful learners and effective teachers. Such characteristics would confer considerable benefits within the remit of a Macmillan CNS position.


Daily sedation interruption in mechanically ventilated critically ill patients cared for with a sedation protocol: a randomized controlled trial.
Protocolized sedation and daily sedation interruption are 2 strategies to minimize sedation and reduce the duration of mechanical ventilation and intensive care unit (ICU) stay. We hypothesized that combining these strategies would augment the benefits. To compare protocolized sedation with protocolized sedation plus daily sedation interruption in critically ill patients. Randomized controlled trial of 430 critically ill, mechanically ventilated adults conducted in 16 tertiary care medical and surgical ICUs in Canada and the United States between January 2008 and July 2011. Continuous opioid and/or benzodiazepine infusions and random allocation to protocolized sedation (n = 209) (control) or to protocolized sedation plus daily sedation interruption (n = 214). Using validated scales, nurses titrated infusions to achieve light sedation. For patients receiving daily interruption, nurses resumed infusions, if indicated, at half of previous doses. Patients were assessed for delirium and for readiness for unassisted breathing. Time to successful extubation. Secondary outcomes included duration of stay, doses of sedatives and opioids, unintentional device removal, delirium, and nurse and respiratory therapist clinical workload (on a 10-point visual analog scale [VAS]). Median time to successful extubation was 7 days in both the interruption and control groups (median [IQR], 7 [4-13] vs 7 [3-12]; interruption group hazard ratio, 1.08; 95% CI, 0.86-1.35; P = .52). Duration of ICU stay (median [IQR], 10 [5-17] days vs 10 [6-20] days; P = .36) and hospital stay (median [IQR], 20 [10-36] days vs 20 [10-48] days; P = .42) did not differ between the daily interruption and control groups, respectively. Daily interruption was associated with higher mean daily doses of midazolam (102 mg/d vs 82 mg/d; P = .04) and fentanyl (median [IQR], 550 [50-1850] vs 260 [0-1400]; P < .001) and more daily boluses of benzodiazepines (mean, 0.253 vs 0.177; P = .007) and opiates (mean, 2.18 vs 1.79; P < .001). Unintentional endotracheal tube removal occurred in 10 of 214 (4.7%) vs 12 of 207 patients (5.8%) in the interruption and control groups, respectively (relative risk, 0.82; 95% CI, 0.36-1.84; P = .64). Rates of delirium were not significantly different between groups (53.3% vs 54.1%; relative risk, 0.98; 95% CI, 0.82-1.17; P = .83). Nurse workload was greater in the interruption group (VAS score, 4.22 vs 3.80; mean difference, 0.41; 95% CI, 0.17-0.66; P = .001). For mechanically ventilated adults managed with protocolized sedation, the addition of daily sedation interruption did not reduce the duration of mechanical ventilation or ICU stay. clinicaltrials.gov Identifier: NCT00675363.


Seismic images of the far side of the Sun
Images of an active region on the far side of the sun were derived by applying seismic holography to recent helioseismic observations from space. Active regions are the centers of energetic phenomena such as solar flares and coronal mass ejections, whose resulting electromagnetic and particle radiation interfere with telecommunications and power transmissions on Earth and can pose significant hazards to astronauts and spacecraft. Synoptic seismic imaging of far-side solar activity will now allow anticipation of the appearance of large active regions more than a week ahead of their arrival on the east solar limb.


