Acupuncture for cancer pain in adults.
Forty percent of individuals with early or intermediate stage cancer and 90% with advanced cancer have moderate to severe pain and up to 70% of patients with cancer pain do not receive adequate pain relief. It has been claimed that acupuncture has a role in management of cancer pain and guidelines exist for treatment of cancer pain with acupuncture. To evaluate efficacy of acupuncture for relief of cancer-related pain in adults. CENTRAL, MEDLINE, EMBASE, PsycINFO, AMED, and SPORTDiscus were searched up to November 2010 including non-English language papers. Randomised controlled trials (RCTs) evaluating any type of invasive acupuncture for pain directly related to cancer in adults of 18 years or over. It was planned to pool data to provide an overall measure of effect and to calculate the number needed to treat to benefit, but this was not possible due to heterogeneity. Two review authors (CP, OT) independently extracted data adding it to data extraction sheets. Quality scores were given to studies. Data sheets were compared and discussed with a third review author (MJ) who acted as arbiter. Data analysis was conducted by CP, OT and MJ. Three RCTs (204 participants) were included. One high quality study investigated the effect of auricular acupuncture compared with auricular acupuncture at 'placebo' points and with non-invasive vaccaria ear seeds attached at 'placebo' points. Participants in two acupuncture groups were blinded but blinding wasn't possible in the ear seeds group because seeds were attached using tape. This may have biased results in favour of acupuncture groups. Participants in the real acupuncture group had lower pain scores at two month follow-up than either the placebo or ear seeds group.There was high risk of bias in two studies because of low methodological quality. One study comparing acupuncture with medication concluded that both methods were effective in controlling pain, although acupuncture was the most effective. The second study compared acupuncture, point-injection and medication in participants with stomach cancer. Long-term pain relief was reported for both acupuncture and point-injection compared with medication during the last 10 days of treatment. Although both studies have positive results in favour of acupuncture they should be viewed with caution due to methodological limitations, small sample sizes, poor reporting and inadequate analysis. There is insufficient evidence to judge whether acupuncture is effective in treating cancer pain in adults.


Correspondence between conventional and digitised radiographs for assessment of marginal bone.
To compare reproducibility of marginal bone measurements in conventional film and digitised radiographs and to assess whether variations in reproducibility occurred in measurements taken in a longitudinal, epidemiological survey. Triplicate measurements of the marginal bone level and of remaining bone were obtained from film and digitised full-mouth radiographic surveys from 20 individuals who were examined three times at five-year intervals in a longitudinal study design. The digitalisation of the films was conducted by scanning the film with a flatbed scanner. The standard deviation (SD) of the triplicate measurements served as the statistic for reproducibility. The time spent for recording one radiographic survey, which consisted of 14 periapicals and 2 bitewings, was documented. Statistically significant differences existed in the reproducibility of marginal bone level measurements obtained at the first examination and the two subsequent examinations both for film and digitised radiographs (P < 0.05). The difference in marginal bone level measurements (film vs digitised) was 0.16 mm (SD = 0.45 mm). Similarly, the overall difference in measurements of the remaining bone was 0.12 mm (SD = 0.61 mm). Recording of a digitised survey lasted on average 5 min (SD = 1.5 min), while the recording of a film survey lasted on average 14 min (SD = 1 min). Digitising film is an acceptable method for the purpose of assessing the marginal bone level and will save time in longitudinal, epidemiological studies.


Interaction of polyacrylates with porcine pepsin and the gastric mucus barrier: a mechanism for mucosal protection.
1. The mechanism of interaction of the polyacrylates, carbopols with the mucus barrier in vivo has been investigated in vitro. 2. Carbopol caused a dramatic increase in the viscosity of porcine gastric mucin solutions that was up to 19-fold greater than that of the sum of the individual polymers. 3. The mucin-carbopol interaction was stable after an initial 30 min period for up to 36 h at 25 degrees C or 37 degrees C. It was reduced by increasing the temperature from 20 degrees C to 45 degrees C, was unaffected by pH and ionic strength, but was enhanced by Ca2+. 4. The magnitude of the interaction between mucin and carbopol depended on the polymeric structure of the mucin and the molecular size and level of cross-linking of the carbopol. 5. The interactions were reversible and increased with increasing carbopol and mucin concentration. The dramatic increase in viscosity can be explained in terms of space filling by the mucin molecules leading to predominantly carbopol-carbopol interactions. 6. Carbopol 934P inhibits pepsin hydrolysis and therefore has potential as a mucosal protective agent in vivo.


The electromotor system of the stargazer: a model for integrative actions at electrotonic synapses.
The electric organs of Astroscopus are modified from extraocular muscles and innervated by the enlarged oculomotor nuclei. The electromotor neuron somata are contacted by fine processes with which they form gap junctions. Presynaptic vesicles and active zones are also present, although physiological data give no indication of chemically mediated transmission. Antidromic stimulation produces long lasting graded depolarizations in the electromotor neurons. The latency is sufficiently short to indicate that the cells are electrotonically coupled, which was confirmed by direct measurement. Antidromic invasion may normally fail and is easily blocked by hyperpolarization revealing initial segment and axon spikes. Spinal stimulation evokes postsynaptic potentials (PSPs) and orthodromic impulses; the PSPs are not smoothly graded in amplitude. A medullary nucleus innervates the electromotor nucleus; the medullary cells also show short latency graded antidromic depolarizations and presumably are electrotonically coupled. Their coupling accounts for the variability in PSPs evoked by spinal stimulation. Apparent time constants differ greatly for direct stimulation of a single cell, decay of afterhyperpolarization, electrotonic spread from one cell to a neighbor, and decay of PSPs and graded antidromic depolarizations. The differences can be accounted for in terms of a highly interconnected network of electrotonically coupled cells, which was simulated computationally. Because of the long membrane time constant graded antidromic depolarizations summate. Because antidromic invasion is facilitated by depolarization, the antidromic depolarizations can show pronounced facilitation. The observed "plasticity" within this electrotonically coupled system provides a model for integrative actions at other sites of coupling.


Regulation of endothelial permeability and transendothelial migration of cancer cells by tropomyosin-1 phosphorylation.
Loss of endothelial cell integrity and selective permeability barrier is an early event in the sequence of oxidant-mediated injury and may result in atherosclerosis, hypertension and facilitation of transendothelial migration of cancer cells during metastasis. We already reported that endothelial cell integrity is tightly regulated by the balanced co-activation of p38 and ERK pathways. In particular, we showed that phosphorylation of tropomyosin-1 (tropomyosin alpha-1 chain = Tm1) at Ser283 by DAP kinase, downstream of the ERK pathway might be a key event required to maintain the integrity and normal functions of the endothelium in response to oxidative stress. Endothelial permeability was assayed by monitoring the passage of Dextran-FITC through a tight monolayer of HUVECs grown to confluence in Boyden chambers. Actin and Tm1 dynamics and distribution were evaluated by immunofluorescence. We modulated the expression of Tm1 by siRNA and lentiviral-mediated expression of wild type and mutated forms of Tm1 insensitive to the siRNA. Transendothelial migration of HT-29 colon cancer cells was monitored in Boyden chambers similarly as for permeability. We provide evidence indicating that Tm1 phosphorylation at Ser283 is essential to regulate endothelial permeability under oxidative stress by modulating actin dynamics. Moreover, the transendothelial migration of colon cancer cells is also regulated by the phosphorylation of Tm1 at Ser283. Our finding strongly support the role for the phosphorylation of endothelial Tm1 at Ser283 to prevent endothelial barrier dysfunction associated with oxidative stress injury.


Mothers' comfort with screening questions about sensitive issues, including domestic violence.
To assess patient ratings of comfort alone and in front of children with 5 domestic violence (DV) screening questions designed with less graphic language compared with questions about other sensitive issues. A sample of mothers (n = 200), including a small sample of Spanish-speaking women, were recruited from community locations. Mothers rated their perceptions of comfort for answering 13 sensitive issue screening questions (including sexual risk, substance abuse, depression, and DV questions). Logistic regression was performed to analyze participants' characteristics with respect to summary comfort scores. In addition, 40 mothers were asked to talk about their comfort in answering the DV questions. These interviews were audiotaped and analyzed. Mothers preferred to answer all questions alone. Comfort with answering the DV screening questions in front of their children was higher than comfort with sexual risk or depression questions and was similar to comfort with substance abuse questions. Latina mothers had more discomfort with the DV questions than other ethnicities. Although mothers were more comfortable with answering sensitive questions alone than in the presence of children, this may not be feasible in busy offices. General DV questions may be appropriate to ask in front of children as an initial screen.


The effect of transcutaneous electrical acupoint stimulation on pregnancy rates in women undergoing in vitro fertilization: a study protocol for a randomized controlled trial.
The latest meta-analysis demonstrated that acupuncture improves pregnancy rates among women undergoing in vitro fertilization-embryo transfer (IVF-ET), and surface acupoint stimulation, such as transcutaneous electrical acupoint stimulation (TEAS), may have the same or better potential. To explore the effect of TEAS on the clinical pregnancy rate (CPR) and live birth rate (LBR) compared with real acupuncture and controls in women undergoing IVF, a multicenter, randomized controlled trial will be conducted. The inclusion criteria are the following: infertile women <40 years of age undergoing a fresh IVF or intracytoplasmic sperm injection cycle, and the study will be restricted to women with the potential for a lower success rate as defined by two or more previous unsuccessful ETs (fresh or frozen). Those who have severe illnesses possibly precluding IVF or pregnancy, have FSH levels greater than 20 IU/L, received donor eggs, had been previously randomized for this study or had undergone acupuncture (in any modality) as infertility treatment will be excluded. The subjects will be randomly assigned to the TEAS group (IVF + TEAS), the electro-acupuncture (EA) group (IVF + EA), or the control group (only IVF). A total sample size of 2,220 women is required to detect differences in CPR among the three groups. TEAS or EA treatments will start once every two or three days from day 3 of menstruation in the ovarian stimulation cycle until the day of ET. The parameters of TEAS or EA will be the following: a frequency of 2/100 Hz, a moderate electrical current of 3 to 5 mA for TEAS and 0.8 to 1.0 mA for EA. The primary outcome is CPR. Secondary outcomes are LBR, the number of oocytes aspirated and the total gonadotropin dose used in the stimulation cycle. This study will provide significant evidence for using a new method (TEAS) in IVF. ClinicalTrials.govID: NCT01608048 (05/24/2012).


