Effect of lycopene from Chlorella marina on high cholesterol-induced oxidative damage and inflammation in rats.
Even though the role of all-trans lycopene from tomato in controlling atherosclerosis was reported, but no report is available on the cis-isomer of lycopene obtained from an easily available source green algae Chlorella marina. So in this study, Sprague Dawley rats fed with high-cholesterol diet were given standard drug lovastatin; algal lycopene (AL) (cis/all-trans 40:60) and tomato all-trans lycopene (TL) and the following parameters were studied. Total cholesterol, low-density lipoprotein, triglycerides were decreased significantly and the high-density lipoprotein levels were increased on treatment with AL. The activities of antioxidant enzymes catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase were found to be increased, whereas thiobarbituric acid reactive substances levels were decreased in AL when compared to the drug and TL-treated rats. The activities of inflammatory marker enzymes like cyclooxygenase, 15-lipoxygenase in monocytes and myeloperoxidase, C-reactive protein and ceruloplasmin levels in serum were found to be decreased on treatment with AL. Histopathological studies revealed that lycopene from this alga could reduce fatty liver and aortic plaque when compared to the drug and TL. Algal lycopene showed very significant antioxidant and anti-inflammatory effect in high-cholesterol fed rats. Therefore, AL from C. marina would be recommended for the treatment of hyperlipidemia.


Synthesis, self-assembly, and immunological activity of α-galactose-functionalized dendron-lipid amphiphiles.
Nanoassemblies presenting multivalent displays of biologically active carbohydrates are of significant interest for a wide array of biomedical applications ranging from drug delivery to immunotherapy. In this study, glycodendron-lipid hybrids were developed as a new and tunable class of dendritic amphiphiles. A modular synthesis was used to prepare dendron-lipid hybrids comprising distearylglycerol and 0 through 4th generation polyester dendrons with peripheral protected amines. Following deprotection of the amines, an isothiocyanate derivative of C-linked α-galactose (α-Gal) was conjugated to the dendron peripheries, affording amphiphiles with 1 to 16 α-Gal moieties. Self-assembly in water through a solvent exchange process resulted in vesicles for the 0 through 2nd generation systems and micelles for the 3rd and 4th generation systems. The critical aggregation concentrations decreased with increasing dendron generation, suggesting that the effects of increasing molar mass dominated over the effects of increasing the hydrophilic weight fraction. The binding of the assemblies to Griffonia simplicifolia Lectin I (GSL 1), a protein with specificity for α-Gal was studied by quantifying the binding of fluorescently labeled assemblies to GSL 1-coated beads. It was found that binding was enhanced for amphiphiles containing higher generation dendrons. Despite their substantial structural differences with the natural ligands for the CD1d receptor, the glycodendron-lipid hybrids were capable of stimulating invariant natural killer T (iNKT) cells, a class of innate-like T cells that recognize lipid and glycolipid antigens presented by CD1d and that are implicated in a wide range of diseases and conditions including but not limited to infectious diseases, diabetes and cancer.


Extracellular Vesicles from Wharton's Jelly Mesenchymal Stem Cells Suppress CD4 Expressing T Cells Through Transforming Growth Factor Beta and Adenosine Signaling in a Canine Model.
Mesenchymal stem cells (MSCs) are widely investigated as potential therapeutic agents due to their potent immunomodulatory capacity. Although specific mechanisms by which MSC acts on immune cells are emerging, many questions remain, including the potential of extracellular vesicles (EVs) to mediate biological activities. Canine MSCs are of interest for both veterinary and comparative models of disease and have been shown to suppress CD4pos T cell proliferation. The aim of this study was to determine whether EV isolated from canine Wharton's jelly-derived MSC (WJ-MSC EV) suppresses CD4pos T cell proliferation using biochemical mechanisms previously ascribed to soluble mediators [transforming growth factor beta (TGF-β) and adenosine]. WJ-MSC EV exhibited mode of 125 nm diameter, low buoyant density (1.1 g/mL), and expression of EV proteins Alix and TSG101. Functionally, EVs inhibited CD4pos T cell proliferation in a dose-dependent manner, which was absent in EV-depleted samples and EVs from non-MSC fibroblasts. EV suppression of CD4pos T cell proliferation was inhibited by a TGF-βRI antagonist, neutralizing antibodies to TGF-β, or A2A adenosine receptor blockade. TGF-β was present on EVs as latent complexes most likely tethered to EV membrane by betaglycan. These data demonstrate that canine WJ-MSC EV utilizes TGF-β and adenosine signaling to suppress proliferation of CD4pos T cell and will enable further investigation into mechanisms of immune cell modulation, as well as refinement of WJ-MSC and their EVs for therapeutic application.


Academic abilities and glycaemic control in children and young people with Type 1 diabetes mellitus.
To determine if children and young people aged < 23 years with Type 1 diabetes differ in academic ability from age-matched control subjects without Type 1 diabetes and whether academic scores are related to glycaemic control. Using a cross-sectional study design, we administered cognitive and academic tests (Woodcock-Johnson III Spatial Relations, General Information, Letter-Word Recognition, Calculation and Spelling tests) to young people with Type 1 diabetes (n=61) and control subjects (n=26) aged 9-22 years. The groups did not differ in age or gender. Participants with Type 1 diabetes had a disease duration of 5-17.7 years. History of glycaemic control (HbA1c , diabetic ketoacidosis and severe hypoglycaemic episodes) was obtained via medical records and interviews. The participants with Type 1 diabetes had a lower mean estimated verbal intelligence (IQ) level compared with those in the control group (P=0.04). Greater exposure to hyperglycaemia over time was associated with lower spelling abilities within the group with Type 1 diabetes (P=0.048), even after controlling for age, gender, socio-economic status, blood glucose level at time of testing and verbal IQ (P=0.01). History of severe hypoglycaemia or ketoacidosis was not associated with differences in academic abilities. In children and young people, Type 1 diabetes was associated with a lower verbal IQ. Moreover, increased exposure to hyperglycaemia was associated with lower spelling performance. These results imply that hyperglycaemia can affect cognitive function and/or learning processes that may affect academic achievement.


The Influence of Hospital Site on Emergency Physician Press Ganey Scores.
The use of physician satisfaction scores to evaluate emergency medicine physicians' performance and compensation is controversial. Prior studies have shown that the clinical environment may influence scores. This study compared satisfaction scores for the same physician at different emergency departments (ED). Differences in their individual score may indicate the ED environment could be as important as the physician's interaction. Press Ganey satisfaction scores were obtained for physicians at three EDs-Grand Strand, South Strand and North Strand-between July 2018 and June 2019. Included physicians worked at all 3 facilities and had at least 6 patient satisfaction surveys at each site. The Press Ganey scale ranges from 1-5, with 1 as "very poor" and 5 as "very good". Using top-box methodology, the total physician score was generated from the average of 4 questions: courtesy, keeping patients informed, patient comfort and listening. We utilized descriptive statistics to compare scores for all physicians at each of the 3 sites. In addition, each physician's top box scores were averaged by site for analysis (two-way ANOVA) to determine if individual physician scores varied in different EDs. Fourteen physicians met inclusion criteria. Physicians at the main ED had an average total score of 73.37 ± 6.08 (SD) versus 76.5 ± 8.87 and 85.09 ± 7.75 at the 2 free standing EDs. Two-way ANOVA showed that the Press Ganey scores were significantly different for individual physicians between the newer free-standing ED and either the main ED or the other free-standing ED, p<0.001 and p=0.014, respectively. The observed difference between the main ED and the older free-standing ED was not statistically significant, p=0.111. When applying the same analysis to the 4 individual physician questions, the significant differences or trends persisted. Physician satisfaction scores demonstrated a significant variance depending on where they practiced. The highest patient satisfaction scores were received at the newest of the 3 facilities with individual rooms. The findings suggest that Press Ganey scores may not be reliable when comparing patient satisfaction scores for providers who practice in different EDs.


The squid axon as a model for studying plasma membrane mechanisms for calcium regulation.
Calcium movement across plasma membranes occurs mainly by three routes: voltage-dependent calcium channels, adenosine 5'-triphosphate-driven calcium pump, and Na+-Ca2 exchange. The regulation of the intracellular ionized calcium is the consequence of two parallel calcium transport mechanisms: a high affinity, low capacity system responsible for extruding calcium during resting conditions (calcium pump) and a low affinity and high capacity system (Na+-Ca2 antiporter). This last system is designed to extrude calcium ions when intracellular calcium rises above certain levels and also to lead calcium ions into the cell under conditions that favor the reverse mode of operation of the exchanger. This short review provides an analysis of the most conspicuous features of the two membrane transport mechanisms determined in dialyzed squid axons with special emphasis on both the complexity of the Na+-Ca2+ exchange system and its marked asymmetry.


Sequence and phylogenetic analysis of S1, S2, M, and N genes of infectious bronchitis virus isolates from Malaysia.
Two Malaysian infectious bronchitis virus isolates, MH5365/95 and V9/04 were characterized based on sequence and phylogenetic analyses of S1, S2, M, and N genes. Nucleotide sequence alignments revealed many point mutations, short deletions, and insertions in S1 region of both IBV isolates. Phylogenetic analysis of S1 gene and sequences analysis of M gene indicated that MH5365/95 and V9/04 belong to non-Massachusetts strain. However, both isolates share only 77% identity. Analysis based on S1 gene showed that MH5365/95 shared more than 87% identity to several Chinese strains. Meanwhile, V9/04 showed only 67-77% identity to all the previously studied IBV strains included in this study suggesting it is a variant of IBV isolate that is unique to Malaysia. Phylogenetic analysis suggests, although both isolates were isolated 10 years apart from different states in Malaysia, they shared a common origin. Analysis based on S2 and N genes indicated that both strains are highly related to each other, and there are fewer mutations which occurred in the respective genes.