Variation of LPS-binding capacity, epitope expression, and shedding of membrane-bound CD14 during differentiation of human monocytes.
The myeloid differentiation Ag CD14 is considered to play a critical role in the binding of LPS to monocytes. To determine if differences in LPS-binding capacities of cells could reflect a variability of CD14 molecules, we analyzed the interactions of various reagents with these molecules in human blood monocytes and in promyelocytic (HL60) and monocytic (THP-1) cell lines. The expression of CD14 epitopes was analyzed with the fluorescent anti-CD14 mAbs My4 and LeuM3. Expression of LPS-binding sites (LPS+ molecules) was detected with LPS-FITC. THP-1 cells stimulated with calcitriol (VitD3), as well as the majority of blood monocytes (50-90%) were My4+/LPS+. However, untreated THP-1 cells, and a substantial population (10-50%) of human monocytes from healthy donors, were My4+/LPS-, thus suggesting the existence of CD14 isoforms with different LPS-binding capacities. In line with this assumption, monocytes stimulated with PMA selectively shed LeuM3+ molecules, but almost no My4+ and LPS+ constituents. Analysis of monocytes after treatment with phosphatidylinositol-specific phospholipase C indicated that among CD14 molecules with LPS-binding capacity, some are susceptible and others are resistant to the enzyme, each type being mainly expressed by a different monocyte subset. Studies of uninduced and chemically induced THP-1 cells showed that wheat-germ agglutinin blocked the binding of My4 to constitutive, but not to chemically inducible CD14. The overall results suggest the existence of at least three different forms of CD14, which may reflect different stages of cell maturation.


Global in vivo terminal amino acid labeling for exploring differential expressed proteins induced by dialyzed serum cultivation.
Taking advantage of reliable metabolic labeling and accurate isobaric MS2 quantification, we developed a global in vivo terminal amino acid labeling (G-IVTAL) strategy by combining metabolic labeling and isotopic dimethyl labeling for quantifying tryptic peptides. With G-IVTAL, the scale of qualitative and quantitative data can be increased twofold compared with in vivo termini amino acid labeling (IVTAL) in which Lys-N and Arg-C are used for digestion. As a result, up to 81.78% of the identified proteins have been confidently quantified in G-IVTAL-labeled HepG2 cells. Dialyzed serum has been used in most SILAC studies to ensure complete labeling. However, dialysis requires the removal of low molecular weight hormones, cytokines, and cellular growth factors, which are essential for the cell growth of certain cell lines. To address the influence of dialyzed serum in HepG2 growth, the G-IVTAL strategy was applied to quantify the expression differences between dialyzed serum- and normal serum-cultured HepG2 cells. Finally, we discovered 111 differentially expressed proteins, which could be used as references to improve the reliability of the SILAC quantification. Among these, by using western blotting, the differential expressions of MTDH, BCAP31, and GPC3 were confirmed as being influenced by dialyzed serum. The experimental results demonstrate that the G-IVTAL strategy is a powerful tool to achieve accurate and reliable protein quantification.


Pollination biology of fruit-bearing hedgerow plants and the role of flower-visiting insects in fruit-set.
In the UK, the flowers of fruit-bearing hedgerow plants provide a succession of pollen and nectar for flower-visiting insects for much of the year. The fruits of hedgerow plants are a source of winter food for frugivorous birds on farmland. It is unclear whether recent declines in pollinator populations are likely to threaten fruit-set and hence food supply for birds. The present study investigates the pollination biology of five common hedgerow plants: blackthorn (Prunus spinosa), hawthorn (Crataegus monogyna), dog rose (Rosa canina), bramble (Rubus fruticosus) and ivy (Hedera helix). The requirement for insect pollination was investigated initially by excluding insects from flowers by using mesh bags and comparing immature and mature fruit-set with those of open-pollinated flowers. Those plants that showed a requirement for insect pollination were then tested to compare fruit-set under two additional pollination service scenarios: (1) reduced pollination, with insects excluded from flowers bagged for part of the flowering period, and (2) supplemental pollination, with flowers hand cross-pollinated to test for pollen limitation. The proportions of flowers setting fruit in blackthorn, hawthorn and ivy were significantly reduced when insects were excluded from flowers by using mesh bags, whereas fruit-set in bramble and dog rose were unaffected. Restricting the exposure of flowers to pollinators had no significant effect on fruit-set. However, blackthorn and hawthorn were found to be pollen-limited, suggesting that the pollination service was inadequate in the study area. Ensuring strong populations of insect pollinators may be essential to guarantee a winter fruit supply for birds in UK hedgerows.


