Development of a Coding Instrument to Assess the Quality and Content of Anti-Tobacco Video Games.
Previous research has shown the use of electronic video games as an effective method for increasing content knowledge about the risks of drugs and alcohol use for adolescents. Although best practice suggests that theory, health communication strategies, and game appeal are important characteristics for developing games, no instruments are currently available to examine the quality and content of tobacco prevention and cessation electronic games. This study presents the systematic development of a coding instrument to measure the quality, use of theory, and health communication strategies of tobacco cessation and prevention electronic games. Using previous research and expert review, a content analysis coding instrument measuring 67 characteristics was developed with three overarching categories: type and quality of games, theory and approach, and type and format of messages. Two trained coders applied the instrument to 88 games on four platforms (personal computer, Nintendo DS, iPhone, and Android phone) to field test the instrument. Cohen's kappa for each item ranged from 0.66 to 1.00, with an average kappa value of 0.97. Future research can adapt this coding instrument to games addressing other health issues. In addition, the instrument questions can serve as a useful guide for evidence-based game development.


The impact of rheumatoid foot on disability in Colombian patients with rheumatoid arthritis.
Alterations in the feet of patients with rheumatoid arthritis (RA) are a cause of disability in this population. The purpose of this research was to evaluate the impact that foot impairment has on the patients' global quality of life (QOL) based on validated scales and its relationship to disease activity. This was a cross-sectional study in which 95 patients with RA were enrolled. A complete physical examination, including a full foot assessment, was done. The Spanish versions of the Health Assessment Questionnaire (HAQ) Disability Index and of the Disease Activity Score (DAS 28) were administered. A logistic regression model was used to analyze data and obtain adjusted odds ratios (AORs). Foot deformities were observed in 78 (82%) of the patients; hallux valgus (65%), medial longitudinal arch flattening (42%), claw toe (lesser toes) (39%), dorsiflexion restriction (tibiotalar) (34%), cock-up toe (lesser toes) (25%), and transverse arch flattening (25%) were the most frequent. In the logistic regression analysis (adjusted for age, gender and duration of disease), forefoot movement pain, subtalar movement pain, tibiotalar movement pain and plantarflexion restriction (tibiotalar) were strongly associated with disease activity and disability. The positive squeeze test was significantly associated with disability risk (AOR = 6,3; 95% CI, 1.28-30.96; P = 0,02); hallux valgus, and dorsiflexion restriction (tibiotalar) were associated with disease activity. Foot abnormalities are associated with active joint disease and disability in RA. Foot examinations provide complementary information related to the disability as an indirect measurement of quality of life and activity of disease in daily practice.


Evaluating Effectively Maintained Inequality: School and post-school transitions, socioeconomic background, academic ability and curricular placement.
Effectively Maintained Inequality (EMI) is proposed as an explanation for contemporary socioeconomic inequalities in education. Socioeconomic inequalities are 'maintained' by students from lower socioeconomic backgrounds taking less advantageous curricula influencing their post-school destinations. The purpose of this study is to evaluate EMI by addressing several hypotheses derived from the EMI thesis using Australian longitudinal data. It analyses within-school transitions and the transition from school to post-school destinations (elite university, other university, vocational and no post-school study or training). The study also models curricular placement (subject choice). It finds that the transitions within- and post-school are more powerfully influenced by students' academic ability than by socioeconomic background. Furthermore, subject choice has strong impacts on the transitions. Similarly, Year 12 subject choice is only weakly predicted by socioeconomic background, and more strongly influenced by ability and occupational interests. In turn, occupational interests are largely independent of socioeconomic background. The EMI thesis is not supported.


Exploring fungal mega-diversity: Pseudocercospora from Brazil.
Although the genus Pseudocercospora has a worldwide distribution, it is especially diverse in tropical and subtropical countries. Species of this genus are associated with a wide range of plant species, including several economically relevant hosts. Preliminary studies of cercosporoid fungi from Brazil allocated most taxa to Cercospora, but with the progressive refinement of the taxonomy of cercosporoid fungi, many species were relocated to or described in Pseudocercospora. Initially, species identification relied mostly on morphological features, and thus no cultures were preserved for later phylogenetic comparisons. In this study, a total of 27 Pseudocercospora spp. were collected, cultured, and subjected to a multigene analysis. Four genomic regions (LSU, ITS, tef1 and actA) were amplified and sequenced. A multigene Bayesian analysis was performed on the combined ITS, actA and tef1 sequence alignment. Our results based on DNA phylogeny, integrated with ecology, morphology and cultural characteristics revealed a rich diversity of Pseudocercospora species in Brazil. Twelve taxa were newly described, namely P. aeschynomenicola, P. diplusodonii, P. emmotunicola, P. manihotii, P. perae, P. planaltinensis, P. pothomorphes, P. sennae-multijugae, P. solani-pseudocapsicicola, P. vassobiae, P. wulffiae and P. xylopiae. Additionally, eight epitype specimens were designated, three species newly reported, and several new host records linked to known Pseudocercospora spp.


Single-port thoracoscopic surgery for pneumothorax under two-lung ventilation with carbon dioxide insufflation.
The development of single-port thoracoscopic surgery and two-lung ventilation reduced the invasiveness of minor thoracic surgery. This study aimed to evaluate the feasibility and safety of single-port thoracoscopic bleb resection for primary spontaneous pneumothorax using two-lung ventilation with carbon dioxide insufflation. Between February 2009 and May 2014, 130 patients underwent single-port thoracoscopic bleb resection under two-lung ventilation with carbon dioxide insufflation. Access was gained using a commercial multiple-access single port through a 2.5-cm incision; carbon dioxide gas was insufflated through a port channel. A 5-mm thoracoscope, articulating endoscopic devices, and flexible endoscopic staplers were introduced through a multiple-access single port for bulla resection. The mean time from endotracheal intubation to incision was 29.2±7.8 minutes, the mean operative time was 30.9±8.2 minutes, and the mean total anesthetic time was 75.5±14.4 minutes. There were no anesthesia-related complications or wound problems. The chest drain was removed after a mean of 3.7±1.4 days and patients were discharged without complications 4.8±1.5 days from the operative day. During a mean 7.5±10.1 months of follow-up, there were five recurrences (3.8%) in operated thorax. The anesthetic strategy of single-lumen intubation with carbon dioxide gas insufflation can be a safe and feasible option for single-port thoracoscopic bulla resection as it represents the least invasive surgical option with the potential advantages of reducing operative time and one-lung ventilation-related complications without diminishing surgical outcomes.


