Cumulative live birth rates after one or more complete cycles of IVF: a population-based study of linked cycle data from 178,898 women.
What is the chance of a live birth following one or more linked complete cycles of IVF (including ICSI)? The chance of a live birth after three complete cycles of IVF was 42.3% for treatment commencing from 1999 to 2007. IVF success has generally been reported on the basis of live birth rates after a single episode of treatment resulting in the transfer of a fresh embryo. This fails to capture the real chance of having a baby after a number of complete cycles-each involving the replacement of fresh as well as frozen-thawed embryos. Population-based observational cohort study of 178 898 women between 1992 and 2007. Participants included all women who commenced IVF treatment at a licenced clinic in the UK as recorded in the Human Fertilisation and Embryology Authority (HFEA) national database. Exclusion criteria included women whose treatment involved donor insemination, egg donation, surrogacy and the transfer of more than three embryos. Cumulative rates of live birth, term (>37 weeks) singleton live birth, and multiple pregnancy were estimated for two time-periods, 1992-1998 and 1999-2007. Conservative estimates assumed that women who did not return for IVF would not have the outcome of interest while optimal estimates assumed that these women would have similar outcome rates to those who continued IVF. A total of 71 551 women commenced IVF treatment during 1992-1998 and an additional 107 347 during 1999-2007. After the third complete IVF cycle (defined as three fresh IVF treatments-including replacement of any surplus frozen-thawed embryos), the conservative CLBR in women who commenced IVF during 1992-1998 was 30.8% increasing to 42.3% during 1999-2007. The optimal CLBRs were 44.6 and 57.1%, respectively. After eight complete cycles the optimal CLBR was 82.4% in the latter time period. The conservative rate for multiple pregnancy per pregnant woman fell from 31.9% during the earlier time period to 26.2% during the latter. Linkage of all IVF treatments to individual women was conducted. However, it was not possible to identify with certainty in all cases the episode of ovarian stimulation which generated some of the frozen embryos. Cumulative live birth rates could not be calculated for women who started treatment beyond 2007 as follow-up data were incomplete in some of them. Following a change in legislation in 2008, linked data were only made available for research in women who gave formal consent for this purpose. BMI and ethnicity could not be reported: these demographics are not recorded in the HFEA database. Our results demonstrate, at a national level, the chances of live birth in couples undergoing a number of complete (fresh and frozen) IVF cycles. They reflect improvements in reproductive technology and a more conservative embryo transfer policy. Although most couples in the UK still do not receive three complete IVF cycles; assuming no barriers to continuation of IVF treatment, around 83% of women receiving IVF would achieve a live birth by the eighth complete cycle, similar to the natural live birth rate in a non-contraception practising population. Our results support the call from NICE to develop consistent IVF policies based on three complete cycles. This work was funded by a Chief Scientist Office Postdoctoral Training Fellowship in Health Services Research and Health of the Public Research (Ref PDF/12/06). The views expressed here are those of the authors and not necessarily those of the Chief Scientist Office. S.B. reports grants from Chief Scientist Office Scotland during the conduct of the study. His institution has received support from Pharmaceutical companies (for educational seminars), which is not related to the submitted work. D.J.M., A.M. and A.J.L. have no conflicts of interest to declare.


The colonization of beringia and the peopling of the new world.
The colonization of Beringia appears closely linked to the arrival of the oldest firmly documented archeological tradition in mid-latitude North America (Paleoindian). The discovery of a Paleoindian complex in central Alaska, combined with the recent redating of the Bering Land Bridge and key archeological sites, suggests that Beringia was settled during the final Pleistocene interstadial (12,000 to 11,000 years before present). Its population expanded rapidly into other parts of the New World. Beringia probably was colonized in response to changes in climate and vegetation that occurred during this interstadial. Access to the Americas was controlled by Beringian environments and not by changing sea levels or continental ice masses.


North Asian population relationships in a global context.
Population genetic studies of North Asian ethnic groups have focused on genetic variation of sex chromosomes and mitochondria. Studies of the extensive variation available from autosomal variation have appeared infrequently. We focus on relationships among population samples using new North Asia microhaplotype data. We combined genotypes from our laboratory on 58 microhaplotypes, distributed across 18 autosomes, on 3945 individuals from 75 populations with corresponding data extracted for 26 populations from the Thousand Genomes consortium and for 22 populations from the GenomeAsia 100 K project. A total of 7107 individuals in 122 total populations are analyzed using STRUCTURE, Principal Component Analysis, and phylogenetic tree analyses. North Asia populations sampled in Mongolia include: Buryats, Mongolians, Altai Kazakhs, and Tsaatans. Available Siberians include samples of Yakut, Khanty, and Komi Zyriane. Analyses of all 122 populations confirm many known relationships and show that most populations from North Asia form a cluster distinct from all other groups. Refinement of analyses on smaller subsets of populations reinforces the distinctiveness of North Asia and shows that the North Asia cluster identifies a region that is ancestral to Native Americans.


Diversity of Synechococcus at the Martha's Vineyard Coastal Observatory: Insights from Culture Isolations, Clone Libraries, and Flow Cytometry.
The cyanobacterium Synechococcus is a ubiquitous, important phytoplankter across the world's oceans. A high degree of genetic diversity exists within the marine group, which likely contributes to its global success. Over 20 clades with different distribution patterns have been identified. However, we do not fully understand the environmental factors that control clade distributions. These factors are likely to change seasonally, especially in dynamic coastal systems. To investigate how coastal Synechococcus assemblages change temporally, we assessed the diversity of Synechococcus at the Martha's Vineyard Coastal Observatory (MVCO) over three annual cycles with culture-dependent and independent approaches. We further investigated the abundance of both phycoerythrin (PE)-containing and phycocyanin (PC)-only Synechococcus with a flow cytometric setup that distinguishes PC-only Synechococcus from picoeukaryotes. We found that the Synechococcus assemblage at MVCO is diverse (13 different clades identified), but dominated by clade I representatives. Many clades were only isolated during late summer and fall, suggesting more favorable conditions for isolation at this time. PC-only strains from four different clades were isolated, but these cells were only detected by flow cytometry in a few samples over the time series, suggesting they are rare at this site. Within clade I, we identified four distinct subclades. The relative abundances of each subclade varied over the seasonal cycle, and the high Synechococcus cell concentration at MVCO may be maintained by the diversity found within this clade. This study highlights the need to understand how temporal aspects of the environment affect Synechococcus community structure and cell abundance.


Effects of posture on the distribution of pulmonary ventilation and perfusion in children and adults.
In the adult the distributions of ventilation and of perfusion show the same directional dependence on gravity. In children, however, the distribution of ventilation in response to gravity is the reverse of that seen in adults. The aim of the current study was to determine whether perfusion showed the same reversal in children or followed the adult pattern. Distribution of perfusion was measured with intravenous technetium-99m macroaggregated albumin and distribution of ventilation with inhaled krypton-81m. Eighteen children and seven adults were studied; they had been referred for lung scanning for various respiratory problems. The effect of gravity was examined by giving aliquots of macroaggregated albumin and 81mKr by inhalation to the subject in the supine and the lateral decubitus position. Counts in the dependent lung were compared with those in the upper lung. The dependent lung in the lateral decubitus position received more of the total perfusion than it did in the supine position in seven children with a normal chest radiograph (mean 7.0%, range 4.8-10.9% more) and in 11 children with an abnormal radiograph (mean 3.4%(0.1-10.0%)). Ventilation, however, changed in the opposite direction, falling by 7.1% (-3.2% to -12.8%) in five children with a normal chest radiograph and 11.2% (-2.8% to -19.3%) in eight children with an abnormal radiograph. Fractional V/fractional Q (an index of the ventilation:perfusion ratio) decreased in the dependent lung in the children when they moved from the supine to the decubitus position. The same directional change was recorded in adults, but it was significantly less than in the children, irrespective of whether the chest radiograph was abnormal. In children and adults with various respiratory problems the effect of posture on the distribution of perfusion is similar.


Inclusion of cGAMP within virus-like particle vaccines enhances their immunogenicity.
Cyclic GMP-AMP (cGAMP) is an immunostimulatory molecule produced by cGAS that activates STING. cGAMP is an adjuvant when administered alongside antigens. cGAMP is also incorporated into enveloped virus particles during budding. Here, we investigate whether inclusion of cGAMP within viral vaccine vectors enhances their immunogenicity. We immunise mice with virus-like particles (VLPs) containing HIV-1 Gag and the vesicular stomatitis virus envelope glycoprotein G (VSV-G). cGAMP loading of VLPs augments CD4 and CD8 T-cell responses. It also increases VLP- and VSV-G-specific antibody titres in a STING-dependent manner and enhances virus neutralisation, accompanied by increased numbers of T follicular helper cells. Vaccination with cGAMP-loaded VLPs containing haemagglutinin induces high titres of influenza A virus neutralising antibodies and confers protection upon virus challenge. This requires cGAMP inclusion within VLPs and is achieved at markedly reduced cGAMP doses. Similarly, cGAMP loading of VLPs containing the SARS-CoV-2 Spike protein enhances Spike-specific antibody titres. cGAMP-loaded VLPs are thus an attractive platform for vaccination.


Personalised organs-on-chips: functional testing for precision medicine.
Organs-on-chips are microfluidic systems with controlled, dynamic microenvironments in which cultured cells exhibit functions that emulate organ-level physiology. They can in principle be 'personalised' to reflect individual physiology, for example by including blood samples, primary human tissue, and cells derived from induced pluripotent stem cell-derived cells, as well as by tuning key physico-chemical parameters of the cell culture microenvironment based on personal health data. The personalised nature of such systems, combined with physiologically relevant read-outs, provides new opportunities for person-specific assessment of drug efficacy and safety, as well as personalised strategies for disease prevention and treatment; together, this is known as 'precision medicine'. There are multiple reports of how to personalise organs-on-chips, with examples including airway-on-a-chip systems containing primary patient alveolar epithelial cells, vessels-on-chips with shapes based on personal biomedical imaging data and lung-on-a-chip systems that can be exposed to various regimes of cigarette smoking. In addition, multi-organ chip systems even allow the systematic and dynamic integration of more complex combinations of personalised cell culture parameters. Current personalised organs-on-chips have not yet been used for precision medicine as such. The major challenges that affect the implementation of personalised organs-on-chips in precision medicine are related to obtaining access to personal samples and corresponding health data, as well as to obtaining data on patient outcomes that can confirm the predictive value of personalised organs-on-chips. We argue here that involving all biomedical stakeholders from clinicians and patients to pharmaceutical companies will be integral to transition personalised organs-on-chips to precision medicine.