Biodiversity policy beyond economic growth.
Increasing evidence-synthesized in this paper-shows that economic growth contributes to biodiversity loss via greater resource consumption and higher emissions. Nonetheless, a review of international biodiversity and sustainability policies shows that the majority advocate economic growth. Since improvements in resource use efficiency have so far not allowed for absolute global reductions in resource use and pollution, we question the support for economic growth in these policies, where inadequate attention is paid to the question of how growth can be decoupled from biodiversity loss. Drawing on the literature about alternatives to economic growth, we explore this contradiction and suggest ways forward to halt global biodiversity decline. These include policy proposals to move beyond the growth paradigm while enhancing overall prosperity, which can be implemented by combining top-down and bottom-up governance across scales. Finally, we call the attention of researchers and policy makers to two immediate steps: acknowledge the conflict between economic growth and biodiversity conservation in future policies; and explore socioeconomic trajectories beyond economic growth in the next generation of biodiversity scenarios.


Assessing physical activity in persons with knee osteoarthritis using accelerometers: data from the osteoarthritis initiative.
Physical activity measured by accelerometers requires basic assumptions to translate the output into meaningful measures. We used accelerometer data from the Osteoarthritis Initiative to investigate in the context of knee osteoarthritis (OA) the following data processing assumptions derived from the general US adult population: nonwear (a period the monitor was removed), based on zero activity exceeding 60 minutes; and a valid day of monitoring, based on wear time evidence exceeding 10 hours. We examined the influence of nonwear thresholds ranging from 20 to 300 minutes of zero activity on mean daily activity minutes (counts>0), mean daily activity counts, and mean daily moderate to vigorous physical activity minutes. The effect of selecting minimums of 8, 10, or 12 wear hours to signify a valid day of monitoring on data retention was examined. Our sample of 3,536 days of accelerometer data from 519 persons with knee OA showed that mean daily activity minutes increased with the nonwear threshold until stabilizing at 463 minutes per day, corresponding to the 90-minute nonwear threshold. Similar patterns were observed for mean daily activity counts. Varying the nonwear threshold had no effect on mean daily moderate to vigorous physical activity minutes. Choosing the 90-minute nonwear threshold and a minimum of 10 wear hours to constitute a valid day provided 94% data retention. Data supported applying the 90-minute nonwear threshold to the knee OA population instead of the 60-minute threshold for the general population, while retaining the 10-hour valid day threshold.


Function of quaking in myelination: regulation of alternative splicing.
Proteomic diversity is frequently achieved by alternative RNA-splicing events that can be fine-tuned in tissue-specific and developmentally regulated ways. Understanding this type of genetic regulation is compelling because of the extensive complexity of alternative splicing found in the nervous system. quaking (qk), one of the classical mouse dysmyelination mutants, is defective for the expression of myelin-associated glycoprotein (MAG), and the misregulation of MAG pre-mRNA alternative splicing is implicated as a causal factor. The qk locus encodes several RNA-binding proteins with heterogeneous nuclear ribonucleoprotein K-type homology, a characteristic of several known alternative splicing regulators. Here we test the nuclear-localized qk isoform (QKI-5) for its ability to regulate alternative splicing of MAG pre-mRNA in transient coexpression assays. QKI-5 exhibits properties of a negative regulator of MAG exon 12 alternative splicing. An intronic sequence element required for the repressive function and binding of QKI-5 is also identified. Direct evidence for irregularities in alternative splicing of MAG and other myelin protein transcripts in the qk mouse is demonstrated.