Endocannabinoids modulate human epidermal keratinocyte proliferation and survival via the sequential engagement of cannabinoid receptor-1 and transient receptor potential vanilloid-1.
We have recently shown that lipid mediators of the emerging endocannabinoid system (ECS) are key players of growth control of the human pilosebaceous unit. In this study, we asked whether the prototypic endocannabinoid anandamide (N-arachidonoylethanolamine, AEA) has a role in growth and survival of epidermal keratinocytes (KCs). Using human cultured KCs and skin organ-culture models, and by employing combined pharmacological and molecular approaches, we provide early evidence that AEA markedly suppresses KC proliferation and induces cell death, both in vitro and in situ. Moreover, we present that these cellular actions are mediated by a most probably constitutively active signaling mechanism that involves the activation of the metabotropic cannabinoid receptor CB(1) and a sequential engagement of the "ionotropic cannabinoid receptor" transient receptor potential vanilloid-1 (TRPV1). Finally, we demonstrate that the cellular effects of AEA are most probably due to a Ca(2+) influx via the non-selective, highly Ca(2+)-permeable ion channel TRPV1, and the concomitant elevation of intracellular Ca(2+) concentration. The data reported here may encourage one to explore whether the targeted manipulation of the above signaling pathway of the cutaneous ECS could become a useful adjunct treatment strategy for hyperproliferative human dermatoses such as psoriasis or KC-derived skin tumors.


Control of inducible gene expression links cohesin to hematopoietic progenitor self-renewal and differentiation.
Cohesin is important for 3D genome organization. Nevertheless, even the complete removal of cohesin has surprisingly little impact on steady-state gene transcription and enhancer activity. Here we show that cohesin is required for the core transcriptional response of primary macrophages to microbial signals, and for inducible enhancer activity that underpins inflammatory gene expression. Consistent with a role for inflammatory signals in promoting myeloid differentiation of hematopoietic stem and progenitor cells (HPSCs), cohesin mutations in HSPCs led to reduced inflammatory gene expression and increased resistance to differentiation-inducing inflammatory stimuli. These findings uncover an unexpected dependence of inducible gene expression on cohesin, link cohesin with myeloid differentiation, and may help explain the prevalence of cohesin mutations in human acute myeloid leukemia.


Optically controlled dielectric properties of single-walled carbon nanotubes for terahertz wave applications.
Materials with tunable dielectric properties are valuable for a wide range of electronic devices, but are often lossy at terahertz frequencies. Here we experimentally report the tuning of the dielectric properties of single-walled carbon nanotubes under light illumination. The effect is demonstrated by measurements of impedance variations at low frequency as well as complex dielectric constant variations in the wide frequency range of 0.1-1 THz by time domain spectroscopy. We show that the dielectric constant is significantly modified for varying light intensities. The effect is also practically applied to phase shifters based on dielectric rod waveguides, loaded with carbon nanotube layers. The carbon nanotubes are used as tunable impedance surface controlled by light illumination, in the frequency range of 75-500 GHz. These results suggest that the effect of dielectric constant tuning with light, accompanied by low transmission losses of the carbon nanotube layer in such an ultra-wide band, may open up new directions for the design and fabrication of novel Terahertz and optoelectronic devices.


"TORNADO" - Theranostic One-Step RNA Detector; microfluidic disc for the direct detection of microRNA-134 in plasma and cerebrospinal fluid.
Diagnosis of seizure disorders such as epilepsy currently relies on clinical examination and electroencephalogram recordings and is associated with substantial mis-diagnosis. The miRNA, miR-134 (MIR134 in humans), has been found to be elevated in brain tissue after experimental status epilepticus and in human epilepsy cells and their detection in biofluids may serve as unique biomarkers. miRNAs from unprocessed human plasma and human cerebrospinal fluid samples were used in a novel electrochemical detection based on electrocatalytic platinum nanoparticles inside a centrifugal microfluidic device where the sandwich assay is formed using an event triggered release system, suitable for the rapid point-of-care detection of low abundance biomarkers of disease. The device has the advantage of controlling the rotation speed of the centrifugal device to pump nanoliter volumes of fluid at a set time and manipulate the transfer of liquids within the device. The centrifugal platform improves reaction rates and yields by proposing efficient mixing strategies to overcome diffusion-limited processes and improve mass transport rates, resulting in reduced hybridization times with a limit of detection of 1 pM target concentration. Plasma and cerebrospinal fluid samples (unprocessed) from patients with epilepsy or who experienced status epilepticus were tested and the catalytic response obtained was in range of the calibration plot. This study demonstrates a rapid and simple detection for epilepsy biomarkers in biofluid.


Human Evolution: The Real Cause for Birth Palsy.
Birth palsy, otherwise known as obstetric brachial plexus paralysis (OBPP), is a closed stretch injury to the brachial plexus of nerves during the birth process resulting in varying degree of paralysis and contractures of the upper limb. The study aimed to find out the susceptibility of humans and small-bodied primates to birth palsy. A comparative study on parturition in modern humans, hominoids, hominids, small-bodied primates and great apes was done to determine if the changes in female pelvis and neonatal head and shoulder during human evolution is the real cause for OBPP. During evolution, the morphology of the female pelvis and birth canal changed into a narrow and twisted one and also the size of the fetal head increased. Thus, the narrow and twisted pelvis of the mother, and the relatively large head and broad shoulders of the newborn has made the birthing process of modern human and small bodied primates a precarious fine-tuned act with a very narrow margin for error. This has necessitated proper obstetric care to reduce or even at times obviate the incidence of birth injuries like OBPP. Human evolution has made human babies susceptible to birth palsy and thus is the real cause of birth palsy.