Active elastic dimers: cells moving on rigid tracks.
Experiments suggest that the migration of some cells in the three-dimensional extracellular matrix bears strong resemblance to one-dimensional cell migration. Motivated by this observation, we construct and study a minimal one-dimensional model cell made of two beads and an active spring moving along a rigid track. The active spring models the stress fibers with their myosin-driven contractility and α-actinin-driven extendability, while the friction coefficients of the two beads describe the catch and slip-bond behaviors of the integrins in focal adhesions. In the absence of active noise, net motion arises from an interplay between active contractility (and passive extendability) of the stress fibers and an asymmetry between the front and back of the cell due to catch-bond behavior of integrins at the front of the cell and slip-bond behavior of integrins at the back. We obtain reasonable cell speeds with independently estimated parameters. We also study the effects of hysteresis in the active spring, due to catch-bond behavior and the dynamics of cross linking, and the addition of active noise on the motion of the cell. Our model highlights the role of α-actinin in three-dimensional cell motility and does not require Arp2/3 actin filament nucleation for net motion.


How do (perceptual) distracters distract?
When a target stimulus occurs in the presence of distracters, decisions are less accurate. But how exactly do distracters affect choices? Here, we explored this question using measurement of human behaviour, psychophysical reverse correlation and computational modelling. We contrasted two models: one in which targets and distracters had independent influence on choices (independent model) and one in which distracters modulated choices in a way that depended on their similarity to the target (interaction model). Across three experiments, participants were asked to make fine orientation judgments about the tilt of a target grating presented adjacent to an irrelevant distracter. We found strong evidence for the interaction model, in that decisions were more sensitive when target and distracter were consistent relative to when they were inconsistent. This consistency bias occurred in the frame of reference of the decision, that is, it operated on decision values rather than on sensory signals, and surprisingly, it was independent of spatial attention. A normalization framework, where target features are normalized by the expectation and variability of the local context, successfully captures the observed pattern of results.


Personalised nutrition: ready for practice?
The efficacy by which dietary interventions influence risk markers of multi-factorial diseases is mainly determined by taking population-based approaches. However, there exists considerable inter-individual variation in response to dietary interventions, and some interventions may benefit certain individuals or population subgroups more than others. This review evaluates the application of nutrigenomic technologies to further the concept of personalised nutrition, as well as the process to take personalised nutrition to the marketplace. The modulation of an individual's response is influenced by both genetic and environmental factors. Many nutrigenetics studies have attempted to explain variability in responses based on a single or a few genotypes so that a genotype may be used to define personalised dietary advice. It has, however, proven very challenging to define an individual's responsiveness to complex diets based on common genetic variations. In addition, there is a limited understanding of what constitutes an optimal response because we lack key health biomarkers and signatures. In conclusion, advances in nutrigenomics will undoubtedly further the understanding of the complex interplay between genotype, phenotype and environment, which are required to enhance the development of personalised nutrition in the future. At the same time, however, issues relating to consumer acceptance, privacy protection as well as marketing and distribution of personalised products need to be addressed before personalised nutrition can become commercially viable.


Serial selection for invasiveness increases expression of miR-143/miR-145 in glioblastoma cell lines.
Glioblastoma multiforme (GBM) is the most common primary central nervous system malignancy and its unique invasiveness renders it difficult to treat. This invasive phenotype, like other cellular processes, may be controlled in part by microRNAs - a class of small non-coding RNAs that act by altering the expression of targeted messenger RNAs. In this report, we demonstrate a straightforward method for creating invasive subpopulations of glioblastoma cells (IM3 cells). To understand the correlation between the expression of miRNAs and the invasion, we fully profiled 1263 miRNAs on six different cell lines and two miRNAs, miR-143 and miR-145, were selected for validation of their biological properties contributing to invasion. Further, we investigated an ensemble effect of both miR-143 and miR-145 in promoting invasion. By repeated serial invasion through Matrigel®-coated membranes, we isolated highly invasive subpopulations of glioma cell lines. Phenotypic characterization of these cells included in vitro assays for proliferation, attachment, and invasion. Micro-RNA expression was compared using miRCURY arrays (Exiqon). In situ hybridization allowed visualization of the regional expression of miR-143 and miR-145 in tumor samples, and antisense probes were used investigate in vitro phenotypic changes seen with knockdown in their expression. The phenotype we created in these selected cells proved stable over multiple passages, and their microRNA expression profiles were measurably different. We found that two specific microRNAs expressed from the same genetic locus, miR-143 and miR-145, were over-expressed in our invasive subpopulations. Further, we also found that combinatorial treatment of these cells with both antisense-miRNAs (antimiR-143 and -145) will abrogated their invasion without decreasing cell attachment or proliferation. To best of our knowledge, these data demonstrate for the first time that miR-143 and miR-145 regulate the invasion of glioblastoma and that miR-143 and -145 could be potential therapeutic target for anti-invasion therapies of glioblastoma patients.


Interrelation of oxidative stress and inflammation in neurodegenerative disease: role of TNF.
Neuroinflammation and mitochondrial dysfunction are common features of chronic neurodegenerative diseases of the central nervous system. Both conditions can lead to increased oxidative stress by excessive release of harmful reactive oxygen and nitrogen species (ROS and RNS), which further promote neuronal damage and subsequent inflammation resulting in a feed-forward loop of neurodegeneration. The cytokine tumor necrosis factor (TNF), a master regulator of the immune system, plays an important role in the propagation of inflammation due to the activation and recruitment of immune cells via its receptor TNF receptor 1 (TNFR1). Moreover, TNFR1 can directly induce oxidative stress by the activation of ROS and RNS producing enzymes. Both TNF-induced oxidative stress and inflammation interact and cooperate to promote neurodegeneration. However, TNF plays a dual role in neurodegenerative disease, since stimulation via its second receptor, TNFR2, is neuroprotective and promotes tissue regeneration. Here we review the interrelation of oxidative stress and inflammation in the two major chronic neurodegenerative diseases, Alzheimer's and Parkinson's disease, and discuss the dual role of TNF in promoting neurodegeneration and tissue regeneration via its two receptors.


Neonatal isoerythrolysis in mule foals.
Four mule foals received anti-RBC antibody from their dam's colostrum. Two foals developed anemia, 1 developed severe thrombocytopenia, and 1 did not develop any clinical or laboratory abnormalities. All foals had the same donkey sire. Seven mares, including the dams of foals 1 to 4, bred to the donkey sire produced anti-RBC antibody. Two mares produced anti-RBC antibody to the donkey RBC on the first mating. The donkey sire and 18 of its offspring were found to have an RBC antigen unique to mules and donkeys. Thus, all matings of this donkey to horse mares were incompatible. The reason for the high rate of sensitization of mares bred to this donkey is unknown.


The Port Alfred floods of 17-23 October 2012: A case of disaster (mis)management?
An intense cut-off low weather system, more commonly known regionally as a 'black south-easter', caused severe flooding in Port Alfred and the surrounding coastal areas from 17 to 23 October 2012. Unconfirmed reports of up to 700 mm of rainfall for the period were recorded. Damage caused by the flooding was estimated at R500 million. Eight deaths were recorded. The poorly maintained and ageing infrastructure and storm water systems could not withstand the floodwaters, and as a result, damage was worse than it should have been. Many houses, particularly in the surrounding townships and informal settlements, were destroyed. Disease threats arose, including cholera, diarrhoea and influenza. The South African Weather Service issued weather warnings of severe local flooding in the coastal areas of the Eastern Cape a few days before the flood event. Unfortunately, there was a delay in communicating the severe weather warning effectively to the public, relevant authorities and role-players by local disaster management officials. In addition, there was poor and ineffective local coordination of disaster response and relief efforts. This paper examines the 2012 flood event from both meteorological and disaster management perspectives, using a combined qualitative and quantitative research approach. Findings point to a critical lack of coordination amongst the various role-players before, during and after the disaster. Recommendations for improved proactive and coordinated disaster risk management and disaster risk reduction for the region are made.


The combined effect of mechanical strain and electric field cycling on the ferroelectric performance of P(VDF-TrFE) thin films on flexible substrates and underlying mechanisms.
In this manuscript, we study the combined effect of mechanical strain and electric field cycling on the ferroelectric properties and polarization fatigue of P(VDF-TrFE) based flexible thin film capacitors from the perspective of flexible memory applications. The devices show nearly 80% retention of ferroelectric polarization after 30 000 bending cycles at mechanical strains of up to ca. 0.8%, mimicking a typical number of bending cycles a product is expected to go through. On the other hand, electric field cycling of the unstrained as well as mechanically strained devices results in over 50% drop in the ferroelectric polarization of the capacitors within 105 bipolar switching cycles. We find that 20% reduction in the polarization upon mechanical cycling is due to the formation of cracks in P(VDF-TrFE) thin films whilst ca. 50% polarization reduction during purely electrical or mechano-electrical fatigue is concomitant with the development of bubbles in the top electrode of the devices which eventually coalesce to give rise to bursting and eventual delamination of the electrode. A detailed investigation into the electrical fatigue mechanisms shows that the fatigue is primarily driven by the degradation of the P(VDF-TrFE) thin films due to HF elimination triggered by a high enough electric field, also manifested by reduced crystallinity and a reduced number of total dipoles of P(VDF-TrFE) films. The results clearly suggest that polarization reduction upon electric field cycling i.e. electrical fatigue is a greater bottleneck in the use of flexible memory devices than the mechanical cycling.