How does perceived risk mediate associations between perceived safety and parental restriction of adolescents' physical activity in their neighborhood?
There is evidence that adolescence is a critical period of decline in physical activity. However, adolescents may have limited opportunities to be physically active outdoors if their parents are concerned about neighborhood safety and restrict their adolescent's physical activity within their neighborhood. Pathways that lead to parental restriction of adolescents' physical activity (constrained behavior) are under-researched. This study aimed to examine perceived risk as a potential mediator of associations between perceived safety/victimization and constrained behavior. Cross-sectional study of adolescents (43% boys) aged 15-17 years (n = 270) in Melbourne, Australia. Parents reported perceived safety (road safety, incivilities and personal safety) and prior victimization in their neighborhood, perceived risk of their children being harmed and whether they constrained their adolescent's physical activity. Constrained behavior was categorized as 'avoidance' or 'defensive' behavior depending on a whether physical activity was avoided or modified, respectively, due to perceived risk. MacKinnon's product-of-coefficients test of mediation was used to assess potential mediating pathways between perceived safety/victimization and constrained behavior. For girls only, perceived risk was a significant mediator of associations between perceived road safety and avoidance/defensive behavior, and between perceived incivilities, perceived personal safety, victimization and defensive behavior. Associations between perceived safety/victimization and constrained behavior are complex. Findings may guide the design of interventions that aim to improve actual and perceived levels of safety and reduce perceptions of risk. This is of particular importance for adolescent girls among whom low and declining levels of physical activity have been observed worldwide.


The impact of longer-than-average anesthesia times on the billing of academic anesthesiology departments.
Academic anesthesiology departments provide clinical services for surgical procedures that have longer-than-average surgical times and correspondingly increased anesthesia times. We examined the financial impact of these longer times in three ways: 1) the estimated loss in revenue if billing were done on a flat-fee system by using industry-averaged anesthesia times; 2) the estimation of incremental operating room (OR) sites necessitated by longer anesthesia times; and 3) the estimated potential gain in billed units if the hours of productivity of current anesthesia time were applied to surgical cases of average duration. Health Care Financing Administration average times per anesthesia procedure code were used as industry averages. Billing data were collected from four academic anesthesiology departments for 1 yr. Each claim billed with ASA units was included except for obstetric anesthesia care. All clinical sites that do not bill with ASA units were excluded. Base units were determined for each anesthesia procedure code. The mean commercial conversion factor (US$45 per ASA unit) for reimbursement was used to estimate the impact in dollar amounts. In all four groups, anesthesia times exceeded the Health Care Financing Administration average. The loss per group in billed ASA units if a flat-fee billing system were used ranged from 18,194 to 31,079 units per group, representing a 5% to 15% decrease (estimated billing decrease of US$818,719 to US$1,398,536 per group). The number of excess OR sites necessitated by longer surgical and anesthesia times ranged from 1.95 to 4.57 OR sites per group. The potential gain in billed units if the hours of productivity of current anesthesia time were applied to surgical cases of average duration was estimated to be from 13,273 to 21,368 ASA units. Longer-than-average anesthesia and surgical times result in extra hours or additional OR sites to be staffed and loss of potential reimbursement for the four academic anesthesiology departments. A flat-fee system would adversely affect academic anesthesiology departments. We examined the economic impact of longer-than-average anesthesia times on four academic anesthesiology departments in three ways: the estimated loss in revenue under a flat-fee system, the excess operating room sites staffed, and the potential gain in revenue if the surgeries were of average length. These results should be considered both in productivity measurements and strategies for operating room management.


New developments in multiplier phototubes for space research.
Recent developments in ruggedized high-performance multiplier phototubes are described for the uv and visible. The spectral radiant responses of photocathodes with peak quantum efficiencies up to 30% and higher are detailed over the applicable spectral regions. Photoemissive surfaces with two types of spectral responses are included: (a) spectrally selective cathodes of the extreme solar-blind type for the far uv, and (b) cathodes with broad-band sensitivity over wide spectral ranges. The characteristics of dark current (dc and pulse counting), current amplification, equivalent noise input, and environmental conditions are reviewed for the various new tube types covered.


Coherent control of Snell's law at metasurfaces.
It was recently demonstrated that the well-known Snell's law must be corrected for phase gradient metasurfaces to account for their spatially varying phase, leading to normal and anomalous transmission and reflection of light on such metasurfaces. Here we show that the efficiency of normal and anomalous transmission and reflection of light can be controlled by the intensity or phase of a second coherent wave. The phenomenon is illustrated using gradient metasurfaces based on V-shaped and rectangular apertures in a metal film. This coherent control effect can be exploited for wave front shaping and signal routing.