Association of vaginal dysbiosis and biofilm with contraceptive vaginal ring biomass in African women.
We investigated the presence, density and bacterial composition of contraceptive vaginal ring biomass and its association with the vaginal microbiome. Of 415 rings worn by 120 Rwandese women for three weeks, the biomass density was assessed with crystal violet and the bacterial composition of biomass eluates was assessed with quantitative polymerase chain reaction (qPCR). The biomass was visualised after fluorescence in situ hybridisation (FISH) and with scanning electron microscopy (SEM). The vaginal microbiome was assessed with Nugent scoring and vaginal biofilm was visualised after FISH. All vaginal rings were covered with biomass (mean optical density (OD) of 3.36; standard deviation (SD) 0.64). Lactobacilli were present on 93% of the rings, Gardnerella vaginalis on 57%, and Atopobium vaginae on 37%. The ring biomass density was associated with the concentration of A. vaginae (OD +0.03; 95% confidence interval (CI) 0.01-0.05 for one log increase; p = 0.002) and of G. vaginalis (OD +0.03; (95% CI 0.01-0.05; p = 0.013). The density also correlated with Nugent score: rings worn by women with a BV Nugent score (mean OD +0.26), and intermediate score (mean OD +0.09) had a denser biomass compared to rings worn by participants with a normal score (p = 0.002). Furthermore, presence of vaginal biofilm containing G. vaginalis (p = 0.001) and A. vaginae (p = 0.005) correlated with a denser ring biomass (mean OD +0.24 and +0.22 respectively). With SEM we observed either a loose network of elongated bacteria or a dense biofilm. We found a correlation between vaginal dysbiosis and the density and composition of the ring biomass, and further research is needed to determine if these relationships are causal. As multipurpose vaginal rings to prevent pregnancy, HIV, and other sexually transmitted diseases are being developed, the potential impact of ring biomass on the vaginal microbiota and the release of active pharmaceutical ingredients should be researched in depth.


Haemodilution in acute stroke: results of the Italian haemodilution trial. Italian Acute Stroke Study Group.
In a multicentre clinical trial 1267 patients with hemispheric stroke of duration 12 h or less and haematocrit of 35% or more were prospectively randomised to either haemodilution (by venesection and replacement of the same volume of dextran 40 in saline solution) or control treatment groups. In the haemodiluted group mean haematocrit declined from 43% to 37% at 48 h and this fall was maintained for seven days. A plain computed tomographic scan was obtained in all but 37 patients. 87% of the strokes were infarcts and 13% were haemorrhages. After six months the numbers of dead or severely disabled patients were equally distributed in the two treatment groups, and this was true also within the ischaemic and haemorrhagic subgroups. Furthermore, haemodilution did not improve outcome either in the group with very recent ischaemic stroke (less than 6 h) or in the subgroup with highest haematocrit (greater than 45%). Thus, moderate haemodilution does not improve the outcome in acute stroke patients.


Proteomic analysis of an Aedes albopictus cell line infected with Dengue serotypes 1 and 3 viruses.
Proteomic analysis was performed to identify proteins regulated during infection by Dengue serotypes 1 and 3 in an Aedes albopictus cell line. The potential of these viruses to cause severe disease at primary infection is of interest although few studies have been performed with these two Dengue serotypes. The most relevant observation of our study is the significant overexpression of proteins involved in the cellular stress response and the glycolysis pathway after 48 hours of infection. Viral infection activates the translation of some host genes, which may result in stress due to responses involving unfolded proteins. Therefore, the oxidation reduction and glycolytic mechanisms could participate in the antiviral response against Dengue virus. The results of our study should help to improve our knowledge of the virus-mosquito interaction at a cellular level with the aim of designing efficient strategies for the control of Dengue virus.


Analysis of the cellular functions of PTEN using catalytic domain and C-terminal mutations: differential effects of C-terminal deletion on signalling pathways downstream of phosphoinositide 3-kinase.
The tumour suppressor protein, PTEN (phosphatase and tensin homolog deleted on chromosome 10), is a phosphatase that can dephosphorylate tyrosine-containing peptides, Shc, focal adhesion kinase and phosphoinositide substrates. In cellular assays, PTEN has been shown to antagonize the PI-3K-dependent activation of protein kinase B (PKB) and to inhibit cell spreading and motility. It is currently unclear, however, whether PTEN accomplishes these effects through its lipid- or protein-phosphatase activity, although strong evidence has demonstrated the importance of the latter for tumour suppression by PTEN. By using a PTEN G129E (Gly(129)-->Glu) mutant that has lost its lipid phosphatase activity, while retaining protein phosphatase activity, we demonstrated a requirement for the lipid phosphatase activity of PTEN in the regulation of PKB activity, cell viability and membrane ruffling. We also made a small C-terminal deletion of PTEN, removing a putative PDZ (PSD95, Dlg and ZO1)-binding motif, with no detectable effect on the phosphatase activity of the protein expressed in HEK293 cells (human embryonic kidney 293 cells) assayed in vitro. Surprisingly, expression of this mutant revealed differential requirements for the C-terminus in the different functional assays. Wild-type and C-terminally deleted PTEN appeared to be equally active in down-regulating PKB activity, but this mutant enzyme had no effect on platelet-derived growth factor (PDGF)-induced membrane ruffling and was only partially active in a cell viability assay. These results stress the importance of the lipid phosphatase activity of PTEN in the regulation of several signalling pathways. They also identify a mutation, similar to mutations that occur in some human tumours, which removes the effect of PTEN on membrane ruffling but not that on PKB.


Characterization of single calcium channels in Drosophila embryonic nerve and muscle cells.
Voltage-activated Ca channels play a central role in synaptic transmission, control of cell excitability, and many other cellular processes. It is now clear that there are multiple types of Ca channels with various modes of modulation. Drosophila offers exceptional advantages for studying the molecular basis of the diversity and modulation of Ca channels. As a step in this study, we have characterized the single-channel Ba currents recorded from cell-attached patches on cultured embryonic Drosophila nerve and muscle cells. The voltage dependence and selectivity of the channels carrying these Ba currents identify them as Ca channels. All Ca channels found in Drosophila neurons appear to have the same voltage dependence of activation and similar single-channel conductance, 12-17 pS (100 mM Ba2+). However, the kinetic properties of individual Ca channels vary greatly. The mean open time of individual channels ranges from 2 msec to less than 0.2 msec. Some channels completely inactivate during the first half of a 90 msec depolarization, while others are more active in the second half. Many channels open during almost every depolarization, while others open in less than 20% of the depolarizations. Channels with longer open times tend to inactivate and open during a small fraction of depolarizations. When these kinetic properties were quantified, a continuum of values was found, instead of the clustering of values that might be expected for discrete types of channels. Muscle Ca channels form a more homogeneous class than do the neuronal Ca channels. The muscle Ca channel conductance is 18 pS. These channels do not inactivate during 90 msec depolarizations and open during a majority of depolarizations applied. Muscle Ca channels are similar to a subset of neuronal Ca channels. When a purified toxin from the spider Hololena curta is applied to neurons, the number of active Ca channels is reduced, and those channels still active open in a small fraction of depolarization. Since channels that open in a small fraction of depolarizations tend to inactivate, these data support the hypothesis that this toxin selectively blocks noninactivating neuronal Ca channels. This differential toxin sensitivity and the much larger variability observed in kinetic properties of neuronal, compared to muscle, Ca channels suggest that there are at least two types of neuronal Ca channels in Drosophila.


Scp160p, a multiple KH-domain protein, is a component of mRNP complexes in yeast.
Scp160p is a 160 kDa protein in the yeast Saccharomyces cerevisiae that contains 14 repeats of the hnRNP K-homology (KH) domain, and demonstrates significant sequence homology to a family of proteins collectively known as vigilins. As a first step towards defining the function of Scp160p, we have characterized the subcellular distribution and in vivo interactions of this protein. Using sucrose gradient fractionation studies we have demonstrated that Scp160p in cytoplasmic lysates is predominantly associated with polyribosomes. Furthermore, we have found that Scp160p is released from polyribosomes by EDTA in the form of a large complex of> or =1300 kDa that is sensitive both to RNase and NaCl. Using affinity-chromatography to isolate these complexes, we have identified two protein components other than Scp160p: poly(A) binding protein, Pab1p, and Bfr1p. The presence of Pab1p confirms these complexes to be mRNPs. The presence of Bfr1p is intriguing because the null phenotype for this gene is essentially the same as that reported for scp160 -null cells: increased cell size and aberrant DNA content. These results demonstrate that Scp160p associates with polyribosome-bound mRNP complexes in vivo, implicating a role for this protein in one or more levels of mRNA metabolism in yeast.


Neuroprotection by propofol in acute mechanical injury: role of GABAergic inhibition.
1. Whole cell patch-clamp and extracellular field recordings were obtained from granule cells of the dentate gyrus in 400-microns-thick brain slices of the adult rat to determine the actions of the intravenous general anesthetic 2,6-diisopropylphenol (propofol) on acute neuronal survival and preservation of synaptic integrity after amputation of dendrites (dendrotomy), and to determine the role of gamma-aminobutyric acid-A (GABAA)-receptor-mediated inhibition in the neuroprotective effects of propofol. The actions of propofol were compared with those exerted by another widely used intravenous general anesthetic, 5-ethyl-5-[1-methylbutyl]-2-thiobarbituric acid (thiopental). 2. Propofol (10 microM) increased the frequency (control: 5.9 +/- 0.9 Hz, mean +/- SE; propofol: 10.5 +/- 1.3 Hz) and the single-exponential decay time constant (tau D) (control: 4.5 +/- 0.2 ms; propofol: 15.3 +/- 1.5 ms) of miniature inhibitory postsynaptic currents (mIPSCs) recorded in control neurons. Thiopental (25 microM) also increased the tau D (14.3 +/- 0.9 ms) of mISPCs, but had no effect on mIPSC frequency. Both anesthetics potentiated mIPSCs at low concentrations (propofol: 5 microM; thiopental: 1 microM). Propofol and thiopental did not change the peak amplitude and rise times of mIPSCs. 3. Propofol (10 microM) was able to depress the excitability of control granule cells, as determined by the reduction in the amplitude of the orthodromic population spikes. This depression could be prevented by the GABAA receptor antagonist bicuculline (50 microM), indicating that propofol reduces excitability via GABAA receptor functions. 4. Propofol and thiopental were neuroprotectant (assessed by antidromic population responses 2-5 h after injury) if present before and during the amputation of the granule cell dendrites. The protective actions were dose dependent, and at high doses (propofol: 200 microM; thiopental: 400 microM) the anesthetics were as neuroprotective against dendrotomy-induced cell death as 2-amino 5-phosphovaleric acid (APV) and 6-cyano-7-nitroquinoxaline-2,3 dione (CNQX). The protective effects of the anesthetics were completely blocked with the GABAA receptor antagonists picrotoxin or bicuculline, and were mimicked by the GABAA receptor agonist muscimol (100 microM). 5. Propofol, in contrast to APV and CNQX, could not prevent the dendrotomy-induced Ca(2+)-dependent and long-lasting changes in mIPSC decay kinetics (appearance of a double-exponential, prolonged decay). 6. The protective effects of the anesthetics and those of APV and CNQX on neuronal survival were not significant when the drugs were applied after dendrotomy, indicating that dendrotomy carried out 150-200 microns from the soma without neuroprotective agents rapidly induces irreversible acute degeneration in most injured neurons. The failure to rescue cells from dendrotomy-induced injury did not result from a decreased sensitivity of the GABAA receptors to the anesthetics, because the potentiating effects of the anesthetics on mIPSCs from control and dendrotomized neurons were not different. 7. These data indicate that propofol potentiates synaptic inhibition pre- and postsynaptically, and, when present during dendrotomy, it can protect neurons from acute mechanical-injury induced cell death via potentiation of GABAA receptor functions. However, propofol fails to provide neuroprotection against dendrotomy-induced changes in synaptic physiology.