Mechanisms Underlying Tumor Suppressive Properties of Melatonin.
There is considerable evidence that melatonin may be of use in the prevention and treatment of cancer. This manuscript will review some of the human, animal and cellular studies that provide evidence that melatonin has oncostatic properties. Confirmation that melatonin mitigates pathogenesis of cancer will be described from both direct study of its effects on carcinogenesis, and from indirect findings implicating disruption of the circadian cycle. A distinction is made between the role of melatonin in preventing the initiation of the tumorigenic pathway and the ability of melatonin to retard the progression of cancer. Melatonin appears to slow down the rate of advancement of established tumors and there is evidence that it constitutes a valuable complement to standard pharmacological and radiation treatment modalities. There are instances of the beneficial outcomes in cancer treatment which utilize a range of hormones and vitamins, melatonin being among the constituents of the mix. While these complex blends are empirically promising, they are only briefly mentioned here in view of the confounding influence of a multiplicity of agents studied simultaneously. The last section of this review examines the molecular mechanisms that potentially underlie the oncostatic effects of melatonin. Alterations in gene expression following activation of various transcription factors, are likely to be an important mediating event. These changes in gene activity not only relate to cancer but also to the aging process which underlies the onset of most tumors. In addition, epigenetic events such as modulation of histone acetylation and DNA methylation patterns throughout the lifespan of organisms need to be considered. The antioxidant and immunoregulatory roles of melatonin may also contribute to its cancer modulatory properties. Naturally, these mechanisms overlap and interact extensively. Nevertheless, in the interest of clarity and ease of reading, each is discussed as a separate topic section. The report ends with some general conclusions concerning the clinical value of melatonin which has been rather overlooked and understudied.


National School Lunch Program and School Breakfast Program: Eliminating Applications Through Community Eligibility as Required by the Healthy, Hunger-Free Kids Act of 2010. Final rule.
This final rule establishes requirements for State agencies, local educational agencies, and schools operating the Community Eligibility Provision, a reimbursement option that allows the service of school meals to all children at no-cost in high poverty schools without collecting household applications. By eliminating the household application process and streamlining meal counting and claiming procedures through the Community Eligibility Provision, local educational agencies may substantially reduce administrative burden related to operating the National School Lunch and School Breakfast Programs. This rule codifies many requirements that were implemented through policy guidance following enactment of the Healthy, Hunger-Free Kids Act of 2010, as well as provisions of the proposed rule. These requirements will result in consistent, national implementation of the Community Eligibility Provision.


Housing Improvements and Malaria Risk in Sub-Saharan Africa: A Multi-Country Analysis of Survey Data.
Improvements to housing may contribute to malaria control and elimination by reducing house entry by malaria vectors and thus exposure to biting. We tested the hypothesis that the odds of malaria infection are lower in modern, improved housing compared to traditional housing in sub-Saharan Africa (SSA). We analysed 15 Demographic and Health Surveys (DHS) and 14 Malaria Indicator Surveys (MIS) conducted in 21 countries in SSA between 2008 and 2015 that measured malaria infection by microscopy or rapid diagnostic test (RDT). DHS/MIS surveys record whether houses are built with finished materials (e.g., metal) or rudimentary materials (e.g., thatch). This information was used to develop a binary housing quality variable where houses built using finished wall, roof, and floor materials were classified as "modern", and all other houses were classified as "traditional". Conditional logistic regression was used to determine the association between housing quality and prevalence of malaria infection in children aged 0-5 y, adjusting for age, gender, insecticide-treated net (ITN) use, indoor residual spraying, household wealth, and geographic cluster. Individual survey odds ratios (ORs) were combined to determine a summary OR using a random effects meta-analysis. Of 284,532 total children surveyed, 139,318 were tested for malaria infection using microscopy (n = 131,652) or RDT (n = 138,540). Within individual surveys, malaria prevalence measured by microscopy ranged from 0.4% (Madagascar 2011) to 45.5% (Burkina Faso 2010) among children living in modern houses and from 0.4% (The Gambia 2013) to 70.6% (Burkina Faso 2010) in traditional houses, and malaria prevalence measured by RDT ranged from 0.3% (Senegal 2013-2014) to 61.2% (Burkina Faso 2010) in modern houses and from 1.5% (The Gambia 2013) to 79.8% (Burkina Faso 2010) in traditional houses. Across all surveys, modern housing was associated with a 9% to 14% reduction in the odds of malaria infection (microscopy: adjusted OR 0.91, 95% CI 0.85-0.97, p = 0.003; RDT: adjusted OR 0.86, 95% CI 0.80-0.92, p < 0.001). This association was consistent regardless of ITN usage. As a comparison, the odds of malaria infection were 15% to 16% lower among ITN users versus non-users (microscopy: adjusted OR 0.84, 95% CI 0.79-0.90, p < 0.001; RDT: adjusted OR 0.85, 95% CI 0.80-0.90, p < 0.001). The main limitation of this study is that residual confounding by household wealth of the observed association between housing quality and malaria prevalence is possible, since the wealth index may not have fully captured differences in socioeconomic position; however, the use of multiple national surveys offers the advantage of a large sample size and the elimination of many biases typically associated with pooling observational data. Housing quality is an important risk factor for malaria infection across the spectrum of malaria endemicity in SSA, with a strength of association between housing quality and malaria similar to that observed between ITN use and malaria. Improved housing should be considered a promising intervention for malaria control and elimination and long-term prevention of reintroduction.


Modeling carbon turnover in five terrestrial ecosystems in the boreal zone using multiple criteria of acceptance.
Estimates of carbon fluxes and turnover in ecosystems are key elements in the understanding of climate change and in predicting the accumulation of trace elements in the biosphere. In this paper we present estimates of carbon fluxes and turnover times for five terrestrial ecosystems using a modeling approach. Multiple criteria of acceptance were used to parameterize the model, thus incorporating large amounts of multi-faceted empirical data in the simulations in a standardized manner. Mean turnover times of carbon were found to be rather similar between systems with a few exceptions, even though the size of both the pools and the fluxes varied substantially. Depending on the route of the carbon through the ecosystem, turnover times varied from less than one year to more than one hundred, which may be of importance when considering trace element transport and retention. The parameterization method was useful both in the estimation of unknown parameters, and to identify variability in carbon turnover in the selected ecosystems.


Circadian Rhythm and Nuclear Receptors.
All life of Earth has evolved mechanisms to track time. This permits anticipation of predictable changes in light/dark, and in most cases also directs fed/fasted cycles, and sleep/wake. The nuclear receptors enjoy a close relationship with the molecular machinery of the clock. Some play a core role within the circadian machinery, other respond to ligands which oscillate in concentration, and physical cross-talk between clock transcription factors, eg cryptochromes, and multiple nuclear receptors also enable coupling of nuclear receptor function to time of day. Essential processes including inflammation, and energy metabolism are strongly regulated by both the circadian machinery, and rhythmic behaviour, and also by multiple members of the nuclear receptor family. An emerging theme is reciprocal regulation of key processes by different members of the nuclear receptor family, for example NR1D1/2, and NR1F1, in regulation of the core circadian clock transcription factor BMAL1.


Structure-Based Design of Selective β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors: Targeting the Flap to Gain Selectivity over BACE2.
BACE1 inhibitors hold potential as agents in disease-modifying treatment for Alzheimer's disease. BACE2 cleaves the melanocyte protein PMEL in pigment cells of the skin and eye, generating melanin pigments. This role of BACE2 implies that nonselective and chronic inhibition of BACE1 may cause side effects derived from BACE2. Herein, we describe the discovery of potent and selective BACE1 inhibitors using structure-based drug design. We targeted the flap region, where the shape and flexibility differ between these enzymes. Analysis of the cocrystal structures of an initial lead 8 prompted us to incorporate spirocycles followed by its fine-tuning, culminating in highly selective compounds 21 and 22. The structures of 22 bound to BACE1 and BACE2 revealed that a relatively high energetic penalty in the flap of the 22-bound BACE2 structure may cause a loss in BACE2 potency, thereby leading to its high selectivity. These findings and insights should contribute to responding to the challenges in exploring selective BACE1 inhibitors.


Diagnostic value of musculoskeletal ultrasound in patients with low back pain - a review of the literature.
Patients with low back pain (LBP) frequently undergo various imaging studies in the pursuit of a more precise diagnosis. Ultrasound (US) has the advantage of being a widely available, multiplanar, fast and radiation-free diagnostic tool. Moreover, compared to most of the other imaging modalities, it is particularly efficient in the visualization and assessment of soft tissues. Consequently, the question about the possible diagnostic application of US in such a common pathology as LBP is very relevant to the clinical practice. For this reason, we performed a review of the literature on the diagnostic value of US in differentconditions that could cause LBP. We hereby discuss available studies on the diagnostic application of US in spinal canal stenosis and disc herniation (probably of historical significance only), as well as in the pathology of soft tissue structures like the lumbar and pelvic ligaments, muscles and entheses, the thoracolumbar fascia and the sacroiliac joints (maybe of greater importance nowadays). The evidence for the diagnostic value of US is not equivocal, though promising for some of the causative conditions, and clearly this area remains open to further research.