Anatomy and ultrastructure of embryonic leaves of the C4 species Setaria viridis.
Setaria viridis is being promoted as a model C4 photosynthetic plant because it has a small genome (~515 Mb), a short life cycle (~60 d) and it can be transformed. Unlike other C4 grasses such as maize, however, there is very little information about how C4 leaf anatomy (Kranz anatomy) develops in S. viridis. As a foundation for future developmental genetic studies, we provide an anatomical and ultrastructural framework of early shoot development in S. viridis, focusing on the initiation of Kranz anatomy in seed leaves. Setaria viridis seeds were germinated and divided into five stages covering development from the dry seed (stage S0) to 36 h after germination (stage S4). Material at each of these stages was examined using conventional light, scanning and transmission electron microscopy. Dry seeds contained three embryonic leaf primordia at different developmental stages (plastochron 1-3 primordia). The oldest (P3) leaf primordium possessed several procambial centres whereas P2 displayed only ground meristem. At the tip of P3 primordia at stage S4, C4 leaf anatomy typical of the malate dehydrogenase-dependent nicotinamide dinucleotide phosphate (NADP-ME) subtype was evident in that vascular bundles lacked a mestome layer and were surrounded by a single layer of bundle sheath cells that contained large, centrifugally located chloroplasts. Two to three mesophyll cells separated adjacent vascular bundles and one mesophyll cell layer on each of the abaxial and adaxial sides delimited vascular bundles from the epidermis. The morphological trajectory reported here provides a foundation for studies of gene regulation during early leaf development in S. viridis and a framework for comparative analyses with other C4 grasses.


Tracking emotions in the brain - Revisiting the Empathic Accuracy Task.
Many empathy tasks lack ecological validity due to their use of simplistic stimuli and static analytical approaches. Empathic accuracy tasks overcome these limitations by using autobiographical emotional video clips. Usually, a single measure of empathic accuracy is computed by correlating the participants' continuous ratings of the narrator's emotional state with the narrator's own ratings. In this study, we validated a modified empathic accuracy task. A valence-independent rating of the narrator's emotional intensity was added to provide comparability between videos portraying different primary emotions and to explore changes in neural activity related to variations in emotional intensity over time. We also added a new neutral control condition to investigate general emotional processing. In the scanner, 34 healthy participants watched 6 video clips of people talking about an autobiographical event (2 sad, 2 happy and 2 neutral clips) while continuously rating the narrator's emotional intensity. Fluctuation in perceived emotional intensity correlated with activity in brain regions previously implicated in cognitive empathy (bilateral superior temporal sulcus, temporoparietal junction, and temporal pole) and affective empathy (right anterior insula and inferior frontal gyrus). When emotional video clips were compared to neutral video clips, we observed higher activity in similar brain regions. Empathic accuracy, on the other hand, was only positively related to activation in regions that have been implicated in cognitive empathy. Our modified empathic accuracy task provides a new method for studying the underlying components and dynamic processes involved in empathy. While the task elicited both cognitive and affective empathy, successful tracking of others' emotions relied predominantly on the cognitive components of empathy. The fMRI data analysis techniques developed here may prove valuable in characterising the neural basis of empathic difficulties observed across a range of psychiatric conditions.


Genome Sequence of Mariprofundus sp. Strain EBB-1, a Novel Marine Autotroph Isolated from an Iron-Sulfur Mineral.
Mariprofundus sp. strain EBB-1 was isolated from a pyrrhotite biofilm incubated in seawater from East Boothbay (ME, USA). Strain EBB-1 is an autotrophic member of the class Zetaproteobacteria with the ability to form iron oxide biominerals. Here, we present the 2.88-Mb genome sequence of EBB-1, which contains 2,656 putative protein-coding sequences.