Characteristics of smokers reached and recruited to an internet smoking cessation trial: a case of denominators.
The Internet can deliver smoking cessation interventions to large numbers of smokers. Little is known about the feasibility, reach, or efficacy of Internet cessation interventions. Virtually no data exist on who enrolls in cessation programs or on differences between those who complete enrollment and those who do not. This paper reports recruitment and enrollment findings for the first 764 participants in an ongoing randomized controlled trial that tested the efficacy of a widely disseminated Internet smoking cessation service (www.QuitNet.com) alone and in conjunction with telephone counseling. Study participants were recruited through Internet search engines using an active user sampling protocol. During the first 16 weeks of the study, 28,297 individuals were invited. Of those, 11,147 accepted the invitation, 5,557 screened eligible, 3,614 were recruited, 1,489 provided online informed consent, and 764 were confirmed eligible and enrolled. Of those who were at least curious about a cessation trial (n= 11,147), 6.9% enrolled. Of those who were eligible and recruited (n=3,614), 21.1% enrolled. Depending on the denominator selected, results suggest that 7% to 21% of smokers interested in cessation will enroll into a research trial. Internet recruitment provides unique challenges and opportunities for managing sample recruitment, analyzing subsamples to determine generalizability, and understanding the characteristics of individuals who participate in online research.


A comparison of estimates of glomerular filtration in critically ill patients with augmented renal clearance.
Increasingly, derived estimates of glomerular filtration, such as the modification of diet in renal disease (MDRD) equation and Cockcroft-Gault (CG) formula are being employed in the intensive care unit (ICU). To date, these estimates have not been rigorously validated in those with augmented clearances, resulting in potentially inaccurate drug prescription. Post-hoc analysis of prospectively collected data in two tertiary level ICU's in Australia and Portugal. Patients with normal serum creatinine concentrations manifesting augmented renal clearance (ARC) (measured creatinine clearance (CLCR) > 130 ml/min/1.73 m2) were identified by chart review. Comparison between measured values and MDRD and CG estimates were then undertaken. Spearman correlation coefficients (rs) were calculated to determine goodness of fit, and precision and bias were assessed using Bland-Altman plots. Eighty-six patients were included in analysis. The median [IQR] measured CLCR was 162 [145-190] ml/min/1.73 m2, as compared to 135 [116-171], 93 [83-110], 124[102-154], and 108 [87-135] ml/min/1.73 m2 estimated by CG, modified CG, 4-variable MDRD and 6-variable MDRD formulae. All of the equations significantly under-estimated the measured value, with CG displaying the smallest bias (39 ml/min/1.73 m2). Although a moderate correlation was noted between CLCR and CG (rs = 0.26, P = 0.017) and 4-variable MDRD (rs = 0.22, P = 0.047), neither had acceptable precision for clinical application in this setting. CG estimates had the highest sensitivity for correctly identifying patients with ARC (62%). Derived estimates of GFR are inaccurate in the setting of ARC, and should be interpreted with caution by the physician. A measured CLCR should be performed to accurately guide drug dosing.


PP2A-B55β antagonizes cyclin E1 proteolysis and promotes its dysregulation in cancer.
Cyclin E1 regulates the initiation of S-phase in cellular division. However, in many cancers, cyclin E1 is aberrantly overexpressed and this molecular phenotype correlates with increased tumor aggressiveness and poor patient survival. The molecular cause(s) of cyclin E1 abnormalities in cancers is poorly understood. Here, we show that cyclin E1 overexpression in cancer is promoted by dysregulation of the protein phosphatase PP2A-B55β. PP2A-B55β targets the N- and C-terminal phosphodegrons of cyclin E1 for dephosphorylation, thus protecting it from degradation mediated by the SCF(Fbxw7) ubiquitin ligase. Augmented B55β expression stabilizes cyclin E1 and promotes its overexpression in cancer-derived cell lines and breast tumors. Conversely, B55β ablation enforces the degradation of cyclin E1 and inhibits cancer cell proliferation in vitro and tumor formation in vivo. Therefore, PP2A-B55β promotes cyclin E1 overexpression by antagonizing its degradation and its inhibition could represent a therapeutic mechanism for abrogating cyclin E1 function in cancers.


Drosophila RpS12 controls translation, growth, and cell competition through Xrp1.
Whereas complete loss of Rp function is generally lethal, most heterozygous Rp mutants grow more slowly and are subject to competitive loss from mosaics tissues that also contain wild type cells. The rpS12 gene has a special role in the cell competition of other Ribosomal Protein (Rp) mutant cells in Drosophila. Elimination by cell competition is promoted by higher RpS12 levels and prevented by a specific rpS12 mis-sense mutation, identifying RpS12 as a key effector of cell competition due to mutations in other Rp genes. Here we show that RpS12 is also required for other aspects of Rp mutant phenotypes, including hundreds of gene expression changes that occur in 'Minute' Rp heterozygous wing imaginal discs, overall translation rate, and the overall rate of organismal development, all through the bZip protein Xrp1 that is one of the RpS12-regulated genes. Our findings outline the regulatory response to mutations affecting essential Rp genes that controls overall translation, growth, and cell competition, and which may contribute to cancer and other diseases.


Cyclosporin A and steroid therapy in sixty-six cadaver kidney recipients.
From nine to 18 months ago, 66 patients were given 67 randomly matched cadaveric kidneys with cyclosporin A and steroid therapy. Nine of the recipients were undergoing retransplantation. The over-all kidney survival rate to date has been 77.6 per cent, and 78.8 per cent of the recipients are dialysis-free. The patient mortality in this learning phase was 13.3 per cent. Nephrotoxicity, hepatotoxicity and other side-effects of cyclosporin A could usually be dealt with by dosage adjustments, making feasible the chronic use of this agent. One B-cell immunoblastic sarcoma was encountered which was monoclonal. It was not responsible for death. Another patient had a perforation of the intestine from a lympho-proliferative reaction in which the B cells were polyclonal. After jejunal resection a year ago, there were no further complications. This lesion was not classified as a lymphoma. Both lympho-proliferative lesions were associated with a rise in antibody to viral capsid antigen of Epstein-Barr virus. Results of this study have verified the effectiveness and relative safety of cyclosporin A with steroids for immunosuppression in human recipients of cadaveric kidneys.