Dickkopf-3 regulates prostate epithelial cell acinar morphogenesis and prostate cancer cell invasion by limiting TGF-β-dependent activation of matrix metalloproteases.
Dickkopf-3 (Dkk-3) is a secreted protein whose expression is downregulated in many types of cancer. Endogenous Dkk-3 is required for formation of acini in 3D cultures of prostate epithelial cells, where it inhibits transforming growth factor (TGF)-β/Smad signaling. Here, we examined the effects of Dkk-3 on the expression and activity of matrix metalloproteases (MMPs), which mediate the effects of TGF-β on extracellular matrix disassembly during tissue morphogenesis and promote invasion of tumor cells. Silencing of Dkk-3 in prostate epithelial cells resulted in increased expression and enzyme activity of MMP-2 and MMP-9. Inhibition of MMP-9 partially restored normal acinar morphogenesis in Dkk-3-silenced RWPE-1 prostate epithelial cells. In PC3 prostate cancer cells, Dkk-3 inhibited TGF-β-dependent migration and invasion. Inhibition was mediated by the Dkk-3 C-terminal cysteine-rich domain (Cys2), which also inhibited TGF-β-induced expression of MMP9 and MMP13. In contrast, Dkk-3, but not Cys2, increased formation of normal acini in Dkk-3-silenced prostate epithelial cells. These observations highlight a role for Dkk-3 in modulating TGF-β/MMP signals in the prostate, and suggest that the Dkk-3 Cys2 domain can be used as a basis for therapies that target the tumor promoting effects of TGF-β signaling in advanced prostate cancer.


Validation of a new technique for the quantitation of edema in the experimental setting.
An inherent limitation to the study of in vivo animal models of lymphedema is the potential inaccuracy or unreliability of existing methods for the quantification of edema volume as a surrogate functional measure of lymphatic transport capacity. Circumference-based techniques have been proposed and validated as a suitable alternative to volume displacement measurements in human clinical studies; accordingly, we have elaborated a new application of this approach that can be applied to small animal studies. Acute postsurgical lymphedema was created experimentally in the murine tail. Both normal and lymphedematous murine tails were examined. Tail volume was quantitated both by water displacement and by a digital photographic technique. In selected mice, after sacrificed on postsurgical day 7, a 6 cm segment was resected from the midportion of the tail and cauterized to create a closed space. Known incremental volumes of saline (20-100 microL) were injected for subsequent digital photographic volumetry. The coefficients of variation for volume assessment by water displacement and by digital imaging were 0.08+/-0.09 and 0.01+/-0.009, respectively. The two techniques were poorly correlated: while serial water displacement analysis yielded highly variable measurements within the same tail, concurrent digital imaging of the tail circumference was quite reproducible. Furthermore, after parenteral injection of known incremental volumes of saline, the correlation between the injectate volumes and the digitally measured increases in volume was high, both in the normal and the lymphedematous tail. In the murine tail, when compared to water displacement volumetry, digital photography yields highly reproducible data. We can conclude that the lack of correlation between the two methods, with the relatively flat slope of the linear regression relationship, reflects inherent inaccuracies of the water displacement method.


The effect of hypercapnia on the sensitivity to flicker defined stimuli.
To investigate the effect of increased CO2 levels on flicker defined stimuli. The sensitivity of two flicker defined tasks was measured in nine healthy, trained observers using the Flicker Defined Form (FDF) stimulus of the Heidelberg Edge Perimeter (HEP; Heidelberg Engineering) and Frequency Doubling Technology (FDT) stimulus of the Matrix perimeter (Carl Zeiss Meditec) during normoxia and 15% hypercapnia (end-tidal CO2 increased by 15% relative to baseline). HEP-FDF and Matrix-FDT sensitivities were analysed for the global field, superior and inferior hemifields and at specific matched eccentricities, using repeated measures analysis of variance. The main effect of hypercapnia on flicker sensitivity was analysed using regression models. Higher flicker sensitivity outcomes with increasing CO2 values were found for HEP-FDF and Matrix-FDT with a statistically significant main effect for HEP-FDF global, superior and inferior hemifields (p<0.01 for all) as well as 6°, 18°, 12° and 24° eccentricities (p=0.03, 0.04, 0.01, 0.05, respectively). When comparing mean sensitivity values between normocapnia and hypercapnia conditions, no statistically significantly different results were found for HEP-FDF and Matrix-FDT (p>0.05). As CO2 levels were increased in healthy young individuals, there was an associated increase in visual sensitivity that was only significant for HEP-FDF stimuli, highlighting the different mechanisms involved in processing each of HEP-FDF and Matrix-FDT stimuli. Mean visual sensitivity outcomes were found to be similar for normocapnia and hypercapnia suggesting that a capability to compensate for a mild and stable increase in systemic CO2 levels may exist.


Association of Coffee Consumption With Overall and Cause-Specific Mortality in a Large US Prospective Cohort Study.
Concerns about high caffeine intake and coffee as a vehicle for added fat and sugar have raised questions about the net impact of coffee on health. Although inverse associations have been observed for overall mortality, data for cause-specific mortality are sparse. Additionally, few studies have considered exclusively decaffeinated coffee intake or use of coffee additives. Coffee intake was assessed at baseline by self-report in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Hazard ratios were estimated using Cox proportional hazards models. Among 90,317 US adults without cancer at study baseline (1998-2001) or history of cardiovascular disease at study enrollment (1993-2001), 8,718 deaths occurred during 805,644 person-years of follow-up from 1998 through 2009. Following adjustment for smoking and other potential confounders, coffee drinkers, as compared with nondrinkers, had lower hazard ratios for overall mortality (<1 cup/day: hazard ratio (HR) = 0.99 (95% confidence interval (CI): 0.92, 1.07); 1 cup/day: HR = 0.94 (95% CI: 0.87, 1.02); 2-3 cups/day: HR = 0.82 (95% CI: 0.77, 0.88); 4-5 cups/day: HR = 0.79 (95% CI: 0.72, 0.86); ≥6 cups/day: HR = 0.84 (95% CI: 0.75, 0.95)). Similar findings were observed for decaffeinated coffee and coffee additives. Inverse associations were observed for deaths from heart disease, chronic respiratory diseases, diabetes, pneumonia and influenza, and intentional self-harm, but not cancer. Coffee may reduce mortality risk by favorably affecting inflammation, lung function, insulin sensitivity, and depression.


Enhancement of cell radiation sensitivity by pegylated gold nanoparticles.
Biocompatible Au nanoparticles with surfaces modified by PEG (polyethylene glycol) were developed in view of possible applications for the enhancement of radiotherapy. Such nanoparticles exhibit preferential deposition at tumor sites due to the enhanced permeation and retention (EPR) effect. Here, we systematically studied their effects on EMT-6 and CT26 cell survival rates during irradiation for a dose up to 10 Gy with a commercial biological irradiator (E(average) = 73 keV), a Cu-Kalpha(1) x-ray source (8.048 keV), a monochromatized synchrotron source (6.5 keV), a radio-oncology linear accelerator (6 MeV) and a proton source (3 MeV). The percentage of surviving cells after irradiation was found to decrease by approximately 2-45% in the presence of PEG-Au nanoparticles ([Au] = 400, 500 or 1000 microM). The cell survival rates decreased as a function of the dose for all sources and nanoparticle concentrations. These results could open the way to more effective cancer irradiation therapies by using nanoparticles with optimized surface treatment. Difficulties in applying MTT assays were also brought to light, showing that this approach is not suitable for radiobiology.


Interfacial rheology of polymer/carbon nanotube films co-assembled at the oil/water interface.
At appropriate conditions, water-dispersed acid-functionalized single-walled carbon nanotubes (SWCNTs) co-assemble at the oil/water interface with toluene-dissolved amine-terminated polystyrene (PS-NH2) to form composite thin films displaying pronounced interfacial viscoelasticity. To probe this viscoelasticity, the films were examined under dilatational deformations of pendant drop tensiometry/rheometry, with storage and loss moduli recorded against frequency ω (0.003 < ω < 3 Hz) and time-dependent relaxation modulus recorded against time t (0.2 < t < 2000 s). Without the SWCNTs, PS-NH2-decorated interfaces have little dilatational stiffness, i.e., low storage modulus, but their stiffness grows as SWCNTs are added, reaching 50-100 mN m-1 at large ω. Two characteristic relaxation processes are identified in the composite films: a fast process (ω ∼ 0.1-0.2 Hz) attributable to local structural relaxation of confined PS-NH2 and a slow process (t ∼ 300-2000 s) attributable to component adsorption/desorption (or attachment/detachment). Among the variables that affect positions and strengths of these relaxations are SWCNT and PS-NH2 bulk concentrations as well as water phase pH. In frequency or timescale ranges intermediate between the two relaxations, the co-assembled films display "soft-glass" behavior, with the storage and loss moduli characterized by nearly equal power-law exponents. The relaxation modulus, better able to probe terminal behavior, eventually decays to zero, revealing that the films are fundamentally fluid-like due to the slow relaxation, and in support of this conclusion, large strain compression-induced film wrinkles disappear at large t.


Extracorporeal shock waves lithotripsy versus retrograde ureteroscopy: is radiation exposure a criterion when we choose which modern treatment to apply for ureteric stones?
The aim of this study is to compare two major urological procedures in terms of patient exposure to radiation. We evaluated 175 patients, that were subjected to retrograde ureteroscopy (URS) and extracorporeal shock waves lithotripsy (ESWL) for lumbar or pelvic ureteral lithiasis, at two urological departments. The C-arm Siemens (produced in 2010 by Siemens AG, Germany) was used for ureteroscopy. The radiological devices of the lithotripters used in this study in the two clinical centers had similar characteristics. We evaluated patient exposure to ionizing radiation by using a relevant parameter, the air kerma-area product (PKA; all values in cGy cm(2)), calculated from the radiation dose values recorded by the fluoroscopy device. PKA depends on technical parameters that change due to anatomical characteristics of each case examined, such as body mass index (BMI), waist circumference, and stone location. For the patients subjected to ESWL for lumbar ureteral lithiasis the mean of PKA (cGy cm(2)) was 509 (SD=180), while for those treated for pelvic ureteral lithiasis the mean of PKA was 342 (SD=201). In the URS group for lumbar ureteral lithiasis, the mean of PKA (cGy cm(2)) was 892 (SD=436), while for patients with pelvic ureteral lithiasis, the mean of PKA was 601 (SD=429). The patients treated by URS had higher exposure to ionizing radiation dose than patients treated by ESWL. The risk factors of higher radiation doses were obesity, exposure time, and localization of the stones.