Oncofertility resources at NCI-designated comprehensive cancer centers.
NCI-designated comprehensive cancer centers (CCCs) set the standard for providing exemplary patient care. Quality cancer care includes discussions about fertility and referrals to fertility specialists for patients at risk for sterility. This study sought to determine what fertility preservation (FP) resources are available in CCCs and how well those are integrated into patient care. Leaders at each CCC received a letter requesting a short telephone interview with individuals who could provide information about the institution's FP resources. A semi-structured interview guide was used and responses were audio-recorded. Data were analyzed using content and thematic analysis. Interviews were conducted with 30 of the 39 CCCs that see adult patients (77%). The remaining institutions included 4 nonresponders, 3 that referred the interviewers to childhood cancer survivorship clinics, 1 that refused, and 1 that could not identify any FP resources. Participants were primarily affiliated with reproductive endocrinology (n=15) or hematology/oncology divisions (n=10). Institutional policies regarding consistent provision of FP information were rare (n=4), although most sites (n=20) either had some services on-site or had referral programs (n=8). However, only 13 had some experimental services, such as ovarian tissue cryopreservation. Respondents reported barriers to provision of FP, including oncologists' identification of patients at risk, low referral rates, and perceptions of patient prognosis. Only 8 (27%) sites had staff with time dedicated to FP. CCCs vary widely in implementing FP-recommended practice to their patients. CCCs are positioned to provide exemplary oncofertility care, but most need to better integrate FP information and referral into practice.


Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/06).
Chemotherapy plus bevacizumab is a standard option for first-line treatment in metastatic colorectal cancer (mCRC) patients. We assessed whether no continuation is non-inferior to continuation of bevacizumab after completing first-line chemotherapy. In an open-label, phase III multicentre trial, patients with mCRC without disease progression after 4-6 months of standard first-line chemotherapy plus bevacizumab were randomly assigned to continuing bevacizumab at a standard dose or no treatment. CT scans were done every 6 weeks until disease progression. The primary end point was time to progression (TTP). A non-inferiority limit for hazard ratio (HR) of 0.727 was chosen to detect a difference in TTP of 6 weeks or less, with a one-sided significance level of 10% and a statistical power of 85%. The intention-to-treat population comprised 262 patients: median follow-up was 36.7 months. The median TTP was 4.1 [95% confidence interval (CI) 3.1-5.4] months for bevacizumab continuation versus 2.9 (95% CI 2.8-3.8) months for no continuation; HR 0.74 (95% CI 0.58-0.96). Non-inferiority could not be demonstrated. The median overall survival was 25.4 months for bevacizumab continuation versus 23.8 months (HR 0.83; 95% CI 0.63-1.1; P = 0.2) for no continuation. Severe adverse events were uncommon in the bevacizumab continuation arm. Costs for bevacizumab continuation were estimated to be ∼30,000 USD per patient. Non-inferiority could not be demonstrated for treatment holidays versus continuing bevacizumab monotheray, after 4-6 months of standard first-line chemotherapy plus bevacizumab. Based on no impact on overall survival and increased treatment costs, bevacizumab as a single agent is of no meaningful therapeutic value. More efficient treatment approaches are needed to maintain control of stabilized disease following induction therapy. ClinicalTrials.gov, number NCT00544700.


Laparoscopic adrenalectomy: troublesome cases.
Among 143 cases of laparoscopic adrenalectomy carried out from 1993 to the present, 13 patients in whom the surgical manipulation presented problems were examined. Problems occurred due to the condition of the adrenal tumors themselves in six patients, whereas problems occurred due to the operative history in four patients. There were three patients with no operative history but with strong intraperitoneal adhesion. In patients with a history of laparotomy in other fields such as open cholecystectomy, gastrectomy or colostomy, operations were possible in most patients by examining the trocar site preoperatively. Patients with strong adhesion even without a history of surgery could be handled by full separation of the adhesion during surgery. In patients with bleeding in the adrenal tumors, large adrenal tumors, or tumors impacted in the liver, methods such as changing the sequence of separation procedures were required. In patients with a history of renal subcapsular hematomas due to extracorporeal shock wave lithotripsy (ESWL), it was not possible to understand the conditions of adrenal or perinephritic adhesion in preoperative imaging diagnosis, but resection was possible by changing the order of separation procedures and by using optimal instruments and devices. As with any surgery, including open surgeries, it is necessary to obtain knowledge on how to deal with variations in laparoscopic adrenalectomy to assure safe outcomes and to always consider effective methods for coping with unexpected difficulties.