Evolution of antimicrobial resistance: impact on antibiotic use.
During the past 50 years, the permanent increase in bacterial resistance to antibiotics has led to modifications in therapeutic recommendations. Despite evidence that antimicrobial exposure of human populations is the most important driving force for the continuous increase in bacterial resistance, the studies of the impact of bacterial resistance on antibiotic use have, during the past, focused on clinical efficacy of individual treatments rather than on collective control of resistance. There are current changes in this attitude, mainly in hospitals, probably because hospital prescribers have experienced the consequences of resistance on their patients. However, in the community such an awareness is not likely to develop in the near future. Therefore, there is a need for public health decision makers to become more involved in prevention of the impact of resistance in antibiotic use.


Rates and risk factors for mortality during the first two years of life in rural Malawi.
Developing nations in sub-Saharan Africa experience childhood mortality rates that are much higher than any other region of the world. In a rural Malawian community we investigated risk factors for deaths occurring during the neonatal (birth-28 days), postneonatal (29-365 days), infant (birth-365 days), and second-year (366-730 days) periods among a cohort of 3,724 infants monitored from birth. The neonatal mortality rate in this cohort was 48.6 per 1,000 live births (LB); the postneonatal mortality rate was 108.7/1,000 LB. The overall infant mortality rate was 157.3 deaths/1,000 LB and the mortality rate for the first two years of life was 223.7 deaths/1,000 LB. The predominate risk factors for neonatal deaths identified in multivariate analysis were low (hazard ratio [HR] = 2.3) and very low birth weight (HR = 12.7), first pregnancy (HR = 1.8) and maternal syphilis infection (HR = 2.4). Maternal infection with human immunodeficiency virus (HIV) (HR = 1.5) predominated for postneonatal deaths. Low (HR = 1.4) and very low (HR = 5.0) birth weight, first pregnancy (HR = 1.6), maternal HIV infection (HR = 2.4), and the combination of low education and low socioeconomic status (SES) of the mother (HR = 2.0) were the most important factors during the infant period. Maternal HIV infection (HR = 3.3) and the combination of low education and low SES of the mother (HR = 2.6) were the predominate risk factors for mortality occurring during the second year. Factors that were significant in univariate analysis but not significant in the final multivariate models included prematurity, previous adverse reproductive outcome, dying during high malaria transmission season, and being born at home. Interventions to prevent maternal HIV infection and low birth weight and treatment of syphilis infection would have a great impact on reducing early childhood deaths. Improving the delivery of health care and education to women during their first pregnancy and to the most socially disadvantaged women may also help reduce the burden of early childhood mortality in communities such as the one studied in Malawi.


Withdrawal of artificial nutrition and hydration in the neonatal intensive care unit: parental perspectives.
To review the experience of the practice of withdrawal of artificial nutrition and hydration (WANH) and to describe parental perspectives on the process. A retrospective chart review and parental survey. Tertiary level Neonatal Intensive Care Unit (NICU). Infants who had WANH after withdrawal of other life-sustaining treatment, and their parents. Parental perspectives on the care and process were obtained through a survey administered 1 to 4 years after the death of their infant. Fifteen cases (5.5% of all mortality and 0.5% of all admissions) of WANH were identified, and 10 parents participated in the survey. The median (range) gestational age was 40 weeks (31-42) and birth weight was 3409 g (2000-4640). The reason for WANH was predicted poor outcome due to severe neurological injury/disease. The median (range) time between WANH and death was 16 days (2-37). All parents reported favourable perceptions of preparation, support, communication and care. Seven parents reported concerns regarding pain experienced by their infant. Parents reported the ability to spend quality time, creating tangible memories and the virtues and professional qualities of the caregivers to be helpful, but identified that consistency and continuity of care could be improved. Within the spectrum of palliative care in neonates, WANH can be a tenable, justifiable and humane practice in the NICU.


Temporal airway microbiome changes related to ventilator-associated pneumonia in children.
We sought to determine whether temporal changes in the lower airway microbiome are associated with ventilator-associated pneumonia (VAP) in children.Using a multicentre prospective study of children aged 31 days to 18 years requiring mechanical ventilation support for >72 h, daily tracheal aspirates were collected and analysed by sequencing of the 16S rRNA gene. VAP was assessed using 2008 Centers for Disease Control and Prevention paediatric criteria. The association between microbial factors and VAP was evaluated using joint longitudinal time-to-event modelling, matched case-control comparisons and unsupervised clustering.Out of 366 eligible subjects, 66 (15%) developed VAP at a median of 5 (interquartile range 3-5) days post intubation. At intubation, there was no difference in total bacterial load (TBL), but Shannon diversity and the relative abundance of Streptococcus, Lactobacillales and Prevotella were lower for VAP subjects versus non-VAP subjects. However, higher TBL on each sequential day was associated with a lower hazard (hazard ratio 0.39, 95% CI 0.23-0.64) for developing VAP, but sequential values of diversity were not associated with VAP. Similar findings were observed from the matched analysis and unsupervised clustering. The most common dominant VAP pathogens included Prevotella species (19%), Pseudomonas aeruginosa (14%) and Streptococcus mitis/pneumoniae (10%). Mycoplasma and Ureaplasma were also identified as dominant organisms in several subjects.In mechanically ventilated children, changes over time in microbial factors were marginally associated with VAP risk, although these changes were not suitable for predicting VAP in individual patients. These findings suggest that focusing exclusively on pathogen burden may not adequately inform VAP diagnosis.


Targeting natural killer cell reactivity by employing antibody to NKp46: implications for type 1 diabetes.
Natural killer (NK) cells belong to the innate lymphoid cells. Their cytotoxic activity is regulated by the delicate balance between activating and inhibitory signals. NKp46 is a member of the primary activating receptors of NK cells. We previously reported that the NKp46 receptor is involved in the development of type 1 diabetes (T1D). Subsequently, we hypothesized that blocking this receptor could prevent or hinder disease development. To address this goal, we developed monoclonal antibodies for murine NKp46. One mAb, named NCR1.15, recognizes the mouse homologue protein of NKp46, named Ncr1, and was able to down-regulate the surface expression of NKp46 on primary murine NK cells following antibody injection in vivo. Additionally, NCR1.15 treatments were able to down-regulate cytotoxic activity mediated by NKp46, but not by other NK receptors. To test our primary assumption, we examined T1D development in two models, non-obese diabetic mice and low-dose streptozotocin. Our results show a significantly lower incidence of diabetic mice in the NCR1.15-treated group compared to control groups. This study directly demonstrates the involvement of NKp46 in T1D development and suggests a novel treatment strategy for early insulitis.


Seawater and freshwater challenges affect the insulin-like growth factors IGF-I and IGF-II in liver and osmoregulatory organs of the tilapia.
Contradictory studies suggest IGF-I in fish liver and gills is involved in osmoregulation, but nothing is known about the kidney and intestine's role nor about IGF-II's role in any organ. Tilapia were transferred from freshwater (FW) to seawater (SW) for 1week (wk) and retransferred to FW for another week. At 4h, 1d, 2d, 3d and 1wk after SW-transfer and FW-retransfer IGF-I, IGF-II and growth hormone receptor (GHR1) mRNA were measured by real-time PCR. Hepatic IGF-I, IGF-II and GHR1 mRNA were downregulated in parallel after SW-transfer, recovered and were again downregulated after FW-retransfer. In gills, IGF-I, IGF-II and GHR1 were upregulated synchronously after SW-transfer and, partially also after FW-retransfer. The renal genes were downregulated after SW-transfer and partially upregulated after FW-retransfer. Persisting upregulation in intestinal IGF-I mRNA occurred after FW-retransfer. Thus, endocrine and auto/paracrine IGF-I and IGF-II seem to be involved in fish osmoregulation in an organ-specific manner.


Doublon dynamics and polar molecule production in an optical lattice.
Polar molecules in an optical lattice provide a versatile platform to study quantum many-body dynamics. Here we use such a system to prepare a density distribution where lattice sites are either empty or occupied by a doublon composed of an interacting Bose-Fermi pair. By letting this out-of-equilibrium system evolve from a well-defined, but disordered, initial condition, we observe clear effects on pairing that arise from inter-species interactions, a higher partial-wave Feshbach resonance and excited Bloch-band population. These observations facilitate a detailed understanding of molecule formation in the lattice. Moreover, the interplay of tunnelling and interaction of fermions and bosons provides a controllable platform to study Bose-Fermi Hubbard dynamics. Additionally, we can probe the distribution of the atomic gases in the lattice by measuring the inelastic loss of doublons. These techniques realize tools that are generically applicable to studying the complex dynamics of atomic mixtures in optical lattices.