The binding of beta- and gamma-cyclodextrins to glycogen phosphorylase b: kinetic and crystallographic studies.
A number of regulatory binding sites of glycogen phosphorylase (GP), such as the catalytic, the inhibitor, and the new allosteric sites are currently under investigation as targets for inhibition of hepatic glycogenolysis under high glucose concentrations; in some cases specific inhibitors are under evaluation in human clinical trials for therapeutic intervention in type 2 diabetes. In an attempt to investigate whether the storage site can be exploited as target for modulating hepatic glucose production, alpha-, beta-, and gamma-cyclodextrins were identified as moderate mixed-type competitive inhibitors of GPb (with respect to glycogen) with K(i) values of 47.1, 14.1, and 7.4 mM, respectively. To elucidate the structural basis of inhibition, we determined the structure of GPb complexed with beta- and gamma-cyclodextrins at 1.94 A and 2.3 A resolution, respectively. The structures of the two complexes reveal that the inhibitors can be accommodated in the glycogen storage site of T-state GPb with very little change of the tertiary structure and provide a basis for understanding their potency and subsite specificity. Structural comparisons of the two complexes with GPb in complex with either maltopentaose (G5) or maltoheptaose (G7) show that beta- and gamma-cyclodextrins bind in a mode analogous to the G5 and G7 binding with only some differences imposed by their cyclic conformations. It appears that the binding energy for stabilization of enzyme complexes derives from hydrogen bonding and van der Waals contacts to protein residues. The binding of alpha-cyclodextrin and octakis (2,3,6-tri-O-methyl)-gamma-cyclodextrin was also investigated, but none of them was bound in the crystal; moreover, the latter did not inhibit the phosphorylase reaction.


Relationship between kinematic center and TMJ anatomy and function.
The kinematic center (KC)-defined by coinciding jaw-opening/-closing and protrusion-retrusion trajectories-has been proposed in the literature as a reference point to represent TMJ movements. In this study, we tested whether the KC lies in a peculiar anatomical point and whether its trajectory reflects intra-articular distance. In 11 asymptomatic individuals (seven females, four males, aged 24-37 yrs), 4 openings/closings and 4 protrusions/retrusions were tracked with dynamic stereometry. In a 3D lattice (0.5 mm grid) constructed solidly around each condyle, the KC was the point with maximal cross-correlation between opening-closing and protrusion-retrusion paths. KC trajectories were more cranial on closing than on opening, consistent with intra-articular distances being smaller on closing than on opening. However, KCs were never located on condylar main axes (distance, 4.5 +/- 2.9 mm), nor did they coincide with points best approximating fossa shapes (distance, 12.5 +/- 6.4 mm). The kinematic center's anatomical and functional significance therefore appears to be questionable.


Emotional reactivity in infants with congenital heart defects: findings from a large case-cohort study in Norway.
Advances in medical treatment in recent years have led to dramatically improved survival rates of children with severe congenital heart defects (CHD). However, very little is known about the psychological consequences for these children, particularly during and after the early period of invasive treatment. In this study, we investigated the extent to which the severity of the CHD affects the child's emotional reactivity at 6 months of age. We linked prospective data from the Norwegian Mother and Child Cohort Study, conducted by the Norwegian Institute of Public Health with a nationwide medical CHD registry and identified 212 infants with CHD in a cohort of 61 299 infants. Mothers reported on their child's emotional reactivity at age 6 months by means of a standardized questionnaire. Infants with severe to moderate CHD had 60% higher odds for severe emotional reactivity (cut-off at the 85 percentile) compared with healthy infants, after controlling for important maternal and child confounders. Our study is the first to show elevated emotional reactivity in children with moderate to severe CHD, suggesting a need for special parental attention to soothe their distress. Follow-up studies will show whether this emotional reactivity is transient or an early marker of continuing emotional or behavioural problems.


Treat-to-target (T2T) recommendations for gout.
The treat-to-target (T2T) concept has been applied successfully in several inflammatory rheumatic diseases. Gout is a chronic disease with a high burden of pain and inflammation. Because the pathogenesis of gout is strongly related to serum urate levels, gout may be an ideal disease in which to apply a T2T approach. Our aim was to develop international T2T recommendations for patients with gout. A committee of experts with experience in gout agreed upon potential targets and outcomes, which was the basis for the systematic literature search. Eleven rheumatologists, one cardiologist, one nephrologist, one general practitioner and one patient met in October 2015 to develop T2T recommendations based on the available scientific evidence. Levels of evidence, strength of recommendations and levels of agreement were derived. Although no randomised trial was identified in which a comparison with standard treatment or an evaluation of a T2T approach had been performed in patients with gout, indirect evidence was provided to focus on targets such as normalisation of serum urate levels. The expert group developed four overarching principles and nine T2T recommendations. They considered dissolution of crystals and prevention of flares to be fundamental; patient education, ensuring adherence to medications and monitoring of serum urate levels were also considered to be of major importance. This is the first application of the T2T approach developed for gout. Since no publication reports a trial comparing treatment strategies for gout, highly credible overarching principles and level D expert recommendations were created and agreed upon.