Vitamin D and periodontal health in older men.
Vitamin D, an anti-inflammatory mediator, has potential benefits for physical and oral health. Although it is produced endogenously, some individuals have a greater need for dietary and supplemental sources. This repeated-measures cross-sectional study assessed associations between total vitamin D intake and periodontal health in older men. Participants were 562 members of the Department of Veterans Affairs Dental Longitudinal Study, mean age 62.9 years, who were examined 1 to 4 times between 1986 and 1998. A calibrated examiner measured probing pocket depth (PPD) and attachment loss (AL) on each tooth. Alveolar bone loss (ABL) was determined from radiographs. Severe periodontal disease was defined as PPD ≥ 5 mm on ≥ 1 tooth and AL ≥ 6 mm at ≥ 2 sites (not on same tooth), and moderate-to-severe alveolar bone loss as ABL ≥ 40% at ≥ 3 sites. Generalized estimating equations were used to compute the odds ratios (OR) and 95% confidence intervals (95% CI) of having periodontal disease by level of vitamin D intake. Total vitamin D intake ≥ 800 IU was associated with lower odds of severe periodontal disease (OR = 0.67, 95% CI = 0.55-0.81) and moderate-to-severe ABL (OR = 0.54, 95% CI = 0.30-0.96) relative to intake < 400 IU/day. Vitamin D intake may protect against periodontal disease progression.


A census of baryons in the Universe from localized fast radio bursts.
More than three-quarters of the baryonic content of the Universe resides in a highly diffuse state that is difficult to detect, with only a small fraction directly observed in galaxies and galaxy clusters1,2. Censuses of the nearby Universe have used absorption line spectroscopy3,4 to observe the 'invisible' baryons, but these measurements rely on large and uncertain corrections and are insensitive to most of the Universe's volume and probably most of its mass. In particular, quasar spectroscopy is sensitive either to the very small amounts of hydrogen that exist in the atomic state, or to highly ionized and enriched gas4-6 in denser regions near galaxies7. Other techniques to observe these invisible baryons also have limitations; Sunyaev-Zel'dovich analyses8,9 can provide evidence from gas within filamentary structures, and studies of X-ray emission are most sensitive to gas near galaxy clusters9,10. Here we report a measurement of the baryon content of the Universe using the dispersion of a sample of localized fast radio bursts; this technique determines the electron column density along each line of sight and accounts for every ionized baryon11-13. We augment the sample of reported arcsecond-localized14-18 fast radio bursts with four new localizations in host galaxies that have measured redshifts of 0.291, 0.118, 0.378 and 0.522. This completes a sample sufficiently large to account for dispersion variations along the lines of sight and in the host-galaxy environments11, and we derive a cosmic baryon density of [Formula: see text] (95 per cent confidence; h70 = H0/(70 km s-1 Mpc-1) and H0 is Hubble's constant). This independent measurement is consistent with values derived from the cosmic microwave background and from Big Bang nucleosynthesis19,20.


The importance of configurational disorder in crystal structure prediction: the case of loratadine.
Loratadine, an over-the-counter antihistamine medication, has two known monotropically related polymorphs, both of which feature disorder. A combined experimental and computational approach using variable temperature single crystal X-ray diffraction (VT-SCXRD) analysis and dispersion corrected density functional theory (DFT-D) reveals that the nature of the disorder in each form is markedly different and cannot be described by a simple isolated-site model with thermally populated conformations in either of the two cases. In Form I, the ethyl carbamate functionality adopts two different configurations, with adjacent moieties interacting along one-dimensional chains. The most stable arrangement features alternating configurations, but because of the low energetic cost of stacking faults, the domain sizes are short and an average crystal structure is observed experimentally. The configurational free energy of the disordered structure is lower than the energy of the two corresponding ordered crystal structures, but the energy decrease is dominated by the lower lattice energy of the alternating arrangement with a small entropic contribution. In Form II, the flexible cycloheptane bridge adopts two different configurations. The disorder is not an equilibrium property but is instead frozen-in during the crystallisation process. The configurational free energy of the disordered structure falls in between the lattice energies of the two corresponding ordered structures. The two ordered components of each disordered structure are all found in a crystal structure prediction (CSP) study with the GRACE programme. However, the experimentally observed stability relationship is only reproduced when the energy contribution of disorder is taken into account. The disordered model of Form I is found to be lower in energy than all the other predicted structures and there is no indication of a missing, thermodynamically more stable, form. The case of loratadine demonstrates that experimentally observed disorder close to 50/50 does not necessarily correspond to a free energy decrease by kT ln 2.