[Prevalence of overweight and associated factors in adults: a population survey in Rio Branco, Acre State, Brazil, 2007-2008].
Population studies in Brazil have shown an increased prevalence of overweight and obesity in adult populations in all regions of the country. The objective was to estimate prevalence and identify risk factors associated with overweight among adults in Rio Branco, Acre State, Brazil. The study included a cross-sectional population-based sample of 1,469 adults. Multivariate analysis was performed using Poisson regression, taking overweight (BMI > 25kg/m²) as the dependent variable. Prevalence of overweight was 46.9%, higher among women. Overweight tended to increase with age in both men and women. Overweight was associated with socioeconomic, demographic, and morbidity variables such as hypertension and dyslipidemia. The high prevalence of overweight in adults of both sexes suggests a public health problem. Control measures and prevention of health risks associated with excess weight are necessary.


GDNF delivery for Parkinson's disease.
The mainstays of Parkinson's disease (PD) treatment remain symptomatic, including initial dopamine replacement and subsequent deep brain stimulation, however, neither of these approaches is neuroprotective. Neurotrophic factors - proteins that activate cell signalling pathways regulating neuronal survival, differentiation, growth and regeneration - represent an alternative for treating dopaminergic neurons in PD but are difficult to administer clinically because they do not pass through the blood-brain barrier. Glial cell line-derived neurotrophic factor (GDNF) has potent neurotrophic effects particularly but not exclusively on dopaminergic neurons; in animal models of PD, it has consistently demonstrated both neuroprotective and neuroregenerative effects when provided continuously, either by means of a viral vector or through continuous infusion either into the cerebral ventricles (ICV) or directly into the denervated putamen. This led to a human PD study in which GDNF was administered by monthly bolus intracerebroventricular injections, however, no clinical benefit resulted, probably because of the limited penetration to the target brain areas, and instead significant side effects occurred. In an open-label study of continuous intraputamenal GDNF infusion in five patients (one unilaterally and four bilaterally), we reported excellent tolerance, few side effects and clinical benefit evident within three months of the commencement of treatment. The clinical improvement was sustained and progressive, and by 24-months patients demonstrated a 57 and 63% improvement in their off-medication motor and activities of daily living UPDRS subscores, respectively, with clear benefit in dyskinesias. The benefit was associated with a significant increase in putamenal 18F-dopa uptake on positron emission tomography (PET), and in one patient coming to autopsy after 43 months of unilateral infusion there was evident increased tyrosine hydroxylase immunopositive nerve fibres in the infused putamen. A second open trial in 10 patients using unilateral intraputamenal GDNF infusions has also demonstrated a greater than 30% bilateral benefit in both on- and off-medication scores at 24 weeks. Based on our 6-month results, a randomized controlled clinical trial was conducted to confirm the open-label results, however, GDNF infusion over 6-months did not confer the predetermined level of clinical benefit to patients with PD despite increased 18F-dopa uptake surrounding the catheter tip. It is possible that technical differences between this trial and the positive open label studies contributed to this negative outcome.


Transformational adaptation when incremental adaptations to climate change are insufficient.
All human-environment systems adapt to climate and its natural variation. Adaptation to human-induced change in climate has largely been envisioned as increments of these adaptations intended to avoid disruptions of systems at their current locations. In some places, for some systems, however, vulnerabilities and risks may be so sizeable that they require transformational rather than incremental adaptations. Three classes of transformational adaptations are those that are adopted at a much larger scale, that are truly new to a particular region or resource system, and that transform places and shift locations. We illustrate these with examples drawn from Africa, Europe, and North America. Two conditions set the stage for transformational adaptation to climate change: large vulnerability in certain regions, populations, or resource systems; and severe climate change that overwhelms even robust human use systems. However, anticipatory transformational adaptation may be difficult to implement because of uncertainties about climate change risks and adaptation benefits, the high costs of transformational actions, and institutional and behavioral actions that tend to maintain existing resource systems and policies. Implementing transformational adaptation requires effort to initiate it and then to sustain the effort over time. In initiating transformational adaptation focusing events and multiple stresses are important, combined with local leadership. In sustaining transformational adaptation, it seems likely that supportive social contexts and the availability of acceptable options and resources for actions are key enabling factors. Early steps would include incorporating transformation adaptation into risk management and initiating research to expand the menu of innovative transformational adaptations.


The diagnostic value of C-reactive protein in infected total hip arthroplasties.
In 50 patients with non-infected total hip arthroplasties (THA), 233 C-reactive protein (CRP) values were obtained over a three-year period. Six of these 50 patients occasionally had CRP values of over 20 mg/l. The erythrocyte sedimentation rate (ESR) and CRP concentration were measured in 23 patients with deep infections of THA before revision. In 11 patients the infections were caused by coagulase-negative staphylococci. CRP exceeded 20 mg/l in 18 patients and the ESR was more than 30 mm/hr in 14. In only one infected patient were both CRP and ESR below these levels. All of 33 patients with non-septic loosening had CRP less than 20 mg/l and ESR less than 30 mm/hr before revision. C-reactive protein seems to be a valuable supplement to the ESR in the monitoring of infection after THA.


CSF amyloid-beta and tau proteins, and cognitive performance, in early and untreated Parkinson's disease: the Norwegian ParkWest study.
Alzheimer's disease (AD) pathology is found in a considerable portion of patients with Parkinson's disease (PD), particularly those with early dementia (PDD). Altered cerebrospinal fluid (CSF) levels of amyloid-β (Aβ) and tau proteins have been found in PDD, with intermediate changes for Aβ42 in non-demented PD. The authors investigated whether AD-related CSF protein levels are altered and relate to neuropsychological performance in early, untreated PD. CSF concentrations of Aβ42, Aβ40 and Aβ38 were measured by electrochemiluminiscene and levels of total tau (T-tau) and phosphorylated tau (P-tau) by ELISA in 109 newly diagnosed, unmedicated, non-demented, community-based PD patients who had undergone comprehensive neuropsychological testing, and were compared with those of 36 age-matched normal controls and 20 subjects with mild AD. PD patients displayed significant reductions in Aβ42 (19%; p=0.009), Aβ40 (15.5%; p=0.008) and Aβ38 (23%; p=0.004) but not T-tau (p=0.816) or P-tau (p=0.531) compared with controls. CSF Aβ42 reductions in PD were less marked than in AD (53%; p=0.002). Sequential regression analyses demonstrated significant associations between CSF levels of Aβ42 (β=0.205; p=0.019), Aβ40 (β=0.378; p<0.001) and Aβ38 (β=0.288; p=0.001) and memory impairment, but not executive-attentional or visuospatial dysfunction. Tau protein levels did not correlate with cognitive measures. CSF Aβ levels are altered in a subset of patients with early PD and relate to memory impairment. Our study suggests that alterations in Aβ protein metabolism may contribute to the heterogeneity in pattern and course of cognitive decline associated with PD. Longitudinal studies are needed to clarify the clinical significance of CSF Aβ peptides as prognostic biomarkers in PD.


Autism: the quest for the genes.
Autism, at its most extreme, is a severe neurodevelopmental disorder, and recent studies have indicated that autism spectrum disorders are considerably more common than previously supposed. However, although one of the most heritable neuropsychiatric syndromes, autism has so far eluded attempts to discover its genetic origins in the majority of cases. Several whole-genome scans for autism-susceptibility loci have identified specific chromosomal regions, but the results have been inconclusive and fine mapping and association studies have failed to identify the underlying genes. Recent advances in knowledge from the Human Genome and HapMap Projects, and progress in technology and bioinformatic resources, have aided study design and made data generation more efficient and cost-effective. Broadening horizons about the landscape of structural genetic variation and the field of epigenetics are indicating new possible mechanisms underlying autism aetiology, while endophenotypes are being used in an attempt to break down the complexity of the syndrome and refine genetic data. Although the genetic variants underlying idiopathic autism have proven elusive so far, the future for this field looks promising.


The missing link in parasite manipulation of host behaviour.
The observation that certain species of parasite my adaptively manipulate its host behaviour is a fascinating phenomenon. As a result, the recently established field of 'host manipulation' has seen rapid expansion over the past few decades with public and scientific interest steadily increasing. However, progress appears to falter when researchers ask how parasites manipulate behaviour, rather than why. A vast majority of the published literature investigating the mechanistic basis underlying behavioural manipulation fails to connect the establishment of the parasite with the reported physiological changes in its host. This has left researchers unable to empirically distinguish/identify adaptive physiological changes enforced by the parasites from pathological side effects of infection, resulting in scientists relying on narratives to explain results, rather than empirical evidence. By contrasting correlative mechanistic evidence for host manipulation against rare cases of causative evidence and drawing from the advanced understanding of physiological systems from other disciplines it is clear we are often skipping over a crucial step in host-manipulation: the production, potential storage, and release of molecules (manipulation factors) that must create the observed physiological changes in hosts if they are adaptive. Identifying these manipulation factors, via associating gene expression shifts in the parasite with behavioural changes in the host and following their effects will provide researchers with a bottom-up approach to unraveling the mechanisms of behavioural manipulation and by extension behaviour itself.


The 2016 classification criteria for primary Sjogren's syndrome: what's new?
New 2016 ACR/EULAR classification criteria for primary Sjogren's syndrome (SS) have been developed and endorsed by the ACR. The newly proposed criteria include simple-to-perform items.Two important points of the new criteria should be considered. Firstly, they indicate that either salivary gland biopsy or anti-Ro must be positive in order to corroborate the inflammatory and autoimmune nature of the disease. Secondly, the criteria recognize the systemic nature of SS, namely that patients without salivary or ocular glandular symptoms, but with extraglandular manifestations and B cell activation markers were also included in the SS classification. Additionally, the new criteria modified some technical points. The ocular staining score threshold was increased to 5 due to the higher specificity. The immunological profile includes only anti-Ro antibodies, while positivity for antinuclear antibodies and rheumatoid factor or isolated anti-La was excluded due to a lack of specificity.The 2016 ACR/EULAR criteria are suitable for early identification of SS, providing patients with the opportunity of enrollment in clinical trials for new specific treatment. Although validation has been successful, the real life application of these criteria will test their performance.