Rivastigmine for Alzheimer's disease.
Alzheimer's disease (AD) is the commonest cause of dementia affecting older people. One of the therapeutic strategies aimed at ameliorating the clinical manifestations of Alzheimer's disease is to enhance cholinergic neurotransmission in relevant parts of the brain by the use of cholinesterase inhibitors to delay the breakdown of acetylcholine released into synaptic clefts. Tacrine, the first of the cholinesterase inhibitors to undergo extensive trials for this purpose, was associated with significant adverse effects including hepatotoxicity. Other cholinesterase inhibitors, including rivastigmine, with superior properties in terms of specificity of action and low risk of adverse effects, have now been introduced. Rivastigmine has received approval for use in 60 countries including all member states of the European Union and the USA. To determine the clinical efficacy and safety of rivastigmine for patients with dementia of Alzheimer's type. The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS were searched on 27 March 2008 using the terms: Rivastigmine OR exelon OR ENA OR "SDZ ENA 713" . The CDCIG Specialized Register contains records from all major health care databases (The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS) as well as from many clinical trials registries and grey literature sources. All unconfounded, double-blind, randomized trials in which treatment with rivastigmine was administered to patients with dementia of the Alzheimer's type for more than two weeks and its effects compared with those of placebo in a parallel group of patients. One reviewer (JSB) applied study selection criteria, assessed the quality of studies and extracted data. Nine trials, involving 4775 participants, were included in the analyses. Use of rivastigmine in high doses was associated with statistically significant benefits on several measures. High-dose rivastigmine (6 to 12 mg daily) was associated with a two-point improvement in cognitive function on the ADAS-Cog score compared with placebo (weighted mean difference -1.99, 95% confidence interval -2.49 to -1.50, on an intention-to-treat basis) and a 2.2 point improvement in activities of daily living assessed on the Progressive Deterioration Scale (weighted mean difference -2.15, 95% confidence interval -3.16 to -1.13, on an intention-to-treat basis) at 26 weeks. At lower doses (4 mg daily or lower) differences were in the same direction but were statistically significant only for cognitive function. There were statistically significantly higher numbers of events of nausea, vomiting, diarrhoea, anorexia, headache, syncope, abdominal pain and dizziness among patients taking high-dose rivastigmine than among those taking placebo. There was some evidence that adverse events might be less common with more frequent, smaller doses of rivastigmine. The 2008 update includes a new study testing two types of rivastigmine transdermal patch, one delivering a higher dose than previously tested (17.4 mg/day) and a smaller patch delivering 9.6 mg/day. The efficacy of the smaller patch was not significantly different compared with the capsules of similar daily dose, but was associated with significantly fewer adverse events of nausea, vomiting, dizziness and asthenia. The efficacy of the larger patch was not significantly different compared with the smaller patch, but the smaller patch was associated with significantly fewer adverse events of nausea, vomiting, weight loss and dizziness. There appears to be advantages associated with the smaller patch compared with both the higher dose patch and the 6-12 mg/day capsules. Rivastigmine appears to be beneficial for people with mild to moderate Alzheimer's disease. In comparisons with placebo, improvements were seen in the rate of decline of cognitive function, activities of daily living, and severity of dementia with daily doses of 6 to 12 mg. Adverse events were consistent with the cholinergic actions of the drug. A transdermal patch has been tested in one trial, and there is evidence that the lower dose smaller patch is associated with fewer side effects than the capsules or the higher dose larger patch and has comparable efficacy to both. This review has not examined economic data.


Synthetic D- and L-enantiomers of 2,2-difluoro-2-deoxy-myo-inositol 1,4,5-trisphosphate interact differently with myo-inositol 1,4,5-trisphosphate binding proteins: identification of a potent small molecule 3-kinase inhibitor.
The ability of two enantiomeric fluoro-analogues of D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] to mobilize intracellular Ca2+ stores in SH-SY5Y neuroblastoma cells has been investigated. (-)-D-2,2-difluoro-2-deoxy-myo-Ins(1,4,5)P3 [D-2,2-F2-Ins(1,4,5)P3] was a full agonist [EC50 0.21 microM] and slightly less potent than D-Ins(1,4,5)P3 [EC50 0.13 microM]. (+)-L-2,2-F2Ins(1,4,5)P3 was a very poor agonist, confirming the stereospecificity of the Ins(1,4,5)P3 receptor. D-2,2-F2-Ins(1,4,5)P3 mobilized Ca2+ with broadly similar kinetics to Ins(1,4,5)P3 and was a substrate for Ins(1,4,5)P3 3-kinase inhibiting Ins(1,4,5)P3 phosphorylation (apparent Ki = 10.2 microM) but was recognised less well than Ins(1,4,5)P3. L-2,2-F2-Ins(1,4,5)P3 was a potent competitive inhibitor of 3-kinase (Ki = 11.9 microM). Whereas D-2,2-F2-Ins(1,4,5)P3 was a good substrate for Ins(1,4,5)P3 5-phosphatase, L-2,2-F2Ins(1,4,5)P3 was a relatively potent inhibitor (Ki = 19.0 microM).


Duplication within the SEPT9 gene associated with a founder effect in North American families with hereditary neuralgic amyotrophy.
Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant disorder associated with recurrent episodes of focal neuropathy primarily affecting the brachial plexus. Point mutations in the SEPT9 gene have been previously identified as the molecular basis of HNA in some pedigrees. However in many families, including those from North America demonstrating a genetic founder haplotype, no sequence mutations have been detected. We report an intragenic 38 Kb SEPT9 duplication that is linked to HNA in 12 North American families that share the common founder haplotype. Analysis of the breakpoints showed that the duplication is identical in all pedigrees, and molecular analysis revealed that the duplication includes the 645 bp exon in which previous HNA mutations were found. The SEPT9 transcript variants that span this duplication contain two in-frame repeats of this exon, and immunoblotting demonstrates larger molecular weight SEPT9 protein isoforms. This exon also encodes for a majority of the SEPT9 N-terminal proline rich region suggesting that this region plays a role in the pathogenesis of HNA.


Effect of Contrast on Visual Spatial Summation in Different Cell Categories in Cat Primary Visual Cortex.
Multiple cell classes have been found in the primary visual cortex, but the relationship between cell types and spatial summation has seldom been studied. Parvalbumin-expressing inhibitory interneurons can be distinguished from pyramidal neurons based on their briefer action potential durations. In this study, we classified V1 cells into fast-spiking units (FSUs) and regular-spiking units (RSUs) and then examined spatial summation at high and low contrast. Our results revealed that the excitatory classical receptive field and the suppressive non-classical receptive field expanded at low contrast for both FSUs and RSUs, but the expansion was more marked for the RSUs than for the FSUs. For most V1 neurons, surround suppression varied as the contrast changed from high to low. However, FSUs exhibited no significant difference in the strength of suppression between high and low contrast, although the overall suppression decreased significantly at low contrast for the RSUs. Our results suggest that the modulation of spatial summation by stimulus contrast differs across populations of neurons in the cat primary visual cortex.