Antipsychotic reexposure and recurrent pneumonia in schizophrenia: a nested case-control study.
Few studies have used systematic datasets to assess the safety of antipsychotic rechallenge after an adverse event. This nested case-control study estimated the risk for recurrent pneumonia after reexposure to antipsychotic treatment. In a nationwide schizophrenia (ICD-9-CM code 295) cohort (derived from the National Health Insurance Research Database in Taiwan) who were hospitalized for pneumonia (ICD-9-CM codes 480-486, 507) between 2000 and 2008 (N = 2,201), we identified 494 subjects that developed recurrent pneumonia after a baseline pneumonia episode. Based on risk-set sampling in a 1:3 ratio, 1,438 matched controls were selected from the cohort. Exposures to antipsychotics were categorized by type, duration, and defined daily dose. Using propensity score-adjusted analysis, we assessed individual antipsychotics for the risk of recurrent pneumonia; we furthermore assessed the effect of reexposure to these antipsychotics on the risk of recurrent pneumonia. Of the antipsychotics studied, current use of clozapine was the only one associated with a clear dose-dependent increase in the risk for recurrent pneumonia (adjusted risk ratio = 1.40, P = .024). Intriguingly, patients reexposed to clozapine had a higher risk for recurrent pneumonia (adjusted risk ratio = 1.99, P = .023) than those receiving clozapine only prior to the baseline pneumonia, and this risk was associated with gender. Women reexposed to clozapine were more susceptible to recurrent pneumonia (adjusted risk ratio = 4.93, P = .050). In patients experiencing pneumonia while undergoing clozapine treatment, physicians should carefully consider the increased risk of pneumonia recurrence when clozapine is reintroduced. Future studies should try to quantify the risk of other medical conditions associated with clozapine reexposure.


Development of a clickable bimodal fluorescent/PET probe for in vivo imaging.
Fluorescent imaging agents are becoming evermore important in preclinical and clinical research. They do, however, suffer from poor tissue penetration, which makes optical fluorescence imaging incompatible with whole-body imaging techniques. The design of novel bimodal PET active and fluorescent tracers could therefore combine the benefits of optical imaging with radioactively labeled imaging probes. Herein, we report the synthesis and evaluation of a clickable (18)F-labeled fluorescent dye. An azide-modified BODIPY-Fl dye could be successfully radio-labeled with (18)F using an (18)F/(19)F exchange reaction of the boron-fluoride core of the BODIPY dye to yield a clickable bimodal PET/fluorescent imaging tool. In vitro as well as in vivo imaging (PET/fluorescence) using a bombesin analog was conducted to study the applicability of the dual-modality imaging probe. We use the radio-labeled small molecule, (18)F-BODIPY-azide to label site-specifically different targeted peptides, based on a standard modular labeling protocol. Following the synthesis of a bimodal bombesin analog, we determine the peptide tracer's performance in vitro and in vivo, exploring both the optical as well as PET imaging capabilities. This versatile methodology has the potential to have a transformational impact on (18)F radiotracer synthesis, opening the door for rapid screening of novel-labeled peptide tracers, both on the cellular (optical) as well as whole-body (PET) level.


Street policing, injecting drug use and harm reduction in a Russian city: a qualitative study of police perspectives.
We undertook a qualitative exploration of police perspectives on injecting drug use and needle and syringe access among injecting drug users (IDUs) in a Russian city which has witnessed explosive spread of HIV associated with drug injecting. Twenty-seven in-depth qualitative interviews were conducted in May 2002 with police officers of varying rank who reported having regular contact with IDUs. All interviews were tape-recorded, transcribed, translated and coded thematically. Accounts upheld an approach to policing which emphasised high street-based visibility and close surveillance of IDUs. IDUs were depicted as 'potential criminals' warranting a 'pre-emptive' approach to the prevention of drug-related crime. Street policing was described as a means of maintaining close surveillance leading to the official registration of persons suspected or proven to be users of illicit drugs. Such registration enabled further ongoing surveillance, including through stop and search procedures. While aware of drug users' reluctance to carry injecting equipment linked to their fears of detention or arrest, accounts suggested that the confiscation of previously used injecting equipment can constitute evidence in relation to drugs possession charges and that discovery of clean injecting equipment may be sufficient to raise suspicion and/or further investigation, including through stop and search or questioning. Our findings suggest an uneasy relationship between street policing and needle and syringe access, whereby policing strategies can undermine an HIV prevention ethos promoting needle and syringe accessibility among IDUs. We conclude that facilitating partnerships between policing agencies and HIV prevention initiatives are a critical feature of creating environments conducive for risk reduction.


Induction of potent and long-lasting CD4 and CD8 T-cell responses against hepatitis C virus by immunization with viral antigens plus poly(I:C) and anti-CD40.
Development of vaccination strategies against hepatitis C virus (HCV) is of paramount importance. With this aim, we tested the ability of dendritic cell-activating reagents polyinosinic-polycytidylic acid (poly(I:C)) and anti-CD40, as adjuvants to induce T-cell responses against HCV. Immunization of mice with these adjuvants induced dendritic cell maturation in vivo. Also, joint administration of poly(I:C) and anti-CD40 plus HCV antigens had a synergistic effect on the induction of anti-HCV T-cell responses. CD4 responses displayed a Th1 cytokine profile, and CD8 responses could be induced by immunization with a minimal CD8 epitope. Addition of a low amount of NS3 protein (as a source of Th epitopes) to the immunization mixture enhanced CD8 responses, whereas immunization with higher doses of NS3 induced both CD4 and CD8 responses. Surprisingly, immunization with NS3 protein but not with CD8 epitopes was able to induce CD8 responses and able to recognize cells expressing HCV antigens endogenously. Moreover, immunization with these adjuvants activated NK cells, which in turn helped to induce Th1 responses. Finally, this combined immunization protocol afforded long-lasting T-cell responses, suggesting that this strategy may prove to be useful in vaccination and/or treatment of HCV infection.


Safety and Health Programs in Alaska's Seafood Processing Industry: Interviews with Safety and Health Managers.
Background: The seafood processing industry is critical to Alaska's economy and hazardous to workers; however, limited research has addressed workers' safety and health. Safety and health program management is a decisive factor in preventing fatalities, injuries, and illnesses. We interviewed managers to gain their views on their safety and health programs.Methods: Semi-structured interviews were conducted with 14 upper-level managers who oversaw programs for Alaskan worksites. Interviews were audio-recorded and transcribed. Qualitative content analysis techniques, including inductive coding, were utilized to explore participants' experiences and views regarding: management and workers' roles; hazard control systems; safety and health training; regulatory and economic factors; and programs' challenges and successes.Results: The 14 participants represented 13 companies that operated 32 onshore plants and 30 vessels with processing capabilities. Participants reported managing programs for an estimated 68% of the Alaskan seafood processing industry's workforce. Based on participants' responses, we identified five factors that could be modified to improve safety and health industry-wide: manager training and knowledge sharing; worker training; organizational aspects related to safety culture; application of ergonomic principles; and work hours. Participants reported that fully engaging workers in programs was beneficial.Conclusions: Industry members should more widely share their best practices for protecting workers' safety and health. Occupational safety and health practitioners and researchers should support the development and evaluation of (a) training for non/limited-English-speaking-workers, (b) ergonomic interventions, and (c) fatigue risk management systems. Future research should engage worksite managers and workers to characterize their safety and health experiences and needs.


Respiratory cycle-related electroencephalographic changes during sleep in healthy children and in children with sleep disordered breathing.
To investigate respiratory cycle-related electroencephalographic changes (RCREC) in healthy children and in children with sleep disordered breathing (SDB) during scored event-free (SEF) breathing periods of sleep. Interventional case-control repeated measurements design. Paediatric sleep laboratory in a hospital setting. Forty children with SDB and 40 healthy, age- and sex-matched children. Adenotonsillectomy in children with SDB and no intervention in controls. Overnight polysomnography; electroencephalography (EEG) power variations within SEF respiratory cycles in the overall and frequency band-specific EEG within stage 2 nonrapid eye movement (NREM) sleep, slow wave sleep (SWS), and rapid eye movement (REM) sleep. Within both groups there was a decrease in EEG power during inspiration compared to expiration across all sleep stages. Compared to controls, RCREC in children with SDB in the overall EEG were significantly higher during REM and frequency band specific RCRECs were higher in the theta band of stage 2 and REM sleep, alpha band of SWS and REM sleep, and sigma band of REM sleep. This between-group difference was not significant postadenotonsillectomy. The presence of nonrandom respiratory cycle-related electroencephalographic changes (RCREC) in both healthy children and in children with sleep disordered breathing (SDB) during NREM and REM sleep has been demonstrated. The RCREC values were higher in children with SDB, predominantly in REM sleep and this difference reduced after adenotonsillectomy. Immanuel SA, Pamula Y, Kohler M, Martin J, Kennedy D, Saint DA, Baumert M. Respiratory cycle-related electroencephalographic changes during sleep in healthy children and in children with sleep disordered breathing.


Placebo - More hatred than love.
A placebo is a sham medical intervention that can produce a placebo effect. Laboratory evidence supports the existence of several mechanisms of placebo effects in both healthy population and patients with a variety of medical conditions. The ethics of placebos have long been debated. However, accumulating ethical concern has arisen from the worldwide use of placebo in randomized control trials (RCTs), which may render their participants without early and optimal treatment. Although the pilgrimage of placebo is still on the way, refinement of controls in RCTs is worth paying new attention to.