Epidemiologic studies in agricultural populations: observations and future directions.
This paper reviews epidemiologic studies of cancer among agricultural populations to identify possible associations and to provide a focus for future investigations. Meta-analyses of mortality surveys of farmers find excesses of several cancers, including connective tissue, non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma and cancers of the skin, stomach, and brain, and deficits for total mortality, heart disease, total cancer, and cancers of the esophagus, colon, lung, and bladder. Meta-analyses of studies of individual cancers also support these findings, indicating a need to identify exposures and lifestyle factors that might account for this mortality pattern. Although cancer studies of other occupations that might have pesticide exposures in common with farmers show some similarities with observations among farmers, the overall patterns are quite different. This suggests that pesticides are not likely to fully explain the cancer and other disease patterns observed among farmers. Because exposures vary by type of farm operation, exposures for individual farmers can differ considerably. Studies in the future need to focus on the full range of exposures to fully understand the cancer pattern in farmers.


Tailoring periodical collections to meet institutional needs.
A system for tailoring journal collections to meet institutional needs is described. The approach is based on the view that reference work and collection development are variant and complementary forms of the same library function; both tasks have as their objective a literature response to information problems. Utilizing the tools and procedures of the reference search in response to a specific collection development problem topic, the author created a model ranked list of relevant journals. Finally, by linking the model to certain operational and environmental factors in three different health care organizations, he tailored the collection to meet the institutions' respective information needs.


Measuring social support for healthy eating and physical activity in obesity.
This study sought to investigate the psychometric properties of two commonly used measures of social support in obesity, namely, the Social Support for Eating Habits (SSEH) and Social Support for Physical Activity (SSPA) scales. Cross-sectional and longitudinal study design. Participants were 200 adults with obesity taking part in a 12-month cognitive behavioural weight loss programme. At pre-treatment, participants completed the SSEH and SSPA as well as measures of social support, motivation, self-efficacy, and health-related quality of life to assess concurrent validity. Predictive validity was assessed in terms of baseline SSEH and SSPA scores predicting post-treatment weight while controlling for pre-treatment weight. Factor analysis supported a two-factor solution for both the SSEH ('Encouragement' and 'Discouragement') and SSPA ('Participation' and 'Punishment') scales, with each subscale demonstrating acceptable internal consistency. While the results provided some support for the concurrent validity of the SSEH Discouragement and SSPA Participation subscales, there was mixed support for the SSEH Encouragement subscale and poor support for the SSPA Punishment subscale. No support was found in terms of predictive validity. The findings question the validity of the SSEH and SSPA scales in obesity, with behaviours deemed to be supportive in non-obese populations not necessarily perceived as such by people with obesity. The development of a psychometrically sound measure of social support in the obesity context is needed. Statement of contribution What is already known on this subject? Social support is a robust predictor of positive health outcomes. There is mixed support for the association between social support and weight-related outcomes in obesity. Discrepant findings may be due to social support measures of questionable reliability and validity in obesity. What does this study add? The SSEH and SSPA scales have questionable validity in obesity. Behaviours deemed to be supportive by family and friends may not be perceived as such by individuals with obesity. A psychometrically sound measure of social support in the obesity context is needed.


Regulation of cardiomyocyte DNA damage and cell death by the type 2A protein phosphatase regulatory protein alpha4.
The type 2A protein phosphatase regulatory protein alpha4 (α4) constitutes an anti-apoptotic protein in non-cardiac tissue, however it's anti-apoptotic properties in the heart are poorly defined. To this end, we knocked down α4 protein expression (α4 KD) using siRNA in cultured H9c2 cardiomyocytes and confirmed the lack of DNA damage/cell death by TUNEL staining and MTT assay. However, α4 KD did increase the phosphorylation of p53 and ATM/ATR substrates, decreased the expression of poly ADP-ribose polymerase and associated fragments. Expression of anti-apoptotic proteins Bcl-2 and Bcl-xL was reduced, whereas expression of pro-apoptotic BAX protein did not change. Alpha4 KD reduced basal H2AX Ser139 phosphorylation, whereas adenoviral-mediated re-expression of α4 protein following α4 KD, restored basal H2AX phosphorylation at Ser139. The sensitivity of H9c2 cardiomyocytes to doxorubicin-induced DNA damage and cytotoxicity was augmented by α4 KD. Adenoviral-mediated overexpression of α4 protein in ARVM increased PP2AC expression and augmented H2AX Ser139 phosphorylation in response to doxorubicin. Furthermore, pressure overload-induced heart failure was associated with reduced α4 protein expression, increased ATM/ATR protein kinase activity, increased H2AX expression and Ser139 phosphorylation. Hence, this study describes the significance of altered α4 protein expression in the regulation of DNA damage, cardiomyocyte cell death and heart failure.


Thalamic Volume Is Reduced in Cervical and Laryngeal Dystonias.
Dystonia, a debilitating movement disorder characterized by abnormal fixed positions and/or twisting postures, is associated with dysfunction of motor control networks. While gross brain lesions can produce secondary dystonias, advanced neuroimaging techniques have been required to identify network abnormalities in primary dystonias. Prior neuroimaging studies have provided valuable insights into the pathophysiology of dystonia, but few directly assessed the gross volume of motor control regions, and to our knowledge, none identified abnormalities common to multiple types of idiopathic focal dystonia. We used two gross volumetric segmentation techniques and one voxelwise volumetric technique (voxel based morphometry, VBM) to compare regional volume between matched healthy controls and patients with idiopathic primary focal dystonia (cervical, n = 17, laryngeal, n = 7). We used (1) automated gross volume measures of eight motor control regions using the FreeSurfer analysis package; (2) blinded, anatomist-supervised manual segmentation of the whole thalamus (also gross volume); and (3) voxel based morphometry, which measures local T1-weighted signal intensity and estimates gray matter density or volume at the level of single voxels, for both whole-brain and thalamus. Using both automated and manual gross volumetry, we found a significant volume decrease only in the thalamus in two focal dystonias. Decreases in whole-thalamic volume were independent of head and brain size, laterality of symptoms, and duration. VBM measures did not differ between dystonia and control groups in any motor control region. Reduced thalamic gross volume, detected in two independent analyses, suggests a common anatomical abnormality in cervical dystonia and spasmodic dysphonia. Defining the structural underpinnings of dystonia may require such complementary approaches.


Effects of loss aversion on post-decision wagering: implications for measures of awareness.
Wagering contingent on a previous decision, or post-decision wagering, has recently been proposed to measure conscious awareness. Whilst intuitively appealing, it remains unclear whether economic context interacts with subjective confidence and how such interactions might impact on the measurement of awareness. Here we propose a signal detection model which predicts that advantageous wagers placed on the identity of preceding stimuli are affected by loss aversion, despite stimulus visibility remaining constant. This pattern of predicted results was evident in a psychophysical task where we independently manipulated perceptual and economic factors. Changes in wagering behaviour induced by changes in wager size were largely driven by changes in criterion, consistent with the model. However, for near-threshold stimuli, a reduction in wagering efficiency was also evident, consistent with an apparent but potentially illusory decrease in awareness of the stimulus. These findings challenge an assertion that post-decision wagering provides a direct index of subjective awareness.


Optical disc technology-enabled analytical devices: from hardware modification to digitized molecular detection.
Beyond their essential applications in portable data storage for the past 30 years, optical discs and corresponding recording/reading technologies have been extensively explored with the ultimate goal of creating novel analytical tools for on-site chemical analysis and point-of-care (POC) medical diagnosis. In particular, the disc media (CD, DVD, and BD) are proven to be inexpensive and versatile substrate materials for the preparation of various biochips and microfluidic systems; conventional computer drives and disc players are widely adapted for biochip signal reading and microscopic imaging. Herein we provide an overview of such optical disc technology-enabled analytical devices, e.g., integrated systems developed from specifically fabricated analog disks, modified optical drives, or adapted software algorithms.


Unifying Microscopic and Continuum Treatments of van der Waals and Casimir Interactions.
We present an approach for computing long-range van der Waals (vdW) interactions between complex molecular systems and arbitrarily shaped macroscopic bodies, melding atomistic treatments of electronic fluctuations based on density functional theory in the former with continuum descriptions of strongly shape-dependent electromagnetic fields in the latter, thus capturing many-body and multiple scattering effects to all orders. Such a theory is especially important when considering vdW interactions at mesoscopic scales, i.e., between molecules and structured surfaces with features on the scale of molecular sizes, in which case the finite sizes, complex shapes, and resulting nonlocal electronic excitations of molecules are strongly influenced by electromagnetic retardation and wave effects that depend crucially on the shapes of surrounding macroscopic bodies. We show that these effects together can modify vdW interaction energies and forces, as well as molecular shapes deformed by vdW interactions, by orders of magnitude compared to previous treatments based on Casimir-Polder, nonretarded, or pairwise approximations, which are valid only at macroscopically large or atomic-scale separations or in dilute insulating media, respectively.


Optimizing the role of androgen deprivation therapy in advanced prostate cancer: Challenges beyond the guidelines.
For specific clinical indications, androgen deprivation therapy (ADT) will induce disease prostate cancer (PC) regression, relieve symptoms and prolong survival; however, ADT has a well-described range of side effects, which may have a detrimental effect on the patient's quality of life, necessitating additional interventions or changes in PC treatment. The risk-benefit analysis for initiating ADT in PC patients throughout the PC disease continuum warrants review. A 14-member panel comprised of urologic and medical oncologists were chosen for an expert review panel, to provide guidance on a more judicious use of ADT in advanced PC patients. Panel members were chosen based upon their academic and community experience and expertise in the management of PC patients. Four academic members of the panel served as group leaders; the remaining eight panel members were from Large Urology Group Practice Association practices with proven experience in leading their advanced PC clinics. The panel members were assigned to four separate working groups, and were tasked with addressing the role of ADT in specific PC settings. This article describes the practical recommendations of an expert panel for the use of ADT throughout the PC disease continuum, as well as an algorithm summarizing the key recommendations. The target for this publication is all providers (urologists, medical oncologists, radiation oncologists, or advanced practice providers) who evaluate and manage advanced PC patients, regardless of their practice setting. The panel has provided recommendations for monitoring PC patients while on ADT, recognizing that PC patients will progress despite testosterone suppression and, therefore, early identification of conversion from castrate-sensitive to castration resistance is critical. Also, the requirement to both identify and mitigate side effects of ADT as well as the importance of quality of life maintenance are essential to the optimization of patient care, especially as more combinatorial therapeutic strategies with ADT continue to emerge.