Critical role of Ras in the proliferation and prevention of apoptosis mediated by IL-2.
Activation of the Ras small guanine nucleotide-binding proteins upon IL-2 stimulation of T lymphocytes has been described previously. However, the relevance of the Ras molecules in the cellular events triggered by IL-2 still remained to be clarified. To analyze the effects of Ras inhibition in early proliferative responses to IL-2, we have transiently expressed a Ras dominant negative mutant carrying a point mutation in codon 17 (Ser17Asn or N17) under a tetracycline-controlled expression system. We have found that Ras has a crucial role in both proliferation and prevention of apoptosis through IL-2R, while IL-4 promotes proliferation and inhibits apoptosis by Ras-independent signals. The use of flow cytometry has allowed us to correlate the effects in proliferation and apoptosis with the expression level of the Ras mutant among the transfected population. Furthermore, the availability of a murine T cell line that can be maintained independently in the presence of IL-2 or IL-4 has provided specificity controls, since IL-4 does not trigger Ras activation.


Structure of a three-dimensional, microporous molybdenum phosphate with large cavities.
The synthesis, single-crystal x-ray structural characterization, and sorption properties of a microporous molybdenum phosphate, (Me(4)N)(1.3)(H(3)O)(0.7)[Mo(4)O(8)(PO(4))(2)] . 2H(2)O (Me, methyl), are presented. The three-dimensional framework is built up from Mo(4)O(8)(4+) cubes and PO(4)(3-) tetrahedra that are connected in such a way that large, cation-filled voids are generated; these voids constitute 25% of the volume of the solid. Absorption isotherms for water show the completely reversible uptake of 4 to 5 percent by weight water into the micropores of this compound, which corresponds to 10 to 12 percent by volume.


Morphology of a self-doped conducting oligomer for green energy applications.
A recently synthesized self-doped conducting oligomer, salt of bis[3,4-ethylenedioxythiophene]3thiophene butyric acid, ETE-S, is a novel promising material for green energy applications. Recently, it has been demonstrated that it can polymerize in vivo, in plant systems, leading to a formation of long-range conducting wires, charge storage and supercapacitive behaviour of living plants. Here we investigate the morphology of ETE-S combining the experimental characterisation using Grazing Incidence Wide Angle X-ray Scattering (GIWAXS) and atomistic molecular dynamics (MD) simulations. The GIWAXS measurements reveal a formation of small crystallites consisting of π-π stacked oligomers (with the staking distance 3.5 Å) that are further organized in h00 lamellae. These experimental results are confirmed by MD calculations, where we calculated the X-ray diffraction pattern and the radial distribution function for the distance between ETE-S chains. Our MD simulations also demonstrate the formation of the percolative paths for charge carriers that extend throughout the whole structure, despite the fact that the oligomers are short (6-9 rings) and crystallites are thin along the π-π stacking direction, consisting of only two or three π-π stacked oligomers. The existence of the percolative paths explains the previously observed high conductivity in in vivo polymerized ETE-S. We also explored the geometrical conformation of ETE-S oligomers and the bending of their aliphatic chains as a function of the oligomer lengths.


Methadone and buprenorphine for the management of opioid dependence in pregnancy.
This article provides an overview and discussion of the collective maternal, fetal and neonatal outcome research on women maintained on methadone or buprenorphine during pregnancy. Its focus is on an assessment of the comparative effectiveness of methadone and buprenorphine pharmacotherapy, with particular attention given to recent findings from the literature. Recommendations for clinical practice are outlined, and directions for future research are presented. Findings from comparative studies of methadone and buprenorphine underscore the efficacy of both medications in preventing relapse to illicit opioid use in the treatment of opioid-dependent pregnant patients, as well as the simplicity of induction onto methadone and patient retention while receiving such therapy. Fetal monitoring suggests that buprenorphine results in less fetal cardiac and movement suppression than does methadone. The clinical implications of these findings need future exploration. For the neonate, evidence from studies using a wide range of designs, including retrospective chart reviews, prospective observational studies, and randomized clinical trials, show consistent results, with prenatal exposure to buprenorphine resulting in less severe neonatal abstinence syndrome relative to methadone. Any medication given to pregnant women should be prescribed only after considering the risk : benefit ratio for the maternal-fetal dyad. Medication choices for each opioid-dependent patient during pregnancy need to be made on a patient-by-patient basis, taking into consideration the patient's opioid dependence history, previous and current treatment experiences, medical circumstances and treatment preferences. Moreover, for a full remission of opioid addiction to be sustainable, both post-partum and across the lifespan, treatment providers must not rely solely on medication to treat their patients but should also utilize women-specific comprehensive treatment models that address the underlying multifaceted complexities of their patient's lives.


Machine learning models of the energy curvature vs particle number for optimal tuning of long-range corrected functionals.
The average energy curvature as a function of the particle number is a molecule-specific quantity, which measures the deviation of a given functional from the exact conditions of density functional theory. Related to the lack of derivative discontinuity in approximate exchange-correlation potentials, the information about the curvature has been successfully used to restore the physical meaning of Kohn-Sham orbital eigenvalues and to develop non-empirical tuning and correction schemes for density functional approximations. In this work, we propose the construction of a machine-learning framework targeting the average energy curvature between the neutral and the radical cation state of thousands of small organic molecules (QM7 database). The applicability of the model is demonstrated in the context of system-specific gamma-tuning of the LC-ωPBE functional and validated against the molecular first ionization potentials at equation-of-motion coupled-cluster references. In addition, we propose a local version of the non-linear regression model and demonstrate its transferability and predictive power by determining the optimal range-separation parameter for two large molecules relevant to the field of hole-transporting materials. Finally, we explore the underlying structure of the QM7 database with the t-SNE dimensionality-reduction algorithm and identify structural and compositional patterns that promote the deviation from the piecewise linearity condition.


Examination of prevalence rates of possible risk factors in a population with a fracture of the proximal femur.
No statistical increase in the prevalence of either diabetes, rheumatoid arthritis or primary hyperparathyrodism was found among the hip fracture patient population. Since the relative risks for these diseases is small, the statistics suggest that these conditions are either noncontributory or represent only a minor risk factor in the overall pathogenesis of hip fractures. About 20% of the hip fracture patients had a history of other identifiable risk factors such as thyrotoxicosis, hemiplegia, malabsorption syndromes and corticosteroid therapy. Of these conditions only thyrotoxicosis could be evaluated by comparison of prevalence rates, and a significant increase was found among the fracture patients. A highly significant correlation was found between the side of a previous hemiplegia and side of he subsequent hip fracture; this may be due to the development of disuse osteoporosis in the hemiplegic limb. Recent reports have shown that a reduction in the number of hip fractures is associated with a high calcium intake or prophylactic estrogen therapy. Preventive therapy in patients with hemiplegia, thyrotoxicosis, or other predisposing conditions leading to osteopenia might result in a further reduction of the hip fracture rate.


Association of cholecystectomy with metabolic syndrome in a Chinese population.
An association between cholecystectomy and metabolic syndrome has not been fully established. Here we analyzed the association between cholecystectomy and metabolic syndrome in a Chinese population of 5672 subjects who undergone annual health checkups at the First Affiliated Hospital, College of Medicine, Zhejiang University between January 2011 and December 2012. The prevalences of gallstones, cholecystectomy and metabolic syndrome were 6.0%, 3.6%, and 32.5%, respectively. The prevalence of metabolic syndrome was significantly higher in subjects with a history of cholecystectomy (63.5%) than in those with gallstones (47.0%) or in those without gallstone disease (30.3%; P<0.01 for both). Multivariate logistic regression analysis showed that cholecystectomy was significantly associated with increased risk of metabolic syndrome (OR = 1.872; 95% CI: 1.193-2.937). However, the association of gallstones with metabolic syndrome was not statistically significant (OR = 1.267; 95% CI: 0.901-1.782). Altogether, our results suggest that cholecystectomy significantly increases the risk of metabolic syndrome.


Nonpharmacologic Pain Interventions: A Review of Evidence-Based Practices for Reducing Chronic Cancer Pain .
Pain is a common issue for patients with cancer and can be challenging to manage effectively. Healthcare professionals need to be knowledgeable about evidence-based nonpharmacologic interventions. . This systematic review critically appraises the strength and quality of the empirical evidence for nonpharmacologic interventions in reducing chronic cancer pain. . Intervention studies were critically appraised and summarized by an Oncology Nursing Society Putting Evidence Into Practice team of RNs, advanced practice nurses, and nurse scientists. A level of evidence and a practice recommendation was assigned to each intervention. . Based on evidence, recommended interventions to reduce chronic cancer pain are celiac plexus block for pain related to pancreatic and abdominal cancers and radiation therapy for bone pain. Although psychoeducational interventions are considered likely to be effective, the effective components of these interventions and their dose and duration need to be determined through additional research.


On the intrinsic dynamic nature of the rigid UiO-66 metal-organic framework.
UiO-66 is a showcase example of an extremely stable metal-organic framework, which maintains its structural integrity during activation processes such as linker exchange and dehydration. The framework can even accommodate a substantial number of defects without compromising its stability. These observations point to an intrinsic dynamic flexibility of the framework, related to changes in the coordination number of the zirconium atoms. Herein we follow the dynamics of the framework in situ, by means of enhanced sampling molecular dynamics simulations such as umbrella sampling, during an activation process, where the coordination number of the bridging hydroxyl groups capped in the inorganic Zr6(μ3-O)4(μ3-OH)4 brick is reduced from three to one. Such a reduction in the coordination number occurs during the dehydration process and in other processes where defects are formed. We observe a remarkable fast response of the system upon structural changes of the hydroxyl group. Internal deformation modes are detected, which point to linker decoordination and recoordination. Detached linkers may be stabilized by hydrogen bonds with hydroxyl groups of the inorganic brick, which gives evidence for an intrinsic dynamic acidity even in the absence of protic guest molecules. Our observations yield a major step forward in the understanding on the molecular level of activation processes realized experimentally but that is hard to track on a purely experimental basis.


Participation in health planning in a decentralised health system: Experiences from facility governing committees in the Kongwa district of Tanzania.
Tanzania introduced the decentralisation of its health systems in the 1990s in order to provide opportunities for community participation in health planning. Health facility governing committees (HFGCs) were then established to provide room for communities to participate in the management of health service delivery. The objective of this study was to explore the challenges and benefits for the participation of HFGCs in health planning in a decentralised health system. Data were collected using semi-structured interviews and focus group discussions (FGDs). A total of 13 key informants were interviewed from the council and lower-level health facilities. Five FGDs were conducted from five health facilities in one district. Data generated were analysed for themes and patterns. The results of the study suggest that HFGCs are instrumental organs in health planning at the community level and there are several benefits resulting from their participation including an opportunity to address community needs and mobilisation of resources. However, there are some challenges associated with the participation of HFGCs in health planning including a low level of education among committee members and late approval of funds for running health facilities. In conclusion, HFGCs potentially play a significant role in health planning. However, their participation is ineffective due to their limited capacities and disabling environment.