Glycaemic control in type 1 diabetes during real time continuous glucose monitoring compared with self monitoring of blood glucose: meta-analysis of randomised controlled trials using individual patient data.
To determine the clinical effectiveness of real time continuous glucose monitoring compared with self monitoring of blood glucose in type 1 diabetes. Meta-analysis of randomised controlled trials. Cochrane database for randomised controlled trials, Ovid Medline, Embase, Google Scholar, lists of papers supplied by manufacturers of continuous glucose monitors, and cited literature in retrieved articles. Studies reviewed Randomised controlled trials of two or more months' duration in men and non-pregnant women with type 1 diabetes that compared real time continuous glucose monitoring with self monitoring of blood glucose and where insulin delivery was the same in both arms. Analysis Two step meta-analysis of individual patient data with the primary outcome of final glycated haemoglobin (HbA(1c)) percentage and area under the curve of hypoglycaemia (glucose concentration <3.9 mmol/L) during either treatment, followed by one step metaregression exploring patient level determinants of HbA(1c) and hypoglycaemia. Six trials were identified, consisting of 449 patients randomised to continuous glucose monitoring and 443 to self monitoring of blood glucose. The overall mean difference in HbA(1c) for continuous glucose monitoring versus self monitoring of blood glucose was -0.30% (95% confidence interval -0.43% to -0.17%) (-3.0, -4.3 to -1.7 mmol/mol). A best fit regression model of determinants of final HbA(1c) showed that for every one day increase of sensor usage per week the effect of continuous glucose monitoring versus self monitoring of blood glucose increased by 0.150% (95% credibility interval -0.194% to -0.106%) (1.5, -1.9 to -1.1 mmol/mol) and every 1% (10 mmol/mol) increase in baseline HbA(1c) increased the effect by 0.126% (-0.257% to 0.0007%) (1.3, -2.6 to 0.0 mmol/mol). The model estimates that, for example, a patient using the sensor continuously would experience a reduction in HbA(1c) of about 0.9% (9 mmol/mol) when the baseline HbA(1c) is 10% (86 mmol/mol). The overall reduction in area under the curve of hypoglycaemia was -0.28 (-0.46 to -0.09), corresponding to a reduction in median exposure to hypoglycaemia of 23% for continuous glucose monitoring compared with self monitoring of blood glucose. In a best fit regression model, baseline area under the curve of hypoglycaemia was only weakly related to the effect of continuous glucose monitoring compared with self monitoring of blood glucose on hypoglycaemia outcome, and sensor usage was unrelated to hypoglycaemia at outcome. Continuous glucose monitoring was associated with a significant reduction in HbA(1c) percentage, which was greatest in those with the highest HbA(1c) at baseline and who most frequently used the sensors. Exposure to hypoglycaemia was also reduced during continuous glucose monitoring. The most cost effective or appropriate use of continuous glucose monitoring is likely to be when targeted at people with type 1 diabetes who have continued poor control during intensified insulin therapy and who frequently use continuous glucose monitoring.


Quantum stress focusing in descriptive chemistry.
We show that several important concepts of descriptive chemistry, such as atomic shells, bonding electron pairs, and lone electron pairs, may be described in terms of quantum stress focusing, i.e., the spontaneous formation of high-pressure regions in an electron gas. This description subsumes previous mathematical constructions, such as the Laplacian of the density and the electron localization function, and provides a new tool for visualizing chemical structure. We also show that the full stress tensor, defined as the derivative of the energy with respect to a local deformation, can be easily calculated from density functional theory.


JAK-STAT pathway targeting for the treatment of inflammatory bowel disease.
Cytokines are involved in intestinal homeostasis and pathological processes associated with inflammatory bowel disease (IBD). The biological effects of cytokines, including several involved in the pathology of Crohn's disease and ulcerative colitis, occur as a result of receptor-mediated signalling through the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) DNA-binding families of proteins. Although therapies targeting cytokines have revolutionized IBD therapy, they have historically targeted individual cytokines, and an unmet medical need exists for patients who do not respond to or lose response to these treatments. Several small-molecule inhibitors of JAKs that have the potential to affect multiple pro-inflammatory cytokine-dependent pathways are in clinical development for the treatment of IBD, with one agent, tofacitinib, already approved for ulcerative colitis and several other agents with demonstrated efficacy in early phase trials. This Review describes the current understanding of JAK-STAT signalling in intestinal homeostasis and disease and the rationale for targeting this pathway as a treatment for IBD. The available evidence for the efficacy, safety and pharmacokinetics of JAK inhibitors in IBD as well as the potential approaches to optimize treatment with these agents, such as localized delivery or combination therapy, are also discussed.


ER+ Breast Cancer Strongly Depends on MCL-1 and BCL-xL Anti-Apoptotic Proteins.
Breast cancer is the most frequent type of cancer and the major cause of mortality in women. The rapid development of various therapeutic options has led to the improvement of treatment outcomes; nevertheless, one-third of estrogen receptor (ER)-positive patients relapse due to cancer cell acquired resistance. Here, we use dynamic BH3 profiling (DBP), a functional predictive assay that measures net changes in apoptotic priming, to find new effective treatments for ER+ breast cancer. We observed anti-apoptotic adaptations upon treatment that pointed to metronomic therapeutic combinations to enhance cytotoxicity and avoid resistance. Indeed, we found that the anti-apoptotic proteins BCL-xL and MCL-1 are crucial for ER+ breast cancer cells resistance to therapy, as they exert a dual inhibition of the pro-apoptotic protein BIM and compensate for each other. In addition, we identified the AKT inhibitor ipatasertib and two BH3 mimetics targeting these anti-apoptotic proteins, S63845 and A-1331852, as new potential therapies for this type of cancer. Therefore, we postulate the sequential inhibition of both proteins using BH3 mimetics as a new treatment option for refractory and relapsed ER+ breast cancer tumors.


Optimizing Drosophila olfactory learning with a semi-automated training device.
Drosophila olfactory aversive conditioning has served as a powerful model system with which to elucidate the molecular and neuronal mechanisms underlying memory formation. In the typical protocol, flies are exposed to a constant odor stream while receiving a pulsed electric shock in the conditioning tube of a manual apparatus. We have devised a simple, low-cost semi-automated conditioning apparatus that computationally controls the delivery of odor and shock. A semiconductor-based odor sensor is employed to monitor the change of odor concentration in the training tube. The system thus allows electric shocks to be precisely matched with odor concentration in the training tube. We found that short-term memory performance was improved with a pulsed odor flow protocol, in which odor is presented in short pulses, each paired with electric shock, rather than as a constant flow. The effect of pulsed odor flow might be ascribed to the phenomenon of 'conditioned approach', where approach toward an odor is induced when the electric shock is presented before odor pulse ends. Our data shows that the system is applicable to the study of olfactory memory formation and to the examination of conditioning parameters at a level of detail not practical with a manual apparatus.


Defect formation of lytic peptides in lipid membranes and their influence on the thermodynamic properties of the pore environment.
We present an experimental study of the pore formation processes of small amphipathic peptides in model phosphocholine lipid membranes. We used atomic force microscopy to characterize the spatial organization and structure of alamethicin- and melittin-induced defects in lipid bilayer membranes and the influence of the peptide on local membrane properties. Alamethicin induced holes in gel DPPC membranes were directly visualized at different peptide concentrations. We found that the thermodynamic state of lipids in gel membranes can be influenced by the presence of alamethicin such that nanoscopic domains of fluid lipids form close to the peptide pores, and that the elastic constants of the membrane are altered in their vicinity. Melittin-induced holes were visualized in DPPC and DLPC membranes at room temperature in order to study the influence of the membrane state on the peptide induced hole formation. Also differential scanning calorimetry was used to investigate the effect of alamethicin on the lipid membrane phase behaviour.


Effect of glucocorticoids on rectal transport in normal subjects and patients with ulcerative colitis.
The acute effects of single pharmacological doses of glucocorticoid hormones on net electrolyte and water transport and electrical potential difference (pd) in the rectum was studied in control subjects and in patients with either active or inactive ulcerative colitis, using a dialysis technique. Compared with 17 control subjects, nine patients with active ulcerative colitis exhibited marked decreases in net sodium absorption and rectal pd, while these transport parameters were normal in six patients with inactive ulcerative colitis. Intravenous administration of hydrocortisone hemisuccinate (100 mg) resulted five hours later in significant and quantitatively similar increases in net sodium and water absorption and pd in nine control subjects, seven patients with active ulcerative colitis, and six patients with inactive ulcerative colitis. Intravenous administration of methylprednisolone phosphate (40 mg) to eight control subjects produced increases in net sodium and water absorption and pd five hours later, which did not differ significantly from those produced by hydrocortisone; methylprednisolone induced similar changes in two patients with active ulcerative colitis. These results indicate that single pharmacological doses of glucocorticoids stimulate acute increases in rectal sodium and water absorption in control subjects and in patients with acute ulcerative colitis. The ability of systemically administered glucocorticoids to reduce diarrhoea in ulcerative colitis may therefore be related to direct effects on distal colonic sodium and water transport, as well as to their better known anti-inflammatory action.


Using a personal digital assistant to increase independent task completion by students with autism spectrum disorder.
In this study, a personal digital assistant (PDA) with picture, auditory, and video prompts with voice over, was evaluated as a portable self-prompting device for students with autism spectrum disorder (ASD). Using a multiple probe design across three cooking recipes and replicated with three students with ASD, the system was tested for its effectiveness in increasing independent performance across the multiple step tasks. In addition, data were recorded for the number and types of prompts used by the students across time. Results indicate that the students with ASD were able to adjust the prompt levels used on the PDA and to maintain their ability to use the device to independently complete recipes over time.


Occupational exposure to hexavalent chromium and cancers of the gastrointestinal tract: a meta-analysis.
We conducted a systematic literature review and meta-analysis of oral cavity, esophageal, stomach, small intestine, colon, and rectal cancers among workers occupationally exposed to Cr(VI). Using PubMed, studies published from 1950 to 2009 evaluating the relationship between Cr(VI) exposure and GI cancers were identified. Measures of effect and variability were extracted from 32 studies meeting specific inclusion criteria, and meta-analysis summary relative risk measures were calculated using random effects models and inverse variance weighting methods. Meta-standardized mortality ratios (SMRs) were, for cancer of the: oral cavity [1.02 (95% CI=0.77-1.34)]; esophagus [1.17 (95% CI=0.90-1.51)]; stomach [1.09 (95% CI=0.93-1.28)]; colon [0.89 (95% CI=0.70-1.12)]; and rectum [1.17 (95% CI=0.98-1.39)]. Analyses of more highly exposed subgroups included in the studies or subgroups based on geographic region or by industry with recognized Cr(VI) exposures (welding, chrome plating, chromate production, and pigment production) did not result in elevated meta-SMRs except for esophageal cancer among US cohorts [meta-SMR=1.49 (95% CI=1.06-2.09)]. However, that finding was based on a subgroup of only four studies, one of which was a PMR study. Potential confounding by socioeconomic status (SES), diet and/or smoking, or limitations due to the healthy-worker effect (HWE) were evaluated, and while smoking, diet and SES may be important factors that may have upwardly biased the meta-SMRs, HWE is not likely to have significantly affected the summary results. None of three studies reporting small intestine cancers observed a statistically significant increased risk. These meta-analyses and literature review indicate that Cr(VI)-exposed workers are not at a greater risk of GI cancers than the general population.