Evidence of dysregulation of dendritic cells in primary HIV infection.
Myeloid and plasmacytoid dendritic cells (DCs) are important mediators of both innate and adaptive immunity against pathogens such as HIV. During the course of HIV infection, blood DC numbers fall substantially. In the present study, we sought to determine how early in HIV infection the reduction occurs and whether the remaining DC subsets maintain functional capacity. We find that both myeloid DC and plasmacytoid DC levels decline very early during acute HIV infection. Despite the initial reduction in numbers, those DCs that remain in circulation retain their function and are able to stimulate allogeneic T-cell responses, and up-regulate maturation markers plus produce cytokines/chemokines in response to stimulation with TLR7/8 agonists. Notably, DCs from HIV-infected subjects produced significantly higher levels of cytokines/chemokines in response to stimulation with TLR7/8 agonists than DCs from uninfected controls. Further examination of gene expression profiles indicated in vivo activation, either directly or indirectly, of DCs during HIV infection. Taken together, our data demonstrate that despite the reduction in circulating DC numbers, those that remain in the blood display hyperfunctionality and implicates a possible role for DCs in promoting chronic immune activation.


Carcinoma of the external auditory canal: histological and treatment groups.
Evaluation of the clinical and pathological factors associated with the treatment and outcomes of external auditory canal (EAC) carcinomas. A retrospective review of clinical and pathological analysis was performed on 23 patients who were histologically diagnosed with EAC carcinomas and treated at Hamamatsu University hospital. We evaluated the clinical staging, treatment methods, pathological diagnosis (particularly squamous cell carcinoma, SCC), and patient outcomes. Main outcome measures include staging, treatment procedures, pathological features, and estimated survival rates. The 5-year overall survival (OS) of study participants was 75.2% and the 10-year OS was 60.2% using the Kaplan-Meier method. The prognosis for SCC was poor compared with other carcinomas (p= 0.0462). The prognoses for SCC patients after treatment with surgery alone and after postoperative radiotherapy or chemoradiotherapy were significantly better than for patients with unresectable tumours (p = 0.0004 and p = 0.0001, respectively). There was no significant difference among the four tumour stage groups. Information about patients' survival status was obtained after a median follow-up period of 57.5 months (range, 7-151 months). Our survival analysis data for carcinoma of the EAC demonstrates that SCC and unresectable cases are associated with poor outcomes. Outcomes for patients with operable disease more closely parallel the survival curves of patients with advanced stage T4 disease. Patients with SCC should be strictly categorized as cases with severe disease.


Specific dynamic action: a review of the postprandial metabolic response.
For more than 200 years, the metabolic response that accompanies meal digestion has been characterized, theorized, and experimentally studied. Historically labeled "specific dynamic action" or "SDA", this physiological phenomenon represents the energy expended on all activities of the body incidental to the ingestion, digestion, absorption, and assimilation of a meal. Specific dynamic action or a component of postprandial metabolism has been quantified for more than 250 invertebrate and vertebrate species. Characteristic among all of these species is a rapid postprandial increase in metabolic rate that upon peaking returns more slowly to prefeeding levels. The average maximum increase in metabolic rate stemming from digestion ranges from a modest 25% for humans to 136% for fishes, and to an impressive 687% for snakes. The type, size, composition, and temperature of the meal, as well as body size, body composition, and several environmental factors (e.g., ambient temperature and gas concentration) can each significantly impact the magnitude and duration of the SDA response. Meals that are large, intact or possess a tough exoskeleton require more digestive effort and thus generate a larger SDA than small, fragmented, or soft-bodied meals. Differences in the individual effort of preabsorptive (e.g., swallowing, gastric breakdown, and intestinal transport) and postabsorptive (e.g., catabolism and synthesis) events underlie much of the variation in SDA. Specific dynamic action is an integral part of an organism's energy budget, exemplified by accounting for 19-43% of the daily energy expenditure of free-ranging snakes. There are innumerable opportunities for research in SDA including coverage of unexplored taxa, investigating the underlying sources, determinants, and the central control of postprandial metabolism, and examining the integration of SDA across other physiological systems.


Diagnosing intramammary infections: evaluation of composite milk samples to detect intramammary infections.
Composite milk samples, in which milk from all 4 bovine quarters is collected in a single vial, are widely used in many developed dairy industries for detection of intramammary infections (IMI). These samples are more economical for use in culturing protocols than individual quarter samples, and may be useful when considering management options at the cow and herd level. The dilution effect may be problematic, however, resulting in lower sensitivity (Se) in IMI detection on composite samples. Relative Se and specificity (Sp) in composite samples have previously been described for some major pathogens, but because the causative organism for IMI is initially unknown, it is beneficial to investigate the reliability of composite samples for detection of all types of mastitis-causing bacteria. The Canadian Bovine Mastitis Research Network has a large data collection platform-the National Cohort of Dairy Farms-containing a vast amount of data on mastitis in Canada. These data have been used to further investigate the Se and Sp of composite samples in detecting IMI caused by specific mastitis pathogens. Milk samplings of selected cows before dry-off, after calving, and during lactation (n=48,835 samples) were employed to this end. Composite samples showed moderately high Se for Staphylococcus aureus (77.1%, 95% CI=73.3-80.5) and Streptococcus dysgalactiae (73.4%, 95% CI=60.9-83.7), with moderate Se for Streptococcus uberis (62.1%, 95% CI=49.3-73.8) and coagulase-negative staphylococci (59.8%, 95% CI=58.4-61.2). Sensitivities always increased as the number of affected quarters increased. Composite samples also showed high Sp (>97%) for most organisms. Factors such as lactation number and stage of lactation were evaluated for their influence on the Se and Sp of composite sampling, but were only found to be significant for coagulase-negative staphylococci. Predictive values using the herd prevalences found across Canada were calculated and can be useful in field scenarios when composite sampling is employed to assist mastitis management. When used to detect newly occurring IMI in pairs of samples taken before dry-off, post-calving, and also prior to and subsequent to the dry period, composite samples were shown to have lower Se but similar Sp for all pathogens investigated. Composite samples can be used to detect IMI and new IMI in dairy cows, but the Se and Sp of the procedure should be taken into account.


Limb apraxia and the "affordance competition hypothesis".
Limb apraxia, a disorder of higher order motor control, has long been a challenge for clinical assessment and understanding (Leiguarda and Marsden, 2000). The deficits originally described in limb apraxia (Liepmann, 1920) have been classified by the nature of the errors made by the patients leading to, namely, ideational and ideomotor apraxia. The dual stream hypothesis (Goodale and Milner, 1992) has been used to explain these categories: ideational apraxia is thought to relate to a deficit in the concept of a movement (coded in the ventral stream). Patients have difficulty using objects, sequencing actions to interact with them or pantomiming their use. Ideomotor apraxia, on the other hand, is thought to arise from problems in the accurate implementation of movements within the dorsal stream. One of the limitations on understanding apraxia is the failure by the clinical literature to draw on knowledge of the factors determining actions in the environment. Here we emphasize the role of affordance. There is much recent work indicating that our responses to stimuli are strongly influenced by the actions that the objects "afford", based on their physical properties and the intentions of the actor (e.g., Tucker and Ellis, 1998). The concept of affordance, originally suggested by Gibson (1979) has been incorporated in a recent model of interactive behavior that draws from findings in non-human primates, namely the "affordance competition hypothesis" (Cisek, 2007). This postulates that interactive behavior arises by a process of competition between possible actions elicited by the environment. In this paper we argue that "affordance competition" may play a role in apraxia. We review evidence that at least some aspects of apraxia may reflect an abnormal sensitivity to competition when multiple affordances are present (Riddoch et al., 1998) and/or a poor ability to exert cognitive control over this competition when it occurs. This framework suggests a new way of conceptualizing deficits in apraxia which invites further investigations in the field.


Targeting the maize T-urf13 product into tobacco mitochondria confers methomyl sensitivity to mitochondrial respiration.
The URF13 protein, which is encoded by the maize mitochondrial T-urf13 gene, is thought to be responsible for pathotoxin and methomyl sensitivity and male sterility. We have investigated whether T-urf13 confers toxin sensitivity and male sterility when expressed in another plant species. The coding sequence of T-urf13 was fused to a mitochondrial targeting presequence, placed under the control of the cauliflower mosaic virus 35S promoter, and introduced into tobacco by Agrobacterium tumefaciens-mediated transformation. Plants expressing high levels of URF13 were methomyl sensitive. Subcellular analysis indicated that URF13 is mainly associated with the mitochondria. Adding methomyl to isolated mitochondria stimulated NADH-linked respiration and uncoupled oxidative phosphorylation, indicating that URF13 was imported into the mitochondria, and conferred toxin sensitivity. Most control plants, which expressed the T-urf13c construct lacking the mitochondrial presequence, were methomyl sensitive and contained URF13 in a membrane fraction. Subcellular fractionation by sucrose gradient centrifugation showed that URF13 sedimented at several positions, suggesting the protein is associated with various organelles, including mitochondria. No methomyl effect was observed in isolated mitochondria, however, indicating that URF13 was not imported and did not confer toxin sensitivity to the mitochondria. Thus, URF13 confers toxin sensitivity to transgenic tobacco with or without import into the mitochondria. There was no correlation between the expression of URF13 and male sterility, suggesting either that URF13 does not cause male sterility in transgenic tobacco or that URF13 is not expressed in sufficient amounts in the appropriate anther cells.


Measuring the prevalence of questionable research practices with incentives for truth telling.
Cases of clear scientific misconduct have received significant media attention recently, but less flagrantly questionable research practices may be more prevalent and, ultimately, more damaging to the academic enterprise. Using an anonymous elicitation format supplemented by incentives for honest reporting, we surveyed over 2,000 psychologists about their involvement in questionable research practices. The impact of truth-telling incentives on self-admissions of questionable research practices was positive, and this impact was greater for practices that respondents judged to be less defensible. Combining three different estimation methods, we found that the percentage of respondents who have engaged in questionable practices was surprisingly high. This finding suggests that some questionable practices may constitute the prevailing research norm.