Ethical implications of HIV self-testing.
In April 2015, the first legally approved HIV self-testing kit went on sale in the UK-except Northern Ireland where they remain illegal. These tests allow individuals to test their HIV status and read the result in the privacy of their own home, much like a home pregnancy test. This paper explores the ethical implications of HIV self-testing. We conclude that there are no strong ethical objections to self-testing being made widely available in the UK. Pretest counselling for an HIV test is not an ethical necessity, and self-testing has the potential to increase early diagnosis of HIV infection and thus improve prognosis and reduce ongoing transmission. Self-testing kits might also empower people and promote autonomy by allowing people to dictate the terms on which they test their HIV status. We accept that there are some potential areas of concern. These include the possibility of user error with the tests, and the concern that individuals may not present to health services following a reactive result. False negatives have the potential to cause harm if the 'window period' is not understood, and false positives might produce psychological distress. There is, however, little evidence to suggest that self-testing kits will cause widespread harm, and we argue that the only way to properly evaluate whether they do cause significant harm is to carefully evaluate their use, now that they are available on the market.


Defining functional classes of Barth syndrome mutation in humans.
The X-linked disease Barth syndrome (BTHS) is caused by mutations in TAZ; TAZ is the main determinant of the final acyl chain composition of the mitochondrial-specific phospholipid, cardiolipin. To date, a detailed characterization of endogenous TAZ has only been performed in yeast. Further, why a given BTHS-associated missense mutation impairs TAZ function has only been determined in a yeast model of this human disease. Presently, the detailed characterization of yeast tafazzin harboring individual BTHS mutations at evolutionarily conserved residues has identified seven distinct loss-of-function mechanisms caused by patient-associated missense alleles. However, whether the biochemical consequences associated with individual mutations also occur in the context of human TAZ in a validated mammalian model has not been demonstrated. Here, utilizing newly established monoclonal antibodies capable of detecting endogenous TAZ, we demonstrate that mammalian TAZ, like its yeast counterpart, is localized to the mitochondrion where it adopts an extremely protease-resistant fold, associates non-integrally with intermembrane space-facing membranes and assembles in a range of complexes. Even though multiple isoforms are expressed at the mRNA level, only a single polypeptide that co-migrates with the human isoform lacking exon 5 is expressed in human skin fibroblasts, HEK293 cells, and murine heart and liver mitochondria. Finally, using a new genome-edited mammalian BTHS cell culture model, we demonstrate that the loss-of-function mechanisms for two BTHS alleles that represent two of the seven functional classes of BTHS mutation as originally defined in yeast, are the same when modeled in human TAZ.


The duration and timing of maternal depression as a moderator of the relationship between dependent interpersonal stress, contextual risk and early child dysregulation.
Risk factors that are associated with depression in the mother also negatively affect the child. This research sought to extend current knowledge by examining the duration and timing of maternal depression as a moderator of: (1) the impact of dependent interpersonal stress (DIS), such as partner conflict or low social support, and contextual risk (e.g. poverty) on child dysregulation; and (2) continuity in early child dysregulation. Mother-child pairs (n = 12 152) who participated in the Avon Longitudinal Study of Parents and Children (ALSPAC) were examined between pregnancy and age 4 years. Data on maternal depression were collected five times between pregnancy and 33 months postpartum; on DIS and contextual risk three times between pregnancy and 33 months; and on child dysregulation at age 2 and 4 years. Longitudinal latent class analysis identified a class of mothers (10%) who evinced a chronic level of depression between pregnancy and 33 months. For chronic-depressed versus non-depressed mothers, the results indicate that: (1) DIS predicted higher child dysregulation if experienced between pregnancy and age 2; (2) contextual risk had a differential effect on child dysregulation if experienced during pregnancy; and (3) children had higher continuity in dysregulation between age 2 and age 4. Assessing the impact of the timing and duration of maternal depression, and different types of co-occurring risk factors, on child well-being is important. Maternal depression and associated DIS, in comparison to contextual risk, may be more responsive to intervention.


Referrals between Public Sector Health Institutions for Women with Obstetric High Risk, Complications, or Emergencies in India - A Systematic Review.
Emergency obstetric care (EmOC) within primary health care systems requires a linked referral system to be effective in reducing maternal death. This systematic review aimed to summarize evidence on the proportion of referrals between institutions during pregnancy and delivery, and the factors affecting referrals, in India. We searched 6 electronic databases, reviewed four regional databases and repositories, and relevant program reports from India published between 1994 and 2013. All types of study or reports (except editorials, comments and letters) which reported on institution-referrals (out-referral or in-referral) for obstetric care were included. Results were synthesized on the proportion and the reasons for referral, and factors affecting referrals. Of the 11,346 articles identified by the search, we included 232 articles in the full text review and extracted data from 16 studies that met our inclusion criteria Of the 16, one was RCT, seven intervention cohort (without controls), six cross-sectional, and three qualitative studies. Bias and quality of studies were reported. Between 25% and 52% of all pregnancies were referred from Sub-centres for antenatal high-risk, 14% to 36% from nurse run delivery or basic EmOC centres for complications or emergencies, and 2 to 7% were referred from doctor run basic EmOC centres for specialist care at comprehensive EmOC centres. Problems identified with referrals from peripheral health centres included low skills and confidence of staff, reluctance to induce labour, confusion over the clinical criteria for referral, non-uniform standards of care at referral institutions, a tendency to by-pass middle level institutions, a lack of referral communication and supervision, and poor compliance. The high proportion of referrals from peripheral health centers reflects the lack of appropriate clinical guidelines, processes, and skills for obstetric care and referral in India. This, combined with inadequate referral communication and low compliance, is likely to contribute to gaps and delays in the provision of emergency obstetric care.