BA321, a novel carborane analog that binds to androgen and estrogen receptors, acts as a new selective androgen receptor modulator of bone in male mice.
Carboranes are a class of carbon-containing polyhedral boron cluster compounds with globular geometry and hydrophobic surface that interact with hormone receptors such as estrogen receptor (ER) and androgen receptor (AR). We have synthesized BA321, a novel carborane compound, which binds to AR. We found here that it also binds to ERs, ERα and ERβ. In orchidectomized (ORX) mice, femoral bone mass was markedly reduced due to androgen deficiency and BA321 restored bone loss in the male, whilst the decreased weight of seminal vesicle in ORX mice was not recovered by administration of BA321. In female mice, BA321 acts as a pure estrogen agonist, and restored both the loss of bone mass and uterine atrophy due to estrogen deficiency in ovariectomized (OVX) mice. In bone tissues, the trabecular bone loss occurred in both ORX and OVX mice, and BA321 completely restored the trabecular bone loss in both sexes. Cortical bone loss occurred in ORX mice but not in OVX mice, and BA321 clearly restored cortical bone loss due to androgen deficiency in ORX mice. Therefore, BA321 is a novel selective androgen receptor modulator (SARM) that may offer a new therapy option for osteoporosis in the male.


Effect of green tea supplementation on blood pressure among overweight and obese adults: a systematic review and meta-analysis.
Emerging randomized controlled trials (RCTs) investigating the effect of green tea or green tea extract (GTE) supplementation on blood pressure (BP) among overweight and obese adults reported inconsistent findings. To conduct a systematic review and meta-analysis to clarify the efficacy of green tea or GTE on BP among overweight and obese adults. Electronic databases, conference proceedings and gray literature were searched systematically to include parallel and cross-over RCTs examining the efficacy of green tea or GTE on BP compared with placebo. Data were meta-analyzed using a random-effects model, to compare the mean difference of the change in BP from baseline in the intervention and the placebo groups. Fourteen RCTs with 971 participants (47% women) were pooled for analysis. Green tea or GTE produced a significant effect on both SBP (mean difference -1.42 mmHg, 95% confidence interval -2.47 to -0.36, P = 0.008; I = 52%, P = 0.01 for heterogeneity) and DBP (mean difference -1.25 mmHg, 95% confidence interval -2.32 to -0.19, P = 0.02; I = 74%, P < 0.001 for heterogeneity), compared with placebo. The quality of evidence across studies was low. Similar results were found in subgroup and sensitivity analyses. Among overweight and obese adults, green tea or GTE supplementation is found to cause a small but significant reduction in BP. More high-quality RCTs with large sample sizes are needed to further confirm the efficacy on BP and make strong recommendations for green tea or GTE supplementation among the overweight and obese adults.


Olfactory preference conditioning changes the reward value of reinforced and non-reinforced odors.
Olfaction is determinant for the organization of rodent behavior. In a feeding context, rodents must quickly discriminate whether a nutrient can be ingested or whether it represents a potential danger to them. To understand the learning processes that support food choice, aversive olfactory learning and flavor appetitive learning have been extensively studied. In contrast, little is currently known about olfactory appetitive learning and its mechanisms. We designed a new paradigm to study conditioned olfactory preference in rats. After 8 days of exposure to a pair of odors (one paired with sucrose and the other with water), rats developed a strong and stable preference for the odor associated with the sucrose solution. A series of experiments were conducted to further analyze changes in reward value induced by this paradigm for both stimuli. As expected, the reward value of the reinforced odor changed positively. Interestingly, the reward value of the alternative odor decreased. This devaluation had an impact on further odor comparisons that the animal had to make. This result suggests that appetitive conditioning involving a comparison between two odors not only leads to a change in the reward value of the reinforced odor, but also induces a stable devaluation of the non-reinforced stimulus.


Subclass-based multi-task learning for Alzheimer's disease diagnosis.
In this work, we propose a novel subclass-based multi-task learning method for feature selection in computer-aided Alzheimer's Disease (AD) or Mild Cognitive Impairment (MCI) diagnosis. Unlike the previous methods that often assumed a unimodal data distribution, we take into account the underlying multipeak distribution of classes. The rationale for our approach is that it is highly likely for neuroimaging data to have multiple peaks or modes in distribution, e.g., mixture of Gaussians, due to the inter-subject variability. In this regard, we use a clustering method to discover the multipeak distributional characteristics and define subclasses based on the clustering results, in which each cluster covers a peak in the underlying multipeak distribution. Specifically, after performing clustering for each class, we encode the respective subclasses, i.e., clusters, with their unique codes. In encoding, we impose the subclasses of the same original class close to each other and those of different original classes distinct from each other. By setting the codes as new label vectors of our training samples, we formulate a multi-task learning problem in a ℓ2,1-penalized regression framework, through which we finally select features for classification. In our experimental results on the ADNI dataset, we validated the effectiveness of the proposed method by improving the classification accuracies by 1% (AD vs. Normal Control: NC), 3.25% (MCI vs. NC), 5.34% (AD vs. MCI), and 7.4% (MCI Converter: MCI-C vs. MCI Non-Converter: MCI-NC) compared to the competing single-task learning method. It is remarkable for the performance improvement in MCI-C vs. MCI-NC classification, which is the most important for early diagnosis and treatment. It is also noteworthy that with the strategy of modality-adaptive weights by means of a multi-kernel support vector machine, we maximally achieved the classification accuracies of 96.18% (AD vs. NC), 81.45% (MCI vs. NC), 73.21% (AD vs. MCI), and 74.04% (MCI-C vs. MCI-NC), respectively.


The eps8 family of proteins links growth factor stimulation to actin reorganization generating functional redundancy in the Ras/Rac pathway.
Sos-1, a guanine nucleotide exchange factor (GEF), eps8 and Abi1, two signaling proteins, and the lipid kinase phosphoinositide 3-kinase (PI3-K), assemble in a multimolecular complex required for Rac activation leading to actin cytoskeletal remodeling. Consistently, eps8 -/- fibroblasts fail to form membrane ruffles in response to growth factor stimulation. Surprisingly, eps8 null mice are healthy, fertile, and display no overt phenotype, suggesting the existence of functional redundancy within this pathway. Here, we describe the identification and characterization of a family of eps8-related proteins, comprising three novel gene products, named eps8L1, eps8L2, and eps8L3. Eps8Ls display collinear topology and 27-42% identity to eps8. Similarly to eps8, eps8Ls interact with Abi1 and Sos-1; however, only eps8L1 and eps8L2 activate the Rac-GEF activity of Sos-1, and bind to actin in vivo. Consistently, eps8L1 and eps8L2, but not eps8L3, localize to PDGF-induced, F-actin-rich ruffles and restore receptor tyrosine kinase (RTK)-mediated actin remodeling when expressed in eps8 -/- fibroblasts. Thus, the eps8Ls define a novel family of proteins responsible for functional redundancy in the RTK-activated signaling pathway leading to actin remodeling. Finally, the patterns of expression of eps8 and eps8L2 in mice are remarkably overlapping, thus providing a likely explanation for the lack of overt phenotype in eps8 null mice.


Sequence upstream of the wheat (Triticum aestivum L.) ALMT1 gene and its relationship to aluminum resistance.
Aluminum (Al) resistance in wheat relies on the Al-activated malate efflux from root apices, which appears to be controlled by an Al-activated anion transporter encoded by the ALMT1 gene on chromosome 4DL. Genomic regions upstream and downstream of ALMT1 in 69 wheat lines were characterized to identify patterns that might influence ALMT1 expression. The first 1,000 bp downstream of ALMT1 was conserved among the lines examined apart from the presence of a transposon-like sequence which did not correlate with Al resistance. In contrast, the first 1,000 bp upstream of the ALMT1 coding region was more variable and six different patterns could be discerned (types I-VI). Type I had the simplest structure, while the others had blocks of sequence that were duplicated or triplicated in different arrangements. A pattern emerged among the lines of non-Japanese origin such that the number of repeats in this upstream region was positively correlated with the levels of ALMT1 expression and Al resistance. In contrast, many of the Japanese lines exhibited a large variation in ALMT1 expression and Al resistance despite possessing the same type of upstream region. Although ALMT1 expression was also poorly correlated with Al-activated malate efflux in the Japanese lines, a strong correlation between malate efflux and Al resistance suggested that malate efflux was still the primary mechanism for Al resistance, and that additional genes are involved in the post-transcriptional regulation of ALMT1 function.


Margarine intake and subsequent coronary heart disease in men.
Margarine is a major source of trans fatty acids, the intake of which has risen since the early 20th century. Some data indicate that consumption of trans fatty acids increases the risk of coronary heart disease (CHD). In 1966-1969, 832 men from the Framingham Study, age 45-64 years and free of CHD, were administered a single 24-hour dietary recall, from which we estimated total daily margarine intake. We calculated CHD cumulative incidence rates and, using proportional hazards regression, CHD incidence rate ratios over 21 years of follow-up. Mean energy intake was 2,619 kcal; mean margarine intake was 1.8 (range 0-12) tsp per day. There were 267 incident cases of CHD. Age-adjusted CHD cumulative incidence rose over categories of margarine intake, but the increased risk was apparent only in the second half of the follow-up period. Adjusted for age and energy intake, the risk ratio for CHD for each increment of 1 teaspoon per day of margarine was 0.98 [95% confidence interval (CI) = 0.91-1.05] for the first 10 years of follow-up and 1.10 (95% CI = 1.04-1.17) for follow-up years 11-21. Adjustment for total fat intake and for cigarette smoking, glucose intolerance, left ventricular hypertrophy, body mass index, blood pressure, physical activity, and alcohol intake did not materially change the results. Butter intake did not predict CHD incidence. These data offer modest support to the hypothesis that margarine intake increases the risk of coronary heart disease.