Genetic analyses reveal a requirement for Dicer1 in the mouse urogenital tract.
Despite the increasing interest in other classes of small RNAs, microRNAs (miRNAs) remain the most widely investigated and have been shown to play a role in a number of different processes in mammals. Many studies investigating miRNA function focus on the processing enzyme Dicer1, which is an RNAseIII protein essential for the biogenesis of active miRNAs through its cleavage of precursor RNA molecules. General deletion of Dicer1 in the mouse confirms that miRNAs are essential for development because embryos lacking Dicer1 fail to reach the end of gastrulation. Here we investigate the role of Dicer1 in urogenital tract development. We utilised a conditional allele of the Dicer1 gene and two Cre-expressing lines, driven by HoxB7 and Amhr2, to investigate the effect of Dicer1 deletion on both male and female reproductive tract development. Data presented here highlight an essential role for Dicer1 in the correct morphogenesis and function of the female reproductive tract and confirm recent findings that suggest Dicer1 is required for female fertility. In addition, HoxB7:Cre-mediated deletion in ureteric bud derivatives leads to a spectrum of anomalies in both males and females, including hydronephrotic kidneys and kidney parenchymal cysts. Male reproductive tract development, however, remains largely unaffected in the absence of Dicer1. Thus, Dicer1 is required for development of the female reproductive tract and also normal kidney morphogenesis.


A systematic review of the influence of the retail food environment around schools on obesity-related outcomes.
The high prevalence of childhood obesity has led to questions about the influence of 'obesogenic' environments on children's health. Public health interventions targeting the retail food environment around schools have been proposed, but it is unclear if they are evidence based. This systematic review investigates associations between food outlets near schools and children's food purchases, consumption and body weight. We conducted a keyword search in 10 databases. Inclusion criteria required papers to be peer reviewed, to measure retailing around schools and to measure obesity-related outcomes among schoolchildren. Thirty papers were included. This review found very little evidence for an effect of the retail food environment surrounding schools on food purchases and consumption, but some evidence of an effect on body weight. Given the general lack of evidence for association with the mediating variables of food purchases and consumption, and the observational nature of the included studies, it is possible that the effect on body weight is a result of residual confounding. Most of the included studies did not consider individual children's journeys through the food environment, suggesting that predominant exposure measures may not account for what individual children actually experience. These findings suggest that future interventions targeting the food environment around schools need careful evaluation.


Validation of the AmpliFLP D1S80 PCR Amplification Kit for forensic casework analysis according to TWGDAM guidelines.
The validation of the AmpliFLP D1S80 PCR Amplification Kit for use in forensic casework was accomplished by performing all the relevant experiments outlined in the TWGDAM guidelines. Standard specimen and reproducibility studies were performed using organic and rapid DNA extraction techniques on both stain and liquid samples (blood, semen and saliva). Over 300 samples from three different populations (US Caucasians, African Americans and US Hispanics) were analyzed to determine allele and genotype frequencies. Purified DNA was mixed in defined ratios (ranging from unmixed DNA samples to 1:9 mixtures of 2 different DNA samples) prior to amplification to demonstrate that samples containing DNA from more than one individual can be detected and, in many cases, that the genotypes contributing to the mixture can be identified. Since casework samples frequently are exposed to environmental insults that can result in DNA degradation, purified DNA was degraded in the laboratory to analyze the effect of DNA fragment length on D1S80 amplification. It is crucial in the validation process to examine actual casework evidentiary material. This D1S80 kit can be used successfully by forensic scientists to amplify and type nonprobative evidentiary material, including bloodstains collected from crime scenes and rape kit materials collected for sexual assault cases. The D1S80 kit is specific to human DNA, and the D1S80 alleles are inherited according to the laws of Mendel. The sensitivity of the novel gel electrophoresis gel matrix allowed the PCR cycle number to be reduced to 29 cycles and the D1S80 kit sensitivity to be increased to 2.5 ng from the previous D1S80 Reagent Set specifications of 30 cycles and 5 ng, respectively.


miRNAs and apoptosis: RNAs to die for.
MicroRNAs (miRNAs) are small non-coding RNAs of about 18-24 nucleotides in length that negatively regulate gene expression. Discovered only recently, it has become clear that they are involved in many biological processes such as developmental timing, differentiation and cell death. Data that connect miRNAs to various kinds of diseases, particularly cancer, are accumulating. miRNAs can influence cancer development in many ways, including the regulation of cell proliferation, cell transformation, and cell death. In this review, we focus on miRNAs that have been shown to play a role in the regulation of apoptosis. We first describe in detail how Drosophila has been utilized as a model organism to connect several miRNAs with the cell death machinery. We discuss the genetic approaches that led to the identification of those miRNAs and subsequent work that helped to establish their function. In the second part of the review article, we focus on the involvement of miRNAs in apoptosis regulation in mammals. Intriguingly, many of the miRNAs that regulate apoptosis have been shown to affect cancer development. In the end, we discuss a virally encoded miRNA that influences the cell death response in the mammalian host cell. In summary, the data gathered over the recent years clearly show the potential and important role of miRNAs to regulate apoptosis at various levels and in several organisms.


3D analysis of facial morphology in Dutch children with cancer.
Background and Objective; Genetic risk factors for childhood cancer may also influence facial morphology. 3D photography can be used in the recognition of differences in face shape among individuals. In previous research, 3D facial photography was used to identify increased facial asymmetry and greater deviation from normal facial morphology in a group of individuals with distinct morphological features who had childhood cancer compared to healthy controls. In this study, we aim to determine whether there is a difference in facial morphology between children with cancer without previously selected morphological features and healthy controls, detected with 3D facial photography. Facial 3D photographic images were obtained of children with a newly diagnosed malignancy. The resulting sample comprised 13 different cancer types. Patients were excluded if they had a known genetic cause of the cancer. Patients were compared to healthy controls, matched for sex, age and ethnic background. The degree of asymmetry and overall deviation of an individual's face from an age and sex typical control face were measured. A total of 163 patients of European descent were included. No significant difference in asymmetry between patients and controls could be identified. On average, patients deviated more from an age and sex typical face than the controls. This study shows that children with cancer deviate more than controls, possibly suggesting a higher prevalence of genetic anomalies within this group. The results suggest that this is not sufficient to discriminate patients from controls. Further research is necessary to explore the patterns of individual variation among the overall deviation of patients and controls.


Biological implications from an autonomous version of Baranyi and Roberts growth model.
An autonomous version of Baranyi and Roberts model (Int. J. Food Microbiology, 23, 1994, pp. 277-294) is developed and analyzed to reveal some subtle points, which are difficult to observe accurately from its equivalent non-autonomous form. In particular we are able to provide a meaningful interpretation to the "physiological state of the cells at inoculation", a parameter introduced by Baranyi and Roberts [Baranyi, J., Roberts, T. A., 1994. A dynamic approach to predicting bacterial growth in food. International Journal of Food Microbiology 23, 277-294] that has a profound impact on microbial growth but is not a direct measurable quantity. In addition, the analysis shows that the transient growth depends on the initial cell concentration and the initial growth rate, but is independent of "the history of the cells" and depends only indirectly (via the initial growth rate) on the previous (pre-inoculation) environment. The stationary solution is independent of the initial conditions. A new, more natural, and biologically meaningful formulation of LAG duration is being suggested in terms of initial conditions being in the neighborhood of one of the unstable stationary points revealed by this autonomous version of the model.


Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility.
The Y chromosome is frequently lost in hematopoietic cells, which represents the most common somatic alteration in men. However, the mechanisms that regulate mosaic loss of chromosome Y (mLOY), and its clinical relevance, are unknown. We used genotype-array-intensity data and sequence reads from 85,542 men to identify 19 genomic regions (P < 5 × 10-8) that are associated with mLOY. Cumulatively, these loci also predicted X chromosome loss in women (n = 96,123; P = 4 × 10-6). Additional epigenome-wide methylation analyses using whole blood highlighted 36 differentially methylated sites associated with mLOY. The genes identified converge on aspects of cell proliferation and cell cycle regulation, including DNA synthesis (NPAT), DNA damage response (ATM), mitosis (PMF1, CENPN and MAD1L1) and apoptosis (TP53). We highlight the shared genetic architecture between mLOY and cancer susceptibility, in addition to inferring a causal effect of smoking on mLOY. Collectively, our results demonstrate that genotype-array-intensity data enables a measure of cell cycle efficiency at population scale and identifies genes implicated in aneuploidy, genome instability and cancer susceptibility.


Challenges and Opportunities with Causal Discovery Algorithms: Application to Alzheimer's Pathophysiology.
Causal Structure Discovery (CSD) is the problem of identifying causal relationships from large quantities of data through computational methods. With the limited ability of traditional association-based computational methods to discover causal relationships, CSD methodologies are gaining popularity. The goal of the study was to systematically examine whether (i) CSD methods can discover the known causal relationships from observational clinical data and (ii) to offer guidance to accurately discover known causal relationships. We used Alzheimer's disease (AD), a complex progressive disease, as a model because the well-established evidence provides a "gold-standard" causal graph for evaluation. We evaluated two CSD methods, Fast Causal Inference (FCI) and Fast Greedy Equivalence Search (FGES) in their ability to discover this structure from data collected by the Alzheimer's Disease Neuroimaging Initiative (ADNI). We used structural equation models (which is not designed for CSD) as control. We applied these methods under three scenarios defined by increasing amounts of background knowledge provided to the methods. The methods were evaluated by comparing the resulting causal relationships with the "gold standard" graph that was constructed from literature. Dedicated CSD methods managed to discover graphs that nearly coincided with the gold standard. For best results, CSD algorithms should be used with longitudinal data providing as much prior knowledge as possible.