Different requirements for conserved post-transcriptional regulators in planarian regeneration and stem cell maintenance.
Planarian regeneration depends on the presence and precise regulation of pluripotent adult somatic stem cells named neoblasts, which differentiate to replace cells of any missing tissue. A characteristic feature of neoblasts is the presence of large perinuclear nonmembranous organelles named "chromatoid bodies", which are comparable to ribonucleoprotein structures found in germ cells of organisms across different phyla. In order to better understand regulation of gene expression in neoblasts, and potentially the function and composition of chromatoid bodies, we characterized homologues to known germ and soma ribonucleoprotein granule components from other organisms and analyzed their function during regeneration of the planarian Dugesia japonica. Expression in neoblasts was detected for 49 of 55 analyzed genes, highlighting the prevalence of post-transcriptional regulation in planarian stem cells. RNAi-mediated knockdown of two factors [ago-2 and bruli] lead to loss of neoblasts, and consequently loss of regeneration, corroborating with results previously reported for a bruli ortholog in the planarian Schmidtea mediterranea (Guo et al., 2006). Conversely, depletion mRNA turnover factors [edc-4 or upf-1], exoribonucleases [xrn-1 or xrn-2], or DEAD box RNA helicases [Djcbc-1 or vas-1] inhibited planarian regeneration, but did not reduce neoblast proliferation or abundance. We also found that depletion of cap-dependent translation initiation factors eIF-3A or eIF-2A interrupted cell cycle progression outside the M-phase of mitosis. Our results show that a set of post-transcriptional regulators is required to maintain the stem cell identity in neoblasts, while another facilitates proper differentiation. We propose that planarian neoblasts maintain pluripotency by employing mechanisms of post-transcriptional regulation exhibited in germ cells and early development of most metazoans.


Illicit substance use after release from prison among formerly incarcerated primary care patients: a cross-sectional study.
More than 80% of people in jail or prison report having used illicit substances in their lifetimes. After release from incarceration, resumption of substance use carries risks, including parole revocation, exacerbation of mental health conditions, transmission of infectious diseases, and drug overdose. This cross-sectional study used baseline data from the Transitions Clinic Network (TCN, www.transitionsclinic.org ), a multi-site prospective longitudinal cohort study of post-incarceration medical care. We investigated substance use among adults, with at least one chronic health condition or age ≥ 50 years, who had been recently released from incarceration and initiated care at a TCN site. Our primary outcome was any self-reported illicit substance use (heroin or other opioids, cocaine, cannabis, amphetamines, hallucinogens, MDMA, or illicit use of prescription medications) following release from incarceration. Alcohol use post-release was a secondary outcome. Using multivariable logistic regression, we also explored factors associated with illicit substance use. Among 751 participants, median age was 47; participants were mostly male (85%), non-white (47% black, 30% Hispanic), and on parole (80%). The proportion of participants reporting any illicit substance use and any alcohol use soon after release from incarceration was 18% and 23%, respectively. In multivariable regression, variables significantly associated with post-release illicit substance use were male gender (aOR = 3.91, 95% CI: 1.73-8.81), housing with friends or family (aOR = 3.33, 95% CI: 1.20-9.28), years incarcerated during latest prison term (aOR = 0.93, 95% CI: 0.89-0.98), weeks elapsed before engagement with TCN (aOR = 1.07, 95% CI: 1.03-1.10), being on parole (aOR = 0.58, 95% CI: 0.34-0.99), and having a drug use disorder (aOR = 2.27, 95% CI: 1.40-3.68). Among individuals seeking medical care after release from incarceration, self-reported substance use was lower than previously reported estimates of post-incarceration substance use. Known risk factors, such as male gender and having a drug use disorder, were associated with illicit substance use, as were novel risk factors, such as less supervised housing. Though illicit substance use post-incarceration can carry severe consequences, treatment and surveillance interventions should be targeted toward individuals with greatest risk.


The prgQ gene of the Enterococcus faecalis tetracycline resistance plasmid pCF10 encodes a peptide inhibitor, iCF10.
Conjugative transfer of the Enterococcus faecalis tetracycline resistance plasmid pCF10 is stimulated by a peptide pheromone, cCF10. Once a recipient strain acquires pCF10 and thus becomes a pheromone-responsive donor, cCF10 activity is no longer detected in culture filtrates. Here we show that pCF10 encodes a peptide inhibitor, iCF10, secreted by donor cells; this inhibitor antagonizes the cCF10 activity in culture filtrates. In order to detect and quantitate iCF10, we developed a reverse-phase high-performance liquid chromatography assay in which the inhibitor peptide elutes separately from the pheromone; this type of assay enabled us to determine that lack of pheromone activity in donor culture filtrates was due to secretion of a mixture of iCF10 and cCF10, rather than abolition of cCF10 secretion. The gene encoding iCF10, prgQ, is located on the EcoRI-C fragment of pCF10. The open reading frame comprising the prgQ gene encodes a 23-amino-acid precursor that resembles a signal peptide. This precursor is cleaved to the mature heptapeptide iCF10 during the secretion process.


Thioredoxin reductase.
The mammalian thioredoxin reductases (TrxRs) are a family of selenium-containing pyridine nucleotide-disulphide oxidoreductases with mechanistic and sequence identity, including a conserved -Cys-Val-Asn-Val-Gly-Cys- redox catalytic site, to glutathione reductases. TrxRs catalyse the NADPH-dependent reduction of the redox protein thioredoxin (Trx), as well as of other endogenous and exogenous compounds. The broad substrate specificity of mammalian TrxRs is due to a second redox-active site, a C-terminal -Cys-SeCys- (where SeCys is selenocysteine), that is not found in glutathione reductase or Escherichia coli TrxR. There are currently two confirmed forms of mammalian TrxRs, TrxR1 and TrxR2, and it is possible that other forms will be identified. The availability of Se is a key factor determining TrxR activity both in cell culture and in vivo, and the mechanism(s) for the incorporation of Se into TrxRs, as well as the regulation of TrxR activity, have only recently begun to be investigated. The importance of Trx to many aspects of cell function make it likely that TrxRs also play a role in protection against oxidant injury, cell growth and transformation, and the recycling of ascorbate from its oxidized form. Since TrxRs are able to reduce a number of substrates other than Trx, it is likely that additional biological effects will be discovered for TrxR. Furthermore, inhibiting TrxR with drugs may lead to new treatments for human diseases such as cancer, AIDS and autoimmune diseases.