The association between child maltreatment and adult poverty - A systematic review of longitudinal research.
Child maltreatment is a global problem affecting millions of children and is associated with an array of cumulative negative outcomes later in life, including unemployment and financial difficulties. Although establishing child maltreatment as a causal mechanism for adult economic outcomes is fraught with difficulty, understanding the relationship between the two is essential to reducing such inequality. This paper presents findings from a systematic review of longitudinal research examining experiences of child maltreatment and economic outcomes in adulthood. A systematic search of seven databases found twelve eligible retrospective and prospective cohort studies. From the available evidence, there was a relatively clear relationship between 'child maltreatment' and poorer economic outcomes such as reduced income, unemployment, lower level of job skill and fewer assets, over and above the influence of family of origin socio-economic status. Despite an extremely limited evidence base, neglect had a consistent relationship with a number of long-term economic outcomes, while physical abuse has a more consistent relationship with income and employment. Studies examining sexual abuse found less of an association with income and employment, although they did find a relationship other outcomes such as sickness absence, assets, welfare receipt and financial insecurity. Nonetheless, all twelve studies showed some association between at least one maltreatment type and at least one economic measure. The task for future research is to clarify the relationship between specific maltreatment types and specific economic outcomes, taking account of how this may be influenced by gender and life course stage.


Neuroophthalmological outcomes associated with use of the Pipeline Embolization Device: analysis of the PUFS trial results.
Neuroophthalmological morbidity is commonly associated with large and giant cavernous and supraclinoid internal carotid artery (ICA) aneurysms. The authors sought to evaluate the neuroophthalmological outcomes after treatment of these aneurysms with the Pipeline Embolization Device (PED). The Pipeline for Uncoilable or Failed Aneurysms (PUFS) trial was an international, multicenter prospective trial evaluating the safety and efficacy of the PED. All patients underwent complete neuroophthalmological examinations both before the PED procedure and at a 6-month follow-up. All examinations were performed for the purpose of this study and according to study criteria. In total, 108 patients were treated in the PUFS trial, 98 of whom had complete neuroophthalmological follow-up. Of the patients with complete follow-up, 39 (40%) presented with a neuroophthalmological baseline deficit that was presumed to be attributable to the aneurysm, and patients with these baseline deficits had significantly larger aneurysms. In 25 of these patients (64%), the baseline deficit showed at least some improvement 6 months after PED treatment, whereas in 1 patient (2.6%), the deficits only worsened. In 5 patients (5%), new deficits had developed at the 6-month follow-up, while in another 6 patients (6%), deficits that were not originally assumed to be related to the aneurysm had improved by that time. A history of diabetes was associated with failure of the baseline deficits to improve after the treatment. The aneurysm maximum diameter was significantly larger in patients with a new deficit or a worse baseline deficit at 6 months postprocedure. Patients treated with the PED for large and giant ICA aneurysms had excellent neuroophthalmological outcomes 6 months after the procedure, with deficits improving in most of the patients, very few deficits worsening, and few new deficits developing.


Women with false positive screening mammograms: how do they cope?
To assess the long term psychological impact on women who were recalled for further investigation after mammography screening and to find any factors that might predict coping ability in order to identify those subjects who require additional support at an earlier stage. Counties of Västerbotten and Västernorrland, Sweden. A prospective design was used in which 252 recalled women completed questionnaires twice--once within a week of having received the all-clear and again at follow up six months later. A group of 1104 randomly selected, screen negative women were followed up in the same way for comparison. The questionnaire included the Psychological Consequences Questionnaire (PCQ) and basic sociodemographic data. The main outcome measure was the total score on the PCQ at six months. Of the 252 women, 235 (93%) completed both questionnaires. In the control group, 987 (89.4%) women responded. Six months after the all-clear, recalled women were still significantly more anxious (p < 0.001) than those who had been screened but not recalled. The strongest predictor of psychological distress at six months was the PCQ score at the first measurement. Other predictors were a low level of education, living in high density urban areas, and having only one child or no children at all. Widows appeared to cope better than other women. It is possible to define a group of women with false positive results who are already at risk of coping less effectively at the time of recall. Offering these women counselling or other types of support should be considered.


Clamp-Tapering Increases the Quality Factor of Stressed Nanobeams.
Stressed nanomechanical resonators are known to have exceptionally high quality factors ( Q) due to the dilution of intrinsic dissipation by stress. Typically, the amount of dissipation dilution and thus the resonator Q is limited by the high mode curvature region near the clamps. Here we study the effect of clamp geometry on the Q of nanobeams made of high-stress Si3N4. We find that tapering the beam near the clamps, thus locally increasing the stress, leads to an increased Q of MHz-frequency low order modes due to enhanced dissipation dilution. Contrary to recent studies of tethered-membrane resonators, we find that widening the clamps leads to a decreased Q despite increased stress in the beam bulk. The tapered-clamping approach has practical advantages compared to the recently developed "soft-clamping" technique, as it enhances the Q of the fundamental mode and can be implemented without increasing the device size.


Hospitals Using Bundled Payment Report Reducing Skilled Nursing Facility Use And Improving Care Integration.
A goal of Medicare's bundled payment models is to improve quality and control costs after hospital discharge. Little is known about how participating hospitals are focusing their efforts to achieve these objectives, particularly around the use of skilled nursing facilities (SNFs). To understand hospitals' approaches, we conducted semistructured interviews with an executive or administrator in each of twenty-two hospitals and health systems participating in Medicare's Comprehensive Care for Joint Replacement model or its Bundled Payments for Care Improvement initiative for lower extremity joint replacement episodes. We identified two major organizational responses. One principal strategy was to reduce SNF referrals, using risk-stratification tools, patient education, home care supports, and linkages with home health agencies to facilitate discharges to home. Another was to enhance integration with SNFs: fifteen hospitals or health systems in our sample had formed networks of preferred SNFs to exert influence over SNF quality and costs. Common coordination strategies included sharing access to electronic medical records, embedding providers across facilities, hiring dedicated care coordination staff, and creating platforms for data sharing. As hospitals presumably move toward home-based care and more selective SNF referrals, more evidence is needed to understand how these discharge practices affect the quality of care and patient outcomes.


Artificial Inclusion Bodies for Clinical Development.
Bacterial inclusion bodies (IBs) are mechanically stable protein particles in the microscale, which behave as robust, slow-protein-releasing amyloids. Upon exposure to cultured cells or upon subcutaneous or intratumor injection, these protein materials secrete functional IB polypeptides, functionally mimicking the endocrine release of peptide hormones from secretory amyloid granules. Being appealing as delivery systems for prolonged protein drug release, the development of IBs toward clinical applications is, however, severely constrained by their bacterial origin and by the undefined and protein-to-protein, batch-to-batch variable composition. In this context, the de novo fabrication of artificial IBs (ArtIBs) by simple, cell-free physicochemical methods, using pure components at defined amounts is proposed here. By this, the resulting functional protein microparticles are intriguing, chemically defined biomimetic materials that replicate relevant functionalities of natural IBs, including mammalian cell penetration and local or remote release of functional ArtIB-forming protein. In default of severe regulatory issues, the concept of ArtIBs is proposed as a novel exploitable category of biomaterials for biotechnological and biomedical applications, resulting from simple fabrication and envisaging soft developmental routes to clinics.


Usefulness of coenzyme Q10 in clinical cardiology: a long-term study.
Over an eight year period (1985-1993), we treated 424 patients with various forms of cardiovascular disease by adding coenzyme Q10 (CoQ10) to their medical regimens. Doses of CoQ10 ranged from 75 to 600 mg/day by mouth (average 242 mg). Treatment was primarily guided by the patient's clinical response. In many instances, CoQ10 levels were employed with the aim of producing a whole blood level greater than or equal to 2.10 micrograms/ml (average 2.92 micrograms/ml, n = 297). Patients were followed for an average of 17.8 months, with a total accumulation of 632 patient years. Eleven patients were omitted from this study: 10 due to non-compliance and one who experienced nausea. Eighteen deaths occurred during the study period with 10 attributable to cardiac causes. Patients were divided into six diagnostic categories: ischemic cardiomyopathy (ICM), dilated cardiomyopathy (DCM), primary diastolic dysfunction (PDD), hypertension (HTN), mitral valve prolapse (MVP) and valvular heart disease (VHD). For the entire group and for each diagnostic category, we evaluated clinical response according to the New York Heart Association (NYHA) functional scale, and found significant improvement. Of 424 patients, 58 per cent improved by one NYHA class, 28% by two classes and 1.2% by three classes. A statistically significant improvement in myocardial function was documented using the following echocardiographic parameters: left ventricular wall thickness, mitral valve inflow slope and fractional shortening. Before treatment with CoQ10, most patients were taking from one to five cardiac medications. During this study, overall medication requirements dropped considerably: 43% stopped between one and three drugs. Only 6% of the patients required the addition of one drug. No apparent side effects from CoQ10 treatment were noted other than a single case of transient nausea. In conclusion, CoQ10 is a safe and effective adjunctive treatment for a broad range of cardiovascular diseases, producing gratifying clinical responses while easing the medical and financial burden of multidrug therapy.


Confronting the scientific obstacles to global control of tuberculosis.
Tuberculosis (TB) is a major threat to global health, recently exacerbated by the emergence of highly drug-resistant forms of the disease-causing pathogen and synergy with HIV/AIDS. In 2006, the Stop TB Partnership published "The global plan to stop TB: 2006--2015," which set out a vision of halving the prevalence of and mortality caused by the disease by 2015, followed by eliminating the disease as a public health problem by 2050. This vision depends on the development of improved diagnostics, simpler treatment, and more effective vaccination. Recently, active translational research pipelines directed toward each of these goals have been established, but improved understanding of the fundamental biology of this complex disease will prove to be the key to radical advances in TB control.