Quantification of osmotic water transport in vivo using fluorescent albumin.
Osmotic water transport across the peritoneal membrane is applied during peritoneal dialysis to remove the excess water accumulated in patients with end-stage renal disease. The discovery of aquaporin water channels and the generation of transgenic animals have stressed the need for novel and accurate methods to unravel molecular mechanisms of water permeability in vivo. Here, we describe the use of fluorescently labeled albumin as a reliable indicator of osmotic water transport across the peritoneal membrane in a well-established mouse model of peritoneal dialysis. After detailed evaluation of intraperitoneal tracer mass kinetics, the technique was validated against direct volumetry, considered as the gold standard. The pH-insensitive dye Alexa Fluor 555-albumin was applied to quantify osmotic water transport across the mouse peritoneal membrane resulting from modulating dialysate osmolality and genetic silencing of the water channel aquaporin-1 (AQP1). Quantification of osmotic water transport using Alexa Fluor 555-albumin closely correlated with direct volumetry and with estimations based on radioiodinated ((125)I) serum albumin (RISA). The low intraperitoneal pressure probably accounts for the negligible disappearance of the tracer from the peritoneal cavity in this model. Taken together, these data demonstrate the appropriateness of pH-insensitive Alexa Fluor 555-albumin as a practical and reliable intraperitoneal volume tracer to quantify osmotic water transport in vivo.


Enhanced tolerability of the 5-hydroxytryptophane challenge test combined with granisetron.
A recently developed oral serotonergic challenge test consisting of 5-Hydroxytryptophane (5-HTP, 200 mg) combined with carbidopa (CBD, 100 mg + 50 mg) exhibited dose-related neuroendocrine responsiveness and predictable pharmacokinetics. However, its applicability is limited by nausea and vomiting. A randomized, double-blind, placebo-controlled, four-way crossover trial was performed in 12 healthy male volunteers. The 5-HTP/CBD-challenge was combined with two oral anti-emetics (granisetron, 2 mg or domperidone, 10 mg) to investigate its reliability when side-effects are suppressed. The neuroendocrine response (serum cortisol and prolactin), the side-effect profile [Visual Analogue Scale Nausea (VAS)] and vomiting subjects per treatment were the main outcome measures. Compared to 5-HTP/CBD/placebo, 5-HTP/CBD/ granisetron had no impact on cortisol [% change with 95% confidence interval: -7.1% (18.9; 6.5)] or prolactin levels [-9.6% (-25.1; 9.1)]; 5-HTP/CBD/domperidone increased cortisol [+13.0% (-4.2; 33.4)], and increased prolactin extensively [+336.8% (245.7; 451.9)]. Compared to placebo, VAS Nausea increased non-significantly with granisetron [+7.6 mm (-1.3; 16.5)], as opposed to domperidone [+16.2 mm (7.2; 25.2)] and 5-HTP/CBD/placebo [+14.7 mm (5.5; 23.8)]. No subjects vomited with granisetron, compared to two subjects treated with 5-HTP/CBD/placebo and five subjects with domperidone. Compared with 5-HTP/CBD/placebo, granisetron addition decreased C(max) of 5-HTP statistically significantly different (from 1483 to 1272 ng/ml) without influencing AUC(0- infinity). Addition of granisetron to the combined 5-HTP/CBD challenge suppresses nausea and vomiting without influencing the neuroendocrine response or pharmacokinetics, enhancing its clinical applicability in future psychiatric research and drug development.


Evaluation of rabies virus characterization to enhance early detection of important rabies epizootic events in the United States.
To evaluate rabies virus (RABV) characterization data obtained from animal specimens submitted to the US public health rabies surveillance system and propose a standardized approach to sample selection for RABV characterization that could enhance early detection of important rabies epizootic events in the United States. United States public health rabies surveillance system data collected from January 1, 2010, through December 31, 2015. Data were reviewed to identify RABV-positive specimens for which virus characterization would likely provide information regarding any of 4 overarching events (discovery of novel variants, translocation of RABV variants, host-shift events, and any unusual rabies-related event) that could substantially alter animal rabies epizootiology in the United States. These specimens were designated as specimens of epizootiological importance (SEIs). Estimates of the additional number of specimens that public health laboratories could expect to process each year if all SEIs underwent RABV characterization were calculated. During the 6-year period, the mean annual number of SEIs was 855 (95% CI, 739 to 971); the mean number of SEIs that underwent virus characterization was 270 (95% CI, 187 to 353). Virus characterization of all SEIs would be expected to increase the public health laboratories' test load by approximately 585 (95% CI, 543 to 625) specimens/y. Prioritization of RABV characterization of SEIs may improve early detection of rabies events associated with RABV host shifts, variant translocations, and importation. Characterization of SEIs may help refine wildlife rabies management practices. Each public health laboratory should evaluate testing of SEIs to ensure diagnostic laboratory capacity is not overstretched.


Expanding HIV testing efforts in concentrated epidemic settings: a population-based survey from rural Vietnam.
To improve HIV prevention and care programs, it is important to understand the uptake of HIV testing and to identify population segments in need of increased HIV testing. This is particularly crucial in countries with concentrated HIV epidemics, where HIV prevalence continues to rise in the general population. This study analyzes determinants of HIV testing in a rural Vietnamese population in order to identify potential access barriers and areas for promoting HIV testing services. A population-based cross-sectional survey of 1874 randomly sampled adults was linked to pregnancy, migration and economic cohort data from a demographic surveillance site (DSS). Multivariate logistic regression analysis was used to determine which factors were associated with having tested for HIV. The age-adjusted prevalence of ever-testing for HIV was 7.6%; however 79% of those who reported feeling at-risk of contracting HIV had never tested. In multivariate analysis, younger age (aOR 1.85, 95% CI 1.14-3.01), higher economic status (aOR 3.4, 95% CI 2.21-5.22), and semi-urban residence (aOR 2.37, 95% CI 1.53-3.66) were associated with having been tested for HIV. HIV testing rates did not differ between women of reproductive age who had recently been pregnant and those who had not. We found low testing uptake (6%) among pregnant women despite an existing prevention of mother-to-child HIV testing policy, and lower-than-expected testing among persons who felt that they were at-risk of HIV. Poverty and residence in a more geographically remote location were associated with less HIV testing. In addition to current HIV testing strategies focusing on high-risk groups, we recommend targeting HIV testing in concentrated HIV epidemic settings to focus on a scaled-up provision of antenatal testing. Additional recommendations include removing financial and geographic access barriers to client-initiated testing, and encouraging provider-initiated testing of those who believe that they are at-risk of HIV.


Electronic spectroscopy of I(2)-Xe complexes in solid Krypton.
In the present work, we have studied ion-pair states of matrix-isolated I(2) with vacuum-UV absorption and UV-vis-NIR emission, where the matrix environment is systematically changed by mixing Kr with Xe, from pure Kr to a more polarizable Xe host. Particular emphasis is put on low doping levels of Xe that yield a binary complex I(2)-Xe, as verified by coherent anti-Stokes Raman scattering (CARS) measurements. Associated with interaction of I(2) with Xe we can observe strong new absorption in vacuum-UV, redshifted 2400 cm(-1) from the X → D transition of I(2). Observed redshift can be explained by symmetry breaking of ion-pair states within the I(2)-Xe complex. Systematic Xe doping of Kr matrices shows that at low doping levels, positions of I(2) ion-pair emissions are not significantly affected by complexation with Xe, but simultaneous increase of emissions from doubly spin-excited states indicates non-radiative relaxation to valence states. At intermediate doping levels ion-pair emissions shift systematically to red due to change in the average polarizability of the environment. We have conducted spectrally resolved ultrafast pump-probe ion-pair emission studies with pure and Xe doped Kr matrices, in order to reveal the influence of Xe to I(2) dynamics in solid Kr. Strikingly, relaxed emission from the ion-pair states shows no indication of complex presence. It further indicates that the complex escapes detection due to a non-radiative relaxation.


Impaired killing of HCMV-infected retinal pigment epithelial cells by anti-pp65 CD8(+) cytotoxic T cells.
Host defense against infection by human cytomegalovirus (HCMV) is ensured in great part by cytotoxic CD8(+) T lymphocytes (CTLs) directed against the tegument protein pp65. The hyperimmediate release of incoming pp65 into the major histocompatibility complex (MHC) class I pathway after fusion of the virus with the cell membrane provides a very early mechanism of defense. In retinal pigment epithelial (RPE) cells HCMV is known to enter through endocytosis. This study was conducted to determine whether this means of penetration into the cells would allow the virus to elude immune surveillance. Infection of RPE cells with HCMV AD169 was performed for 6 hours, 48 hours, and 8 days. Expression of intracellular pp65 in RPE cells and in the astrocytoma reference cell line U373MG was evaluated by flow cytometry, fluorescence microscopy, and Western blot analysis. Killing of both HCMV-infected cell lines by HLA-A2-restricted CD8(+) CTLs directed against pp65 was monitored by (51)Cr-release assays. RPE cells were not lysed by CTLs directed against incoming pp65, contrary to U373MG. Moreover, both cell lines were not killed by anti-pp65 CTLs later after infection, because of the MHC class-I-downregulating effect of HCMV unique short (US2-11) proteins. In RPE cells, both HCMV entry through endocytosis and the immunosuppressive effect of US proteins could allow the virus to evade immune surveillance at any stage of infection, which could promote viral spreading within the retina.


The UCSC genome browser and associated tools.
The UCSC Genome Browser (http://genome.ucsc.edu) is a graphical viewer for genomic data now in its 13th year. Since the early days of the Human Genome Project, it has presented an integrated view of genomic data of many kinds. Now home to assemblies for 58 organisms, the Browser presents visualization of annotations mapped to genomic coordinates. The ability to juxtapose annotations of many types facilitates inquiry-driven data mining. Gene predictions, mRNA alignments, epigenomic data from the ENCODE project, conservation scores from vertebrate whole-genome alignments and variation data may be viewed at any scale from a single base to an entire chromosome. The Browser also includes many other widely used tools, including BLAT, which is useful for alignments from high-throughput sequencing experiments. Private data uploaded as Custom Tracks and Data Hubs in many formats may be displayed alongside the rich compendium of precomputed data in the UCSC database. The Table Browser is a full-featured graphical interface, which allows querying, filtering and intersection of data tables. The Saved Session feature allows users to store and share customized views, enhancing the utility of the system for organizing multiple trains of thought. Binary Alignment/Map (BAM), Variant Call Format and the Personal Genome Single Nucleotide Polymorphisms (SNPs) data formats are useful for visualizing a large sequencing experiment (whole-genome or whole-exome), where the differences between the data set and the reference assembly may be displayed graphically. Support for high-throughput sequencing extends to compact, indexed data formats, such as BAM, bigBed and bigWig, allowing rapid visualization of large datasets from RNA-seq and ChIP-seq experiments via local hosting.