Predictors of progression from mild cognitive impairment to Alzheimer disease.
To determine the occurrence of neuropsychiatric symptomatology and the relation to future development of Alzheimer disease (AD) in persons with and without mild cognitive impairment (MCI). We followed 185 persons with no cognitive impairment and 47 with MCI (amnestic and multidomain), ages 75 to 95, from the population-based Kungsholmen Project, Stockholm, Sweden, for 3 years. Three types of neuropsychiatric symptoms were assessed at baseline: mood-related depressive symptoms, motivation-related depressive symptoms, and anxiety-related symptomatology. AD at 3-year follow-up was diagnosed according to Diagnostic and Statistical Manual for Mental Disorders-III-R criteria. Psychiatric symptoms occurred more frequently in persons with MCI (36.2% mood, 36.2% motivation, and 46.8% anxiety symptoms) than in cognitively intact elderly individuals (18.4% mood, 13.0% motivation, and 24.9% anxiety). Of persons with both MCI and anxiety symptoms, 83.3% developed AD over follow-up vs 6.1% of cognitively intact persons and 40.9% persons who had MCI without anxiety. Among persons with MCI, the 3-year risk of progressing to AD almost doubled with each anxiety symptom (relative risk [RR] = 1.8 [1.2 to 2.7] per symptom). Conversely, among cognitively intact subjects, only symptoms of depressive mood were related to AD development (RR = 1.9 [1.0 to 3.6] per symptom). The predictive validity of mild cognitive impairment (MCI) for identifying future Alzheimer disease (AD) cases is improved in the presence of anxiety symptoms. Mood-related depressive symptoms (dysphoria, suicidal ideation, etc.) in preclinical AD might be related to the neuropathologic mechanism, as they appear preclinically in persons both with and without MCI.


Nonlinear photonic crystals near the supercollimation point.
We uncover a strong coupling between nonlinearity and diffraction in a photonic crystal at the supercollimation point. We show that this is modeled by a nonlinear diffraction term in a nonlinear-Schrödinger-type equation in which the properties of solitons are investigated. Linear stability analysis shows solitons are stable in an existence domain that obeys the Vakhitov-Kolokolov criterium. In addition, we investigate the influence of the nonlinear diffraction on soliton collision scenarios.


RNAi-Based Suppressor Screens Reveal Genetic Interactions Between the CRL2LRR-1 E3-Ligase and the DNA Replication Machinery in Caenorhabditis elegans.
Cullin-RING E3-Ligases (CRLs), the largest family of E3 ubiquitin-Ligases, regulate diverse cellular processes by promoting ubiquitination of target proteins. The evolutionarily conserved Leucine Rich Repeat protein 1 (LRR-1) is a substrate-recognition subunit of a CRL2LRR-1 E3-ligase. Here we provide genetic evidence supporting a role of this E3-enzyme in the maintenance of DNA replication integrity in Caenorhabditis elegans Through RNAi-based suppressor screens of lrr-1(0) and cul-2(or209ts) mutants, we identified two genes encoding components of the GINS complex, which is part of the Cdc45-MCM-GINS (CMG) replicative helicase, as well as CDC-7 and MUS-101, which drives the assembly of the CMG helicase during DNA replication. In addition, we identified the core components of the ATR/ATL-1 DNA replication checkpoint pathway (MUS-101, ATL-1, CLSP-1, CHK-1). These results suggest that the CRL2LRR-1 E3-ligase acts to modify or degrade factor(s) that would otherwise misregulate the replisome, eventually leading to the activation of the DNA replication checkpoint.