Structure of recombinant human renin, a target for cardiovascular-active drugs, at 2.5 A resolution.
The x-ray crystal structure of recombinant human renin has been determined. Molecular dynamics techniques that included crystallographic data as a restraint were used to improve an initial model based on porcine pepsinogen. The present agreement factor for data from 8.0 to 2.5 angstroms (A) is 0.236. Some of the surface loops are poorly determined, and these disordered regions border a 30 A wide solvent channel. Comparison of renin with other aspartyl proteinases shows that, although the structural cores and active sites are highly conserved, surface residues, some of which are critical for specificity, vary greatly (up to 10A). Knowledge of the actual structure, as opposed to the use of models based on related enzymes, should facilitate the design of renin inhibitors.


Historical patterns in mercury exposure for North American songbirds.
Methylmercury (MeHg) is a global environmental contaminant that poses significant risks to the health of humans, wildlife, and ecosystems. Assessing MeHg exposure in biota across the landscape and over time is vital for monitoring MeHg pollution and gauging the effectiveness of regulations intended to reduce new mercury (Hg) releases. We used MeHg concentrations measured in museum specimen feathers (collected between 1869 and 2014) and total Hg concentrations (as a proxy for MeHg) of feathers sampled from wild birds (collected between 2008 and 2017) to investigate temporal patterns in exposure over approximately 150 years for North American songbirds. For individual species, we found greater concentrations for samples collected post-2000 compared to those collected during historic times (pre-1900) for six of seven songbird species. Mean feather concentrations measured in samples collected post-2000 ranged between 1.9 and 17 times (mean 6.6) greater than historic specimens. The proportion of individual songbirds with feather concentrations that exceeded modeled toxicity benchmarks increased in samples collected after 1940. Only 2% of individual songbirds collected prior to 1940 had feather concentrations greater than 2.4 μg/g (a toxicity benchmark related to a 10% decrease in nest success) compared to 35% of individuals collected post-1940. Many species included in this study have a vulnerable or near-threatened conservation status, suggesting recovery actions are needed to address mercury pollution.


A comparison of the Twin Block and Herbst mandibular advancement splints in the treatment of patients with obstructive sleep apnoea: a prospective study.
This prospective, randomized, crossover study of 16 patients with obstructive sleep apnoea (OSA) [12 males, four females; median body mass index (BMI) 29.2 kg/m(2) (range 23.8-51.1); median age 44.8 years (range 24.0-68.4)] analysed the efficacy of the Twin Block (TB) in relation to the Herbst appliance as a mandibular advancement splint (MAS). Each subject was fitted with a TB and Herbst MAS in a random order with a washout period of 2 weeks between appliances. Once each patient was subjectively happy with the performance of each appliance, questionnaires and a visual analogue scale (VAS) were used to determine differences in snoring, daytime sleepiness, quality of life, side-effects of the appliances and patient preference. All patients underwent overnight domiciliary sleep recordings prior to and after fitting each appliance in order to objectively assess sleep quality in terms of the apnoea-hypopnoea index (AHI), snoring frequency and arterial oxygen saturation. The results suggested that there was no difference in the treatment performance of the TB and Herbst MAS for AHI (P = 0.71), snoring frequency (P = 0.49), arterial blood oxygen saturation (P = 0.97), quality of life and side-effects. The Herbst MAS proved to be the more effective appliance for reducing daytime sleepiness (P = 0.04) and was the more popular appliance among the patients. Side-effects with both appliances were minor and improved in the longer term. The TB MAS represents a viable alternative to the Herbst MAS in the treatment of patients with OSA.


Ligament and tendon injury to the elbow: clinical, surgical, and imaging features.
Significant advances in the understanding of elbow anatomy, biomechanics, imaging, and surgical technique have been made over the last decade. Tendon injuries are often seen in athletes and physical laborers from repetitive eccentric overload. Ligament injuries are commonly seen in throwing athletes or after elbow dislocation. Magnetic resonance imaging has proven valuable for diagnosing and monitoring most of these soft tissue injuries, and effective surgical techniques have evolved to address them. This article describes typical clinical findings associated with ligament and tendon injuries in the elbow as well as common surgical therapies. The use of magnetic resonance imaging is highlighted throughout because this modality has revolutionized noninvasive evaluation of the elbow.


Correlates of suicide among veterans treated in primary care: case-control study of a nationally representative sample.
Veterans receiving Veterans Affairs (VA) healthcare have increased suicide risk compared to the general population. Many patients see primary care clinicians prior to suicide. Yet little is known about the correlates of suicide among patients who receive primary care treatment prior to death. Our aim was to describe characteristics of veterans who received VA primary care in the 6 months prior to suicide; and to compare these to characteristics of control patients who also received VA primary care. This was a retrospective case-control study. The investigators partnered with VA operations leaders to obtain death certificate data from 11 states for veterans who died by suicide in 2009. Cases were matched 1:2 to controls based on age, sex, and clinician. Demographic, diagnosis, and utilization data were obtained from VA's Corporate Data Warehouse. Additional clinical and psychosocial context data were collected using manual medical record review. Multivariate conditional logistic regression was used to examine associations between potential predictor variables and suicide. Two hundred and sixty-nine veteran cases were matched to 538 controls. Average subject age was 63 years; 97 % were male. Rates of mental health conditions, functional decline, sleep disturbance, suicidal ideation, and psychosocial stressors were all significantly greater in cases compared to controls. In the final model describing men in the sample, non-white race (OR = 0.51; 95 % CI = 0.27-0.98) and VA service-connected disability (OR = 0.54; 95 % CI = 0.36-0.80) were associated with decreased odds of suicide, while anxiety disorder (OR = 3.52; 95 % CI = 1.79-6.92), functional decline (OR = 2.52; 95 % CI = 1.55-4.10), depression (OR = 1.82; 95 % CI = 1.07-3.10), and endorsement of suicidal ideation (OR = 2.27; 95 % CI = 1.07-4.83) were associated with greater odds of suicide. Assessment for anxiety disorders and functional decline in addition to suicidal ideation and depression may be especially important for determining suicide risk in this population. Continued development of interventions that support identifying and addressing these conditions in primary care is indicated.


Risks of paralytic disease due to wild or vaccine-derived poliovirus after eradication.
After the global eradication of wild polioviruses, the risk of paralytic poliomyelitis from polioviruses will still exist and require active management. Possible reintroductions of poliovirus that can spread rapidly in unprotected populations present challenges to policymakers. For example, at least one outbreak will likely occur due to circulation of a neurovirulent vaccine-derived poliovirus after discontinuation of oral poliovirus vaccine and also could possibly result from the escape of poliovirus from a laboratory or vaccine production facility or from an intentional act. In addition, continued vaccination with oral poliovirus vaccines would result in the continued occurrence of vaccine-associated paralytic poliomyelitis. The likelihood and impacts of reintroductions in the form of poliomyelitis outbreaks depend on the policy decisions and on the size and characteristics of the vulnerable population, which change over time. A plan for managing these risks must begin with an attempt to characterize and quantify them as a function of time. This article attempts to comprehensively characterize the risks, synthesize the existing data available for modeling them, and present quantitative risk estimates that can provide a starting point for informing policy decisions.


The RIO trial: rationale, design, and the role of community involvement in a randomised placebo-controlled trial of antiretroviral therapy plus dual long-acting HIV-specific broadly neutralising antibodies (bNAbs) in participants diagnosed with recent HIV infection-study protocol for a two-stage randomised phase II trial.
Antiretroviral therapy (ART) has led to dramatic improvements in survival for people living with HIV, but is unable to cure infection, or induce viral control off therapy. Designing intervention trials with novel agents with the potential to confer a period of HIV remission without ART remains a key scientific and community goal. We detail the rationale, design, and outcomes of a randomised, placebo-controlled trial of two HIV-specific long-acting broadly neutralising antibodies (bNAbs): 3BNC117-LS and 10-1074-LS, which target CD4 binding site and V3 loop respectively, on post-treatment viral control. RIO is a randomised, placebo-controlled, double-blinded prospective phase II study. Eligible individuals will have started ART within 3 months of primary HIV infection and have viral sequences that appear to be sensitive to both bNAbs. It will randomise 72 eligible participants 1:1 to the following arms via a two-stage design. In Stage 1, arm A participants are given dual long-acting (LS-variants) bNAbs infusions, followed by intensively monitored Analytical Treatment Interruption (ATI) (n = 36); in arm B, participants receive placebo infusions followed by ATI. The primary endpoint will be time to viral rebound within 36 weeks after ATI. Upon viral rebound, the participant and researcher are unblinded. Participants in arm A recommence ART and complete the study. Participants in arm B are invited to restart ART and enroll into Stage 2 where they will receive open-label LS bNAbs, followed by a second ATI 24 weeks after. Secondary and exploratory endpoints include adverse events, time to undetectable viraemia after restarting ART, immunological markers, HIV proviral DNA, serum bNAb concentrations in blood, bNAb resistance at viral rebound, and quality of life measures. The two-stage design was determined in collaboration with community involvement. This design allows all participants the option to receive bNAbs. It also tests the hypothesis that bNAbs may drive sustained HIV control beyond the duration of detectable bNAb concentrations. Community representatives were involved at all stages. This included the two-stage design, discussion on the criteria to restart ART, frequency of monitoring visits off ART, and reducing the risk of onward transmission to HIV-negative partners. It also included responding to the challenges of COVID-19. The protocol is registered on Clinical. gov and EudraCT and has approval from UK Ethics and MHRA.


Oxidative Addition, Transmetalation, and Reductive Elimination at a 2,2'-Bipyridyl-Ligated Gold Center.
Three-coordinate bipyridyl complexes of gold, [(κ2-bipy)Au(η2-C2H4)][NTf2], are readily accessed by direct reaction of 2,2'-bipyridine (bipy), or its derivatives, with the homoleptic gold ethylene complex [Au(C2H4)3][NTf2]. The cheap and readily available bipyridyl ligands facilitate oxidative addition of aryl iodides to the Au(I) center to give [(κ2-bipy)Au(Ar)I][NTf2], which undergo first aryl-zinc transmetalation and second C-C reductive elimination to produce biaryl products. The products of each distinct step have been characterized. Computational techniques are used to probe the mechanism of the oxidative addition step, offering insight into both the origin of the reversibility of this process and the observation that electron-rich aryl iodides add faster than electron-poor substrates. Thus, for the first time, all steps that are characteristic of a conventional intermolecular Pd(0)-catalyzed biaryl synthesis are demonstrated from a common monometallic Au complex and in the absence of directing groups.


Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery.
The acronym SePhaChARNS, for "selective pharmacological chaperoning of acetylcholine receptor number and stoichiometry," is introduced. We hypothesize that SePhaChARNS underlies classical observations that chronic exposure to nicotine causes "upregulation" of nicotinic receptors (nAChRs). If the hypothesis is proven, (1) SePhaChARNS is the molecular mechanism of the first step in neuroadaptation to chronic nicotine; and (2) nicotine addiction is partially a disease of excessive chaperoning. The chaperone is a pharmacological one, nicotine; and the chaperoned molecules are alpha4beta2* nAChRs. SePhaChARNS may also underlie two inadvertent therapeutic effects of tobacco use: (1) the inverse correlation between tobacco use and Parkinson's disease; and (2) the suppression of seizures by nicotine in autosomal dominant nocturnal frontal lobe epilepsy. SePhaChARNS arises from the thermodynamics of pharmacological chaperoning: ligand binding, especially at subunit interfaces, stabilizes AChRs during assembly and maturation, and this stabilization is most pronounced for the highest-affinity subunit compositions, stoichiometries, and functional states of receptors. Several chemical and pharmacokinetic characteristics render exogenous nicotine a more potent pharmacological chaperone than endogenous acetylcholine. SePhaChARNS is modified by desensitized states of nAChRs, by acid trapping of nicotine in organelles, and by other aspects of proteostasis. SePhaChARNS is selective at the cellular, and possibly subcellular, levels because of variations in the detailed nAChR subunit composition, as well as in expression of auxiliary proteins such as lynx. One important implication of the SePhaChARNS hypothesis is that therapeutically relevant nicotinic receptor drugs could be discovered by studying events in intracellular compartments rather than exclusively at the surface membrane.


Increased GADD gene expression in human colon epithelial cells exposed to deoxycholate.
The colonic epithelium is often exposed to high concentrations of secondary bile acids, which stresses the epithelial cells, leading potentially to activation of stress-response genes. To examine this possibility in vitro, the purpose of this study was to determine if expression of certain growth arrest and DNA damage-inducible genes (GADD) is upregulated in human colonic epithelial cells exposed to deoxycholate (DOC). DNA macroarray screening of a small cluster of stress/apoptosis-related genes in DOC-treated HCT-116 colonocytes revealed clearly higher expression of only GADD45, which was confirmed by gene-specific relative RT-PCR analysis. Subsequently, it was found that DOC also increased GADD34 mRNA expression. However, mRNA expression of GADD153 was increased most markedly in DOC-treated HCT-116 colonocytes, which express wild-type p53. However, the upregulation of GADD34, GADD45, and GADD153 mRNA expression apparently did not require p53, based on the finding that DOC increased expression of all three GADD genes in HCT-15 colonocytes, which express mutant p53. In further studying GADD153 in particular, the effect of DOC on GADD153 mRNA was prevented by actinomycin-D (Act-D), but not by antioxidants or MAPK inhibitors. DOC also caused GADD153 protein to be expressed in close parallel with increased GADD153 mRNA expression. Induction of GADD153 protein by DOC was prevented by either anisomycin or cycloheximide. These findings suggest that DOC-induced upregulation of GADD153 mRNA expression occurred at the level of transcription without involving reactive oxygen species and MAPK signaling, and that the expression of GADD153 protein was due also to translation of pre-existing, and not just newly synthesized, mRNA.


Usefulness of cystatin C and prognosis following admission for acute heart failure.
Cystatin C is a novel marker of renal function that has been found to predict adverse cardiovascular outcomes in ambulatory patients. The aim of this study was to investigate whether this biomarker predicts the length of hospitalization and adverse outcomes in patients hospitalized for heart failure. Two hundred forty consecutive patients aged > or =25 admitted to Johns Hopkins Hospital with exacerbations of heart failure were prospectively enrolled. Cystatin C levels were measured on admission. Patients were followed for 1 year. The primary outcome measure was the length of hospitalization. Secondary outcomes included all-cause mortality and readmission for heart failure. Cystatin C showed no significant association with the length of hospitalization. Patients in the highest quartile (quartile 4) of cystatin C level were at increased risk for death (hazard ratio 2.07 for quartile 4 vs quartiles 1 to 3, p = 0.01) and death or rehospitalization (hazard ratio 1.61 for quartile 4 vs quartiles 1 to 3, p = 0.01). The association between cystatin C and the combined end point of death or rehospitalization during 1-year follow-up remained significant after adjusting for age, race, gender, co-morbidities, and creatinine. Cystatin C was more predictive of these end points than creatinine, and the combination of cystatin C and creatinine was more predictive than either variable alone. In conclusion, cystatin C may be useful in addition to creatinine for predicting outcomes after admission for acute heart failure exacerbations.


New perspectives on patient expectations of treatment outcomes: results from qualitative interviews with patients seeking complementary and alternative medicine treatments for chronic low back pain.
Positive patient expectations are often believed to be associated with greater benefits from complementary and alternative medicine (CAM) treatments. However, clinical studies of CAM treatments for chronic pain have not consistently supported this assumption, possibly because of differences in definitions and measures of expectations. The goal of this qualitative paper is to provide new perspectives on the outcome expectations of patients prior to receiving CAM therapies for chronic low back pain. We conducted semi-structured interviews with 64 individuals receiving massage, chiropractic, acupuncture or yoga for chronic low back pain. Interviews were recorded and transcribed. Transcripts were analyzed by a team of experienced qualitative researchers using an immersion/crystallization approach to coding and analysis. Overall, participants' expectations of treatment outcomes tended to cluster in four key domains: pain relief, improved function (including an increase in ability to engage in meaningful activities), improved physical fitness, and improved overall well-being (including mental well-being). Typically, patients had modest expectations for outcomes from treatment. Furthermore, outcome expectations were complex on several levels. First, the concept of expectations overlapped with several related concepts; in particular, hopes. Participants sometimes used expectations and hopes interchangeably and at other times made clear distinctions between these two terms depending on context. A related finding was that participants were cautious about stating that they expected positive outcomes. Finally, participants articulated strong interrelationships among the four key domains and often discussed how changes in one domain might affect other domains. Overall, these findings contribute to a growing body of literature exploring the role of expectations in patient outcomes. This paper provides important guidance that may help refine the way treatment expectations are studied in the future. In particular, participants' statements indicate that standardized measures of patient expectations should include items that capture hesitancy to articulate overly optimistic outcomes as well as interrelationships among different outcomes.


Engineered extracellular vesicles for delivering functional Cas9/gRNA to eliminate hepatitis B virus cccDNA and integration.
The persistence of HBV covalently closed circular DNA (cccDNA) and HBV integration into the host genome in infected hepatocytes pose significant challenges to the cure of chronic HBV infection. Although CRISPR/Cas9-mediated genome editing shows promise for targeted clearance of viral genomes, a safe and efficient delivery method is currently lacking. Here, we developed a novel approach by combining light-induced heterodimerization and protein acylation to enhance the loading efficiency of Cas9 protein into extracellular vesicles (EVs). Moreover, vesicular stomatitis virus-glycoprotein (VSV-G) was incorporated onto the EVs membrane, significantly facilitating the endosomal escape of Cas9 protein and increasing its gene editing activity in recipient cells. Our results demonstrated that engineered EVs containing Cas9/gRNA and VSV-G can effectively reduce viral antigens and cccDNA levels in the HBV-replicating and infected cell models. Notably, we also confirmed the antiviral activity and high safety of the engineered EVs in the HBV-replicating mouse model generated by hydrodynamic injection and the HBV transgenic mouse model. In conclusion, engineered EVs could successfully mediate functional CRISPR/Cas9 delivery both in vitro and in vivo, leading to the clearance of episomal cccDNA and integrated viral DNA fragments, and providing a novel therapeutic approach for curing chronic HBV infection.


A four-day Western-style dietary intervention causes reductions in hippocampal-dependent learning and memory and interoceptive sensitivity.
In animals, a Western style diet-high in saturated fat and added sugar-causes impairments in hippocampal-dependent learning and memory (HDLM) and perception of internal bodily state (interoception). In humans, while there is correlational support for a link between Western-style diet, HDLM, and interoception, there is as yet no causal data. Here, healthy individuals were randomly assigned to consume either a breakfast high in saturated fat and added sugar (Experimental condition) or a healthier breakfast (Control condition), over four consecutive days. Tests of HDLM, interoception and biological measures were administered before and after breakfast on the days one and four, and participants completed food diaries before and during the study. At the end of the study, the Experimental condition showed significant reductions in HDLM and reduced interoceptive sensitivity to hunger and fullness, relative to the Control condition. The Experimental condition also showed a markedly different blood glucose and triglyceride responses to their breakfast, relative to Controls, with larger changes in blood glucose across breakfast being associated with greater reductions in HDLM. The Experimental condition compensated for their energy-dense breakfast by reducing carbohydrate intake, while saturated fat intake remained consistently higher than Controls. This is the first experimental study in humans to demonstrate that a Western-style diet impacts HDLM following a relatively short exposure-just as in animals. The link between diet-induced HDLM changes and blood glucose suggests one pathway by which diet impacts HDLM in humans.