KSRP, many functions for a single protein.
KSRP is a single-strand nucleic acids binding protein that affects RNA fate at multiple levels. KSRP modular structure and its complex pattern of post-translational modifications underpin the interaction with a wide spectrum of RNA target sequences, as well as with other RNA-binding proteins and molecular adaptors. These interactions are important to the regulation of different steps of mRNA metabolism and, in turn, modulate several aspects of cellular proliferation and differentiation. In this review we will discuss in detail KSRP ability to i) promote decay of labile mRNAs interacting with some components of the mRNA decay machinery and ii) favor the maturation of a select group of microRNA precursors.


Video-based self-review: comparing Google Glass and GoPro technologies.
Professionals in a variety of specialties use video-based review as a method of constant self-evaluation. We believe critical self-reflection will allow a surgical trainee to identify methods for improvement throughout residency and beyond. We have used 2 new popular technologies to evaluate their role in accomplishing the previously mentioned objectives. Our group investigated Google Glass and GoPro cameras. Medical students, residents, and faculty were invited to wear each of the devices during a scheduled operation. After the case, each participant was asked to comment on a number of features of the device including comfort, level of distraction/interference with operating, ease of video acquisition, and battery life. Software and hardware specifications were compiled and compared by the authors. A "proof-of-concept" was also performed using the video-conferencing abilities of Google Glass to perform a simulated flap check. The technical specifications of the 2 cameras favor GoPro over Google Glass. Glass records in 720p with 5-MP still shots, and the GoPro records in 1080p with 12-MP still shots. Our tests of battery life showed more than 2 hours of continuous video with GoPro, and less than 1 hour for Glass. Favorable features of Google Glass included comfort and relative ease of use; they could not comfortably wear loupes while operating, and would have preferred longer hands-free video recording. The GoPro was slightly more cumbersome and required a nonsterile team member to activate all pictures or video; however, loupes could be worn. Google Glass was successfully used in the hospital for a simulated flap check, with overall audio and video being transmitted--fine detail was lost, however. There are benefits and limitations to each of the devices tested. Google Glass is in its infancy and may gain a larger intraoperative role in the future. We plan to use Glass as a way for trainees to easily acquire intraoperative footage as a means to "review tape" and will use the GoPro to amass a video library of commonly performed operations.


A clinical decision support system for integrating tuberculosis and HIV care in Kenya: a human-centered design approach.
With the aim of integrating HIV and tuberculosis care in rural Kenya, a team of researchers, clinicians, and technologists used the human-centered design approach to facilitate design, development, and deployment processes of new patient-specific TB clinical decision support system for medical providers. In Kenya, approximately 1.6 million people are living with HIV and have a 20-times higher risk of dying of tuberculosis. Although tuberculosis prevention and treatment medication is widely available, proven to save lives, and prioritized by the World Health Organization, ensuring that it reaches the most vulnerable communities remains challenging. Human-centered design, used in the fields of industrial design and information technology for decades, is an approach to improving the effectiveness and impact of innovations that has been scarcely used in the health field. Using this approach, our team followed a 3-step process, involving mixed methods assessment to (1) understand the situation through the collection and analysis of site observation sessions and key informant interviews; (2) develop a new clinical decision support system through iterative prototyping, end-user engagement, and usability testing; and, (3) implement and evaluate the system across 24 clinics in rural West Kenya. Through the application of this approach, we found that human-centered design facilitated the process of digital innovation in a complex and resource-constrained context.


Structural basis of the drug-binding specificity of human serum albumin.
Human serum albumin (HSA) is an abundant plasma protein that binds a remarkably wide range of drugs, thereby restricting their free, active concentrations. The problem of overcoming the binding affinity of lead compounds for HSA represents a major challenge in drug development. Crystallographic analysis of 17 different complexes of HSA with a wide variety of drugs and small-molecule toxins reveals the precise architecture of the two primary drug-binding sites on the protein, identifying residues that are key determinants of binding specificity and illuminating the capacity of both pockets for flexible accommodation. Numerous secondary binding sites for drugs distributed across the protein have also been identified. The binding of fatty acids, the primary physiological ligand for the protein, is shown to alter the polarity and increase the volume of drug site 1. These results clarify the interpretation of accumulated drug binding data and provide a valuable template for design efforts to modulate the interaction with HSA.


Localization of cholinergic innervation in guinea pig heart by immunohistochemistry for high-affinity choline transporters.
Previous studies have used acetylcholinesterase (AChE) histochemistry to identify cholinergic nerves in the heart, but this enzyme is not a selective marker for cholinergic neurons. This study maps cholinergic innervation of guinea pig heart using a new antibody to the human high-affinity choline transporter (CHT), which is present only in cholinergic nerves. Immunohistochemistry was used to localize CHTs in frozen and paraffin sections of heart and whole mount preparations of atrial ganglionated nerve plexus. AChE-positive nerve fibers were identified in sections from separate hearts for comparison. Control experiments established that the antibody to human CHT selectively labeled cholinergic neurons in the guinea pig. CHT-immunoreactive nerve fibers and AChE-positive nerves were very abundant in the sinus and AV nodes, bundle of His, and bundle branches. Both markers also delineated a distinct nerve tract in the posterior wall of the right atrium. AChE-positive nerve fibers were more abundant than CHT-immunoreactive nerves in working atrial and ventricular myocardium. CHT-immunoreactive nerves were rarely observed in left ventricular free wall. Both markers were associated with numerous parasympathetic ganglia that were distributed along the posterior atrial walls and within the interatrial septum, including the region of the AV node. Comparison of labeling patterns for CHT and AChE suggests that AChE histochemistry overestimates the density of cholinergic innervation in the heart. The distribution of CHT-immunoreactive nerve fibers and parasympathetic ganglia in the guinea pig heart suggests that heart rate, conduction velocity, and automaticity are precisely regulated by cholinergic innervation. In contrast, the paucity of CHT-immunoreactive nerve fibers in left ventricular myocardium implies that vagal efferent input has little or no direct influence on ventricular contractile function in the guinea pig.


Transforming Care for Victims of Violence.
In this month's Magnet® Perspectives column, Anne Boatright, MSN, RN, SANE, describes her efforts to develop a comprehensive forensic nursing program at Methodist Hospital in Omaha. Ms Boatright transformed a sexual assault nurse examiner (SANE) program into one that provides 24/7 coverage at Methodist's 2 SANE locations and cares not only for victims of sexual assault but also for the victims domestic violence, sex trafficking, strangulation, elder abuse, and neglect. Her work extends beyond the walls of Methodist to the community, where she serves as a core member of the Nebraska Human Trafficking Task Force. She works collaboratively with the Federal Bureau of Investigation and helped Nebraska state senators draft legislation to create a sexual assault payment program. In recognition of her determination to make a difference for victims of violence, she received the 2016 National Magnet Nurse of the Year Award for Transformational Leadership.


Caching mechanisms for habit formation in Active Inference.
A popular distinction in the human and animal learning literature is between deliberate (or willed) and habitual (or automatic) modes of control. Extensive evidence indicates that, after sufficient learning, living organisms develop behavioural habits that permit them saving computational resources. Furthermore, humans and other animals are able to transfer control from deliberate to habitual modes (and vice versa), trading off efficiently flexibility and parsimony - an ability that is currently unparalleled by artificial control systems. Here, we discuss a computational implementation of habit formation, and the transfer of control from deliberate to habitual modes (and vice versa) within Active Inference: a computational framework that merges aspects of cybernetic theory and of Bayesian inference. To model habit formation, we endow an Active Inference agent with a mechanism to "cache" (or memorize) policy probabilities from previous trials, and reuse them to skip - in part or in full - the inferential steps of deliberative processing. We exploit the fact that the relative quality of policies, conditioned upon hidden states, is constant over trials; provided that contingencies and prior preferences do not change. This means the only quantity that can change policy selection is the prior distribution over the initial state - where this prior is based upon the posterior beliefs from previous trials. Thus, an agent that caches the quality (or the probability) of policies can safely reuse cached values to save on cognitive and computational resources - unless contingencies change. Our simulations illustrate the computational benefits, but also the limits, of three caching schemes under Active Inference. They suggest that key aspects of habitual behaviour - such as perseveration - can be explained in terms of caching policy probabilities. Furthermore, they suggest that there may be many kinds (or stages) of habitual behaviour, each associated with a different caching scheme; for example, caching associated or not associated with contextual estimation. These schemes are more or less impervious to contextual and contingency changes.