Endoscopic endonasal approach for craniovertebral junction pathology: a review of the literature.
The transoral approach is the gold standard for ventral decompression of the brainstem caused by craniovertebral junction (CVJ) pathology. This approach is often associated with significant morbidity, related to swallowing and respiratory complications. The endoscopic endonasal approach was introduced to reduce the rate of these complications. However, the exact role of this approach in the treatment of CVJ pathology is not well defined. A comprehensive literature search was performed to identify series of patients with pathology of the CVJ treated via the endoscopie endonasal approach. Data on patient characteristics, indications for treatment, complications, and outcome were obtained and analyzed. Twelve studies involving 72 patients were included. The most common indications for treatment were rheumatoid pannus (38.9%) and basilar invagination (29.2%). Cerebrospinal fluid leak was found in 18% of cases intraoperatively and 4.2% of cases postoperatively. One case of meningitis complicated by sepsis and death represents the procedure-related mortality of 1.4%. Of the patients without preoperative swallowing impairment, 95% returned to oral feeding on the 3rd postoperative day. Ninety-three percent of patients experienced improvement in neurological symptoms after the procedure. The endonasal endoscopie approach is effective for the treatment of neural compression caused by CVJ pathology. It offers advantages such as lower rates of postoperative dysphagia and respiratory complications when compared with the more traditional transoral approach. However, these 2 approaches should be seen as complementary rather than alternatives. Patient-related factors as well as the surgeon's expertise must be considered when making treatment decisions.


Development of potent glucagon antagonists: structure-activity relationship study of glycine at position 4.
We examined the functional role of glycine at position 4 in the potent glucagon antagonist [desHis(1), Glu(9)]glucagon amide, by substituting the L- and D-enantiomers of alanine and leucine for Gly(4) in this antagonist. The methyl and isobutyl side-chain substituents were introduced to evaluate the preference shown by the glucagon receptor, if any, for the orientation of the N-terminal residues. The L-amino acids demonstrated only slightly better receptor recognition than the D-enantiomers. These results suggest that the Gly(4) residue in glucagon antagonists may be exposed to the outside of the receptor. The enhanced binding affinities of analogs 1 and 3 compared with the parent antagonist, [desHis(1), Glu(9)]glucagon amide, may have resulted from the strengthened hydrophobic patch in the N-terminal region and/or the increased propensity for a helical conformation due to the replacement of alanine and leucine for glycine. Thus, as a result of the increased receptor binding affinities, antagonist activities of analogs 1-4 were increased 10-fold compared with the parent antagonist, [desHis(1), Glu(9)]glucagon amide. These potent glucagon antagonists have among the highest pA(2) values of any glucagon analogs reported to date.


Species conservation of the T cell lymphocyte CD2 cell surface antigen.
A rabbit polyclonal antiserum was raised against a synthetic peptide, termed CD2-300, comprizing 18 amino acid resides which are conserved among the cytoplasmic domains of the human, rat and mouse CD2 antigens. Cross-depletion experiments showed that the CD2 monoclonal antibody OKT11 and purified CD2-300 antibodies (Ab) precipitated the same molecules from the surface of human T lymphoblasts. The results of immunoprecipitation analyses indicated that the purified CD2-300 Ab were specific for human and mouse CD2, and that the CD2-300 peptide competitively and specifically inhibited precipitation by CD2-300 Ab in both species. When employed to stain murine tissues, the CD2-300 Ab gave the anticipated pattern of distribution for the CD2 antigen, although there was some nonspecific labeling of non-T cells.


Plasma renin activity and pro-B-type natriuretic peptide levels in different atrial fibrillation types.
Renin-angiotensin system may be activated during atrial fibrillation (AF). Our aim was to evaluate plasma renin activity (PRA) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in patients with different AF types who had normal left ventricular (LV) systolic function. This cross-sectional study included 97 patients with recent (<or=7 days), persistent (7 days to 12 months) and permanent AF (<or=12 months), and age- and sex-matched 30 controls with sinus rhythm. Plasma levels of PRA and NT-pro-BNP were measured and presented as median (25th-75th percentiles). Echocardiographic examination was performed in all population. Variance and logistic regression analyses were also used for multiple comparisons and independent predictors, respectively. Median NT-proBNP levels were higher in overall patients with AF than in controls [114 (63-165) vs 50 (38-58) pg/ml, p=0.001), but PRA level was comparable in both groups. Similarly, NT-proBNP levels were also higher in all subtypes of AF compared with controls (p=0.05). In addition, there was a significant difference in NT-proBNP level among recent, persistent and permanent AF subtypes (p=0.001). This difference mainly derived from the recent AF subtypes. Whereas PRA level was similar in all AF subtypes and controls. Age was an independent predictor of PRA level >or=1.9 ng/ml/hour (OR=1.1, 95% CI 1.01-1.23, p=0.03). With NT-proBNP level >or=52 pg/ml, independent predictors were age (OR=1.1, 95% CI 1.01-1.19, p=0.02), presence of persistent and/or permanent AF (OR=6.8, 95% CI 1.03-45.7, p=0.04) and left atrial dimension (OR=1.2, 95% CI 1.03-1.36, p=0.02). Plasma NT-proBNP levels can be associated with AF and its subtypes in patients with normal LV systolic function, whereas there was no association between PRA levels and AF.


[Association between low serum magnesium levels and the extent of abdominal aortic calcification in renal transplant recipients].
Introduction: In renal transplant recipients (RTRs) vascular calcifications has been associated with an increased risk of cardiovascular as well as all-cause mortality. Recent experimental and clinical studies showed that magnesium (Mg) deficiency may be related to the progression of vascular calcification. Aim of this study was to determine the hypothetical association between Mg and vascular calcifications in RTRs. Methods: Seventy-one RTRs underwent a lateral X-ray of the lumbar spine to assess the presence of calcification of the abdominal aorta. Abdominal aortic calcium (AAC) content was graded with a score ranging from 0 to 24 points. At the same time were evaluated: carotid artery intima-media thickness (IMT); left ventricular mass index (LVMi); sCa, sPO4, sMg, uMg, PTH, HDL, LDL, blood pressure (BP). Results: AAC was correlated with: age (r=0.601; P<0.001), dialysis vintage (r=0.314; P<0.01), sMg (r=-0.438; P<0.001), PTH (r=0.322; P<0.01), SBP (r=0.539; P<0.001), IMT (r=0.706; P<0.001), LVMi (r=0.326; P<0.01). Serum Mg was correlated with PTH (r= -0.304; P<0.01). IMT was correlated with LVMi and SBP (r=0.330, P<0.01; r=0.494, P <0.0001; respectively). Stepwise multiple regression analysis showed that the final model contained six predictor variables for AAC (IMT, sMg, age, SBP, proteinuria, and dialysis vintage; F5,64=31.7, P<0.001; Adjusted R2 =0.718). Patients in higher AAC thirtile (8-24) were older, with longer dialysis vintage, lower sMg, higher PTH, and higher IMT values. Conclusions: Our results suggest a hypothetical interrelationship between sMg and ACC, and IMT in RTRs.


Silver Nanoparticles Impact Biofilm Communities and Mussel Settlement.
Silver nanoparticles (AgNPs) demonstrating good antimicrobial activity are widely used in many fields. However, the impact of AgNPs on the community structures of marine biofilms that drive biogeochemical cycling processes and the recruitment of marine invertebrate larvae remains unknown. Here, we employed MiSeq sequencing technology to evaluate the bacterial communities of 28-day-old marine biofilms formed on glass, polydimethylsiloxane (PDMS), and PDMS filled with AgNPs and subsequently tested the influence of these marine biofilms on plantigrade settlement by the mussel Mytilus coruscus. AgNP-filled PDMS significantly reduced the dry weight and bacterial density of biofilms compared with the glass and PDMS controls. AgNP incorporation impacted bacterial communities by reducing the relative abundance of Flavobacteriaceae (phylum: Bacteroidetes) and increasing the relative abundance of Vibrionaceae (phylum: Proteobacteria) in 28-day-old biofilms compared to PDMS. The settlement rate of M. coruscus on 28-day-old biofilms developed on AgNPs was lower by >30% compared to settlement on control biofilms. Thus, the incorporation of AgNPs influences biofilm bacterial communities in the marine environment and subsequently inhibits mussel settlement.


Structural coercion in the context of community engagement in global health research conducted in a low resource setting in Africa.
While community engagement is increasingly promoted in global health research to improve ethical research practice, it can sometimes coerce participation and thereby compromise ethical research. This paper seeks to discuss some of the ethical issues arising from community engagement in a low resource setting. A qualitative study design focusing on the engagement activities of three biomedical research projects as ethnographic case studies was used to gain in-depth understanding of community engagement as experienced by multiple stakeholders in Malawi. Data was collected through participant observation, 43 In-depth interviews and 17 focus group discussions with community leaders, research staff, community members and research participants. Thematic analysis was used to analyse and interpret the findings. The results showed that structural coercion arose due to an interplay of factors pertaining to social-economic context, study design and power relations among research stakeholders. The involvement of community leaders, government stakeholders, and power inequalities among research stakeholders affected some participants' ability to make autonomous decisions about research participation. These results have been presented under the themes of perception of research as development, research participants' motivation to access individual benefits, the power of vernacular translations to influence research participation, and coercive power of leaders. The study identified ethical issues in community engagement practices pertaining to structural coercion. We conclude that community engagement alone did not address underlying structural inequalities to ensure adequate protection of communities. These results raise important questions on how to balance between engaging communities to improve research participation and ensure that informed consent is voluntarily given.