Anthropometric and training variables related to half-marathon running performance in recreational female runners.
The relationship between skin-fold thickness and running has been investigated in distances ranging from 100 m to the marathon distance (42.195 km), with the exclusion of the half-marathon distance (21.0975 km). We investigated the association between anthropometric variables, prerace experience, and training variables with race time in 42 recreational, nonprofessional, female half-marathon runners using bi- and multivariate analysis. Body weight (r, 0.60); body mass index (r, 0.48); body fat percentage (r, 0.56); pectoral (r, 0.61), mid-axilla (r, 0.69), triceps (r, 0.49), subscapular (r, 0.61), abdominal (r, 0.59), suprailiac (r, 0.55), and medial calf (r, 0.53) skin-fold thickness; mean speed of the training sessions (r, -0.68); and personal best time in a half-marathon (r, 0.69) correlated with race time after bivariate analysis. Body weight (P = 0.0054), pectoral skin-fold thickness (P = 0.0068), and mean speed of the training sessions (P = 0.0041) remained significant after multivariate analysis. Mean running speed during training was related to mid-axilla (r, -0.31), subscapular (r, -0.38), abdominal (r, -0.44), and suprailiac (r, -0.41) skin-fold thickness, the sum of 8 skin-fold thicknesses (r, -0.36); and percent body fat (r, -0.31). It was determined that variables of both anthropometry and training were related to half-marathon race time, and that skin-fold thicknesses were associated with running speed during training. For practical applications, high running speed during training (as opposed to extensive training) may both reduce upper-body skin-fold thicknesses and improve race performance in recreational female half-marathon runners.


Statistical analysis for identifying mediating variables in public health dentistry interventions.
This article provides an overview of statistical mediation analysis methods in the evaluation of public health dentistry interventions. First, reasons for conducting mediation analysis are outlined, followed by a discussion of the link between the mediation model and theoretical bases of interventions. Second, the basic statistical procedures in mediation analysis are presented. An example application to data from a hypothetical intervention is provided in Appendix A. Third, interpretation of the results from statistical mediation analysis is described along with additional information pertinent to identifying true mediation relations. Guidelines for describing mediation analyses in research articles related to public health dentistry intervention studies are outlined.


Statistical principles for omics-based clinical trials.
High-throughput technologies enable the measurement of a large number of molecular characteristics from a small tissue specimen. High-dimensional molecular information (referred to as omics data) offers the possibility of predicting the future outcome of a patient (prognosis) and predicting the likely response to a specific treatment (prediction). Embedded in the vast amount of data is the hope that there exists some signal that will enable practitioners to deliver therapy personalized to the molecular profile of a tumor, thereby improving health outcomes. The challenges are to determine that the omics assays are valid and reproducible in a clinical setting, to develop a valid and optimal omics-based test that algorithmically determines the optimal treatment regime, to evaluate that test in a powerful and unbiased manner, and finally to demonstrate clinical utility: that the test under study improves clinical outcome as compared to not using the test. We review the statistical considerations involved in each of these stages, specifically dealing with the challenges of high-dimensional, omics data.


Practice Nurses' views of their role in the management of Chronic Fatigue Syndrome/Myalagic Encephalitis: a qualitative study.
NICE guidelines suggest that patients with Chronic Fatigue Syndrome/Myalgic Encephalitis (CFS/ME) should be managed in Primary Care. Practice Nurses are increasingly being involved in the management of long-term conditions, so are likely to also have a growing role in managing CFS/ME. However their attitudes to, and experiences of patients with CFS/ME and its management must be explored to understand what barriers may exist in developing their role for this group of patients. The aim of this study was to explore Practice Nurses' understanding and beliefs about CFS/ME and its management. Semi-structured interviews with 29 Practice Nurses. Interviews were transcribed verbatim and an iterative approach used to develop themes from the dataset. Practice nurses had limited understanding about CFS/ME which had been largely gained through contact with patients, friends, personal experiences and the media rather than formal training. They had difficulty seeing CFS/ME as a long term condition. They did identify a potential role they could have in management of CFS/ME but devalued their own skills in psychological intervention, and suggested counselling would be an appropriate therapeutic option. They recognised a need for further training and on going supervision from both medical and psychological colleagues. Some viewed the condition as contentious and held pejorative views about CFS/ME. Such scepticism and negative attitudes will be a significant barrier to the management of patients with CFS/ME in primary care. The current role of Practice Nurses in the ongoing management of patients with CFS/ME is limited. Practice Nurses have little understanding of the evidence-base for treatment of CFS/ME, particularly psychological therapies, describing management options in terms of advice giving, self-help or counselling. Practice Nurses largely welcomed the potential development of their role in this area, but identified barriers and training needs which must be addressed to enable them to feel confident managing of patients with this condition. Training must begin by addressing negative attitudes to patients with CFS/ME.


One-Pot Synthesis of Copper Sulfide Nanowires/Reduced Graphene Oxide Nanocomposites with Excellent Lithium-Storage Properties as Anode Materials for Lithium-Ion Batteries.
Copper sulfide nanowires/reduced graphene oxide (CuSNWs/rGO) nanocompsites are successfully synthesized via a facile one-pot and template-free solution method in a dimethyl sulfoxide (DMSO)-ethyl glycol (EG) mixed solvent. It is noteworthy that the precursor plays a crucial role in the formation of the nanocomposites structure. SEM, TEM, XRD, IR and Raman spectroscopy are used to investigate the morphological and structural evolution of CuSNWs/rGO nanocomposites. The as-fabricated CuSNWs/rGO nanocompsites show remarkably improved Li-storage performance, excellent cycling stability as well as high-rate capability compared with pristine CuS nanowires. It obtains a reversible capacity of 620 mAh g(-1) at 0.5C (1C = 560 mA g(-1)) after 100 cycles and 320 mAh g(-1) at a high current rate of 4C even after 430 cycles. The excellent lithium storage performance is ascribed to the synergistic effect between CuS nanowires and rGO nanosheets. The as-formed CuSNWs/rGO nanocomposites can effectively accommodate large volume changes, supply a 2D conducting network and trap the polysulfides generated during the conversion reaction of CuS.


Public understanding and use of antibiotics in England: findings from a household survey in 2017.
To describe public understanding and use of antibiotics. Ipsos MORI Capibus survey of randomly-selected households. England, January-April 2017. 2283 adults (≥15 years) including 777 parents of children <5 years old. The main survey was undertaken in January 2017 (n=1691); data from an additional sample of parents were collected in April 2017 (n=592). Analyses were weighted to obtain estimates representative of the population. Responses to questions about antibiotics (awareness and perceptions), recent illness (expectations and experience), delayed and leftover antibiotics, and child illness stratified by demographic and socioeconomic characteristics. Most respondents (83% (1404/1691)) recognised that antibiotics kill bacteria/treat bacterial infections, but a sizeable minority (35% (592/1691)) thought that antibiotics kill viruses/treat viral infections. Overall levels of understanding have not changed substantially since similar surveys in 2003 and 2008/2009. One sixth of respondents who were prescribed antibiotics reported having leftovers (14% (64/498)) and 33% (22/64) kept these for possible future use. 1.3% of all respondents (23/1691) reported taking left-over antibiotics in the past year and 1.6% (26/1691) reported taking antibiotics obtained without a prescription. Higher social grade and educational qualifications were strongly positively associated with antibiotic knowledge; youngest (15-24 years), oldest (65 +years) and black, Asian and minority ethnic adults were less knowledgeable. Among 1319 respondents who had an infection or antibiotics within the past year, 43% (568/1319) said that they had not received any advice or information about antibiotics. Despite many campaigns, public understanding of antibiotics in England continues to combine correct basic knowledge held by most people with less prevalent but persistent and potentially harmful misunderstandings. These could be addressed through active provision of advice and information during primary and secondary care consultations and more effective public health interventions.


The effect of maximal vs submaximal exertion on postprandial lipid levels in individuals with and without coronary heart disease.
Decisions about fat consumption and levels of physical activity are among the everyday choices we make in life and risk of coronary heart disease (CHD) can be affected by those choices. The purpose of this study was to investigate the influence of a standard fat load combined with physical exertion of different intensities on the plasma lipid profile of CHD patients and CHD-free individuals. This study looked at the influence of different intensities of physical exercise on postprandial lipid metabolism in 20 healthy men and 36 men with diagnosis of CHD. Venous blood samples were obtained after overnight fasting, 3 hours after standard fat load (before the physical load), and immediately after maximal or submaximal physical exercise on bicycle ergometer. After fat load total cholesterol (TC) concentration did not change in either group. However, after the addition of maximal exercise, TC, triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein (Apo) B increased significantly (P < .01) in both groups. After fat load and maximal exercise, there was no change in high-density lipoprotein cholesterol (HDL-C) in healthy men, but in men with CHD, HDL-C fell significantly (P < .01); and Apo AI rose in healthy men (P < .01) but dropped significantly (P < .01) in men with CHD. Submaximal physical exercise (60% of max VO2 load for 40 minutes) after fat load decreased TG level in CHD patients (P < .01) and improved other lipid parameters in both groups significantly (↓LDL-C, ↑HDL-C, ↑Apo AI, ↓Apo B, P < .01). We observed a worsening of physical work capacity in men with CHD (significant reduction of duration and total amount of work performed, maximal VO2, oxygen pulse), during maximal stress test performed 3 hours after fat load. There was a doubling of the number of abnormal stress test results (P < .01). Healthy persons showed an increase in respiratory parameters (ventilation, CO2 production, maximal VO2, and oxygen pulse), but no significant change was found in work capacity. Thus, maximal physical exercise produced atherogenic blood lipid changes (increased TC, increased LDL-C, increased TG, increased Apo B, P < .01) in men with CHD and in healthy men; however, individuals with CHD also demonstrated a significant decrease in HDL-C and Apo AI (P < .01). In contrast, the submaximal physical load improved postprandial lipid changes in both healthy men and men with CHD. This study demonstrates that moderate exercise is beneficial in improving postprandial lipid abnormalities in both CHD and CHD-free subjects after fatty meal preload. In addition, maximal exercise demonstrated evidence of increase of lipid abnormalities in both CHD and CHD-free individuals under similar conditions of fatty meal preload.


Effects of choir singing or listening on secretory immunoglobulin A, cortisol, and emotional state.
The present study investigates the effects of choir music on secretory immunoglobulin A (S-IgA), cortisol, and emotional states in members of a mixed amateur choir. Subjects participated in two conditions during two rehearsals 1 week apart, namely singing versus listening to choral music. Saliva samples and subjective measures of affect were taken both before each session and 60 min later. Repeated measure analyses of variance were conducted for positive and negative affect scores, S-IgA, and cortisol. Results indicate several significant effects. In particular, singing leads to increases in positive affect and S-IgA, while negative affect is reduced. Listening to choral music leads to an increase in negative affect, and decreases in levels of cortisol. These results suggest that choir singing positively influences both emotional affect and immune competence. The observation that subjective and physiological responses differed between listening and singing conditions invites further investigation of task factors.