The value of FDG positron emission tomography/computerised tomography (PET/CT) in pre-operative staging of colorectal cancer: a systematic review and economic evaluation.
In the UK, colorectal cancer (CRC) is the third most common malignancy (behind lung and breast cancer) with 37,514 cases registered in 2006: around two-thirds (23,384) in the colon and one-third (14,130) in the rectum. Treatment of cancers of the colon can vary considerably, but surgical resection is the mainstay of treatment for curative intent. Following surgical resection, there is a comprehensive assessment of the tumour, it's invasion characteristics and spread (tumour staging). A number of imaging modalities are used in the pre-operative staging of CRCs including; computerised tomography (CT), magnetic resonance imaging, ultrasound imaging and positron emission tomography (PET). This report examines the role of CT in combination with PET scanning (PET/CT 'hybrid' scan). The research objectives are: to evaluate the diagnostic accuracy and therapeutic impact of fluorine-18-deoxyglucose (FDG) PET/CT for the pre-operative staging of primary, recurrent and metastatic cancer using systematic review methods; undertake probabilistic decision-analytic modelling (using Monte Carlo simulation); and conduct a value of information analysis to help inform whether or not there is potential worth in undertaking further research. For each aspect of the research - the systematic review, the handsearch study and the economic evaluation - a database was assembled from a comprehensive search for published and unpublished studies, which included database searches, reference lists search and contact with experts. In the systematic review prospective and retrospective patient series (diagnostic cohort) and randomised controlled trials (RCTs) were eligible for inclusion. Both consecutive series and series that are not explicitly reported as consecutive were included. Two reviewers extracted all data and applied the criteria independently and resolved disagreements by discussion. Data to populate 2 × 2 contingency tables consisting of the number of true positives, true negatives, false positives and false negatives using the studies' own definitions were extracted, as were data relating to changes in management. Fourteen items from the Quality Assessment of Diagnostic Accuracy Studies checklist were used to assess the methodological quality of the included studies. Patient-level data were used to calculate sensitivity and specificity with confidence intervals (CIs). Data were plotted graphically in forest plots. For the economic evaluation, economic models were designed for each of the disease states: primary, recurrent and metastatic. These were developed and populated based on a variety of information sources (in particular from published data sources) and literature, and in consultation with clinical experts. The review found 30 studies that met the eligibility criteria. Only two small studies evaluated the use of FDG PET/CT in primary CRC, and there is insufficient evidence to support its routine use at this time. The use of FDG PET/CT for the detection of recurrent disease identified data from five retrospective studies from which a pooled sensitivity of 91% (95% CI 0.87% to 0.95%) and specificity of 91% (95% CI 0.85% to 0.95%) were observed. Pooled accuracy data from patients undergoing staging for suspected metastatic disease showed FDG PET/CT to have a pooled sensitivity of 91% (95% CI 87% to 94%) and a specificity of 76% (95% CI 58% to 88%), but the poor quality of the studies means the validity of the data may be compromised by several biases. The separate handsearch study did not yield any additional unique studies relevant to FDG PET/CT. Models for recurrent disease demonstrated an incremental cost-effectiveness ratio of £ 21,409 per quality-adjusted life-year (QALY) for rectal cancer, £ 6189 per QALY for colon cancer and £ 21,434 per QALY for metastatic disease. The value of handsearching to identify studies of less clearly defined or reported diagnostic tests is still to be investigated. The systematic review found insufficient evidence to support the routine use of FDG PET/CT in primary CRC and only a small amount of evidence supporting its use in the pre-operative staging of recurrent and metastatic CRC, and, although FDG PET/CT was shown to change patient management, the data are divergent and the quality of research is generally poor. The handsearch to identify studies of less clearly defined or reported diagnostic tests did not find additional studies. The primary limitations in the economic evaluations were due to uncertainty and lack of available evidence from the systematic reviews for key parameters in each of the five models. In order to address this, a conservative approach was adopted in choosing DTA estimates for the model parameters. Probabilistic analyses were undertaken for each of the models, incorporating wide levels of uncertainty particularly for the DTA estimates. None of the economic models reported cost-savings, but the approach adopted was conservative in order to determine more reliable results given the lack of current information. The economic evaluations conclude that FDG PET/CT as an add-on imaging device is cost-effective in the pre-operative staging of recurrent colon, recurrent rectal and metastatic disease but not in primary colon or rectal cancers. There would be value in undertaking an RCT with a concurrent economic evaluation to evaluate the therapeutic impact and cost-effectiveness of FDG PET/CT compared with conventional imaging (without PET) for the pre-operative staging of recurrent and metastatic CRC.


Endovascular aneurysm repair and outcome in patients unfit for open repair of abdominal aortic aneurysm (EVAR trial 2): randomised controlled trial.
Endovascular aneurysm repair (EVAR) to exclude abdominal aortic aneurysm (AAA) was introduced for patients of poor health status considered unfit for major surgery. We instigated EVAR trial 2 to identify whether EVAR improves survival compared with no intervention in patients unfit for open repair of aortic aneurysm. We did a randomised controlled trial of 338 patients aged 60 years or older who had aneurysms of at least 5.5 cm in diameter and who had been referred to one of 31 hospitals in the UK. We assigned patients to receive either EVAR (n=166) or no intervention (n=172). Our primary endpoint was all-cause mortality, with secondary endpoints of aneurysm-related mortality, health-related quality of life (HRQL), postoperative complications, and hospital costs. Analyses were by intention to treat. 197 patients underwent aneurysm repair (47 assigned no intervention) and 80% of patients adhered to protocol. The 30-day operative mortality in the EVAR group was 9% (13 of 150, 95% CI 5-15) and the no intervention group had a rupture rate of 9.0 per 100 person years (95% CI 6.0-13.5). By end of follow up 142 patients had died, 42 of aneurysm-related factors; overall mortality after 4 years was 64%. There was no significant difference between the EVAR group and the no intervention group for all-cause mortality (hazard ratio 1.21, 95% CI 0.87-1.69, p=0.25). There was no difference in aneurysm-related mortality. The mean hospital costs per patient over 4 years were UK pound sterling 13,632 in the EVAR group and pound sterling 4983 in the no intervention group (mean difference pound sterling 8649, SE 1248), with no difference in HRQL scores. EVAR had a considerable 30-day operative mortality in patients already unfit for open repair of their aneurysm. EVAR did not improve survival over no intervention and was associated with a need for continued surveillance and reinterventions, at substantially increased cost. Ongoing follow-up and improved fitness of these patients is a priority.


TRPV channels and vascular function.
Transient receptor potential channels, of the vanilloid subtype (TRPV), act as sensory mediators, being activated by endogenous ligands, heat, mechanical and osmotic stress. Within the vasculature, TRPV channels are expressed in smooth muscle cells, endothelial cells, as well as in peri-vascular nerves. Their varied distribution and polymodal activation properties make them ideally suited to a role in modulating vascular function, perceiving and responding to local environmental changes. In endothelial cells, TRPV1 is activated by endocannabinoids, TRPV3 by dietary agonists and TRPV4 by shear stress, epoxyeicosatrienoic acids (EETs) and downstream of Gq-coupled receptor activation. Upon activation, these channels contribute to vasodilation via nitric oxide, prostacyclin and intermediate/small conductance potassium channel-dependent pathways. In smooth muscle, TRPV4 is activated by endothelial-derived EETs, leading to large conductance potassium channel activation and smooth muscle hyperpolarization. Conversely, smooth muscle TRPV2 channels contribute to global calcium entry and may aid constriction. TRPV1 and TRPV4 are expressed in sensory nerves and can cause vasodilation through calcitonin gene-related peptide and substance P release as well as mediating vascular function via the baroreceptor reflex (TRPV1) or via increasing sympathetic outflow during osmotic stress (TRPV4). Thus, TRPV channels play important roles in the regulation of normal and pathological cellular function in the vasculature.


Nut Consumption and Risk of Cancer: A Meta-analysis of Prospective Studies.
Epidemiologic studies have investigated the association between nut intake and risk for multiple cancers. However, current findings are inconsistent and no definite conclusion has been drawn from prospective studies. We therefore conducted this meta-analysis to evaluate the relationship between nut consumption and risk of cancer. Prospective studies reporting associations between nut intake and risk for all types of cancer were identified by searching Web of Science and PubMed databases up to June 2019. Risk ratios (RR) and 95% confidence intervals (CI) were extracted and then pooled across the studies using a random-effect model. A dose-response analysis was modeled by performing restricted cubic splines when data were available. Thirty-three studies that included more than 50,000 cancer cases were eligible for the analysis. When comparing the highest with the lowest category of nut intake, high consumption of nuts was significantly associated with decreased risk of overall cancer (RR = 0.90; 95% CI, 0.85-0.95). The protective effect of nut consumption was especially apparent against cancers from the digestive system (RR = 0.83; 95% CI, 0.77-0.89). Among different nut classes, significant association was only obtained for intake of tree nuts. We also observed a linear dose-response relationship between nut consumption and cancer: Per 20 g/day increase in nut consumption was related to a 10% (RR = 0.90; 95% CI, 0.82-0.99) decrease in cancer risk. Our analysis demonstrated an inverse association of dietary nut consumption with cancer risk, especially for cancers from the digestive system. This study highlights the protective effect of nuts against cancer.


Remote manipulation of micronanomachines containing magnetic nanoparticles.
We report remote manipulation of micronanomachines containing magnetic nanoparticles. Surface-modified Fe(3)O(4) nanocrystals were synthesized as doping agents of the photopolymerizable resin, which was pinpoint written by femtosecond laser-induced two-photon photopolymerization to create microsprings. Owing to the nature of superparamagnetism of Fe(3)O(4) nanoparticles, force exerted to the microsprings relies sensitively on the field gradient of the external ferromagnet, and various motions like elongation, bending, and swing are achieved in a well-controllable remote manner. As a noncontact, sensitive, easy, and environmentally friendly approach, the magnetic driving of micronanomachines may play an important role for nano and biological applications.


Positron Emission Tomography and Single-Photon Emission Computed Tomography Imaging in the Diagnosis of Cardiac Implantable Electronic Device Infection: A Systematic Review and Meta-Analysis.
The use of cardiac implantable electronic devices (CIED) is increasing, and their associated infections result in significant morbidity and mortality. The introduction of better cardiac imaging techniques could be useful for diagnosing this condition and guiding therapy. Our objective was to systematically assess the diagnostic accuracy of Fluor-18-fluorodeoxyglucose positron emission tomography and computed tomography, labeled leukocyte scintigraphy (LS), and Gallium-67 citrate scintigraphy for the diagnosis of CIED infection. A systematic review of the literature and meta-analysis on the use of all 3 modalities in CIED infection were conducted. Pooled sensitivity, specificity, and summary receiver operating characteristic curves of each imaging modalities were determined. The literature search identified 2493 articles. A total of 13 articles (11 studies for 18F-FDG PET-CT and 2 for LS), met the inclusion criteria. No studies for 67Ga citrate scintigraphy met the inclusion criteria. The pooled sensitivity of 18F-FDG PET-CT for the diagnosis of CIED infection was 87% (95% CI, 82%-91%) and pooled specificity was 94% (95% CI, 88%-98%). The summary receiver operating characteristic curve analysis demonstrated good overall accuracy, with an area under the curve of 0.935. There were insufficient data to do a meta-analysis for LS, but both studies reported sensitivity above 90% and specificity of 100%. Both 18F-FDG PET-CT and LS yield high sensitivity, specificity, and accuracy, and thus seem to be useful for the diagnosis of CIED infection, based on robust data for 18F-FDG PET-CT but limited data for LS. When available,18F-FDG PET-CT may be preferred.