Transcriptional regulation of the human acetoacetyl-CoA synthetase gene by PPARgamma.
In the cytosol of lipogenic tissue, ketone bodies are activated by AACS (acetoacetyl-CoA synthetase) and incorporated into cholesterol and fatty acids. AACS gene expression is particularly abundant in white adipose tissue, as it is induced during adipocyte differentiation. In order to elucidate the mechanism controlling the gene expression of human AACS and to clarify its physiological role, we isolated the human promoter, characterized the elements required to initiate transcription and analysed the expression of the gene in response to PPARgamma (peroxisome-proliferator-activated receptor gamma), an inducer of adipogenesis. We show that the human AACS promoter is a PPARgamma target gene and that this nuclear receptor is recruited to the AACS promoter by direct interaction with Sp1 (stimulating protein-1).


In vitro color evaluation of esthetic coatings for metallic dental implants and implant prosthetic appliances.
The aim of this study was to characterize the optical properties of newly developed esthetic coatings for metallic implants and components for an improved peri-implant soft tissue appearance. Pig maxillae (n = 6) were used for the in vitro color evaluation of coated and uncoated samples. Three different coating systems (Ti-ZrO(2), Ti-Al-ZrO(2), and Ti-Ag-ZrO(2)) were deposited on titanium substrates, which exhibited different roughness (polished, machined, and sand-blasted) and interference colors (pink, yellow, and white). Spectrophotometric measurements were made of samples below three different mucosa thicknesses (1 mm, 2 mm, and 3 mm) and titanium served as negative control. Color difference ΔE was calculated using ΔL, Δa, and Δb values for each sample (in total 30 samples). ΔE values were significantly above the threshold value of 3.70 for sand-blasted Ti and Ti-ZrO(2) samples when tested below 1 mm thick soft tissue, hence resulted in a dark appearance of the soft tissues. In contrast, Ti-Al-ZrO(2) and Ti-Ag-ZrO(2) samples showed significant ΔL values below 1 mm, which indicates a brightening of the covering tissue. In general, ΔE values decreased with increasing thickness of the tissue. At 3 mm thick tissue, ΔE values were significantly below 3.70 for Ti-Al-ZrO(2) and Ti-Ag-ZrO(2) samples. The preferable substrate surface should be machined due increased color brightness, good soft tissue integration and improved adhesion between coating and substrates. Improvement of the optical appearance of the metal was achieved with the coating systems Ti-Al-ZrO(2) and Ti-Ag-ZrO(2). Darkening effects could not be observed for these systems, and partially light brightening of the tissue was observed. Advantageous colors were suggested to be pink and yellow.


Pattern Versus Change: Community-Based Dyadic Heart Failure Self-Care.
It is imperative that dyadic heart failure (HF) self-care be carefully examined so we can develop interventions which improve patient outcomes. The purpose of this study was to qualitatively examine how patient/informal caregiver dyads mutually engage in managing the patient's HF at home. Twenty-seven dyads were interviewed using a theoretically derived interview guide. All interviews were digitally recorded and professionally transcribed, and iterative thematic analysis was conducted. Three descriptive themes emerged-Mutual engagement in self-care involves maintaining established patterns of engagement across the life course of the relationship, changing patterns according to whether it is day-to-day care or symptom management, and mobilizing the help of a third party as consultant. These themes reveal the dyadic conundrum-whether to change or remain the same in the face of a dynamic and progressive condition like HF. The themes suggest potential targets for intervention-interventions focused on the relationship or caregiver activation.


Effects of low intensity static magnetic field on FTIR spectra and ROS production in SH-SY5Y neuronal-like cells.
Biological effects of man-made electromagnetic fields (EMFs) have been studied so far by experimental approaches exposing animals and cell cultures to EMFs. However, the evidence for cell toxicity induced by static magnetic field (SMF) is still uncertain. We investigated the effects produced by the exposure of human SH-SY5Y neuronal-like cells to a uniform magnetic field at intensities of 2.2 mT, which is less than the recommended public exposure limits set by the International Commission on Non-Ionizing Radiation Protection (ICNIRP). A decrease of membrane mitochondrial potential up to 30% was measured after 24 h of exposure to SMF in SH-SY5Y cells, and this effect was associated with reactive oxygen species production increase. Fourier transform infrared spectroscopy (FTIR) analysis showed that exposure to a static magnetic intensity around 2.2 mT changed the secondary structure of cellular proteins and lipid components. The vibration bands relative to the methylene group increased significantly after 4 h of exposure, whereas further exposure up to 24 h produced evident shifts of amide I and II modes and a relative increase in β-sheet contents with respect to α-helix components. Our study demonstrated that a moderate SMF causes alteration in cell homeostasis, as indicated by FTIR spectroscopy observations of changes in protein structures that are part of cell response to magnetic field exposure.


Evaluation of the Renal Arteries of 2,144 Living Kidney Donors Using Computed Tomography Angiography and Comparison with Intraoperative Findings.
A carefully chosen and suitably prepared kidney donor is essential in living-donor kidney transplantation. Computed tomography angiography (CTA) is an effective imaging method for evaluating the renovascular morphology of donor candidates. The aim of this study was to evaluate renal artery variations in kidney donors using CTA and compare the findings with the number of arteries detected during laparoscopic donor nephrectomy. The study included 2,144 living donors who underwent pretransplant renovascular assessment using CTA and laparoscopic donor nephrectomy in our center between August 2012 and October 2018. The number of renal arteries to the donor kidney detected on CTA was compared with the number of arteries discovered intraoperatively. The mean age of the 2,144 living kidney donors included in the study was 47.19 ± 13.3 (18-87) years. According to CTA findings, 81.1% (n = 1,738) had a single renal artery, 17.2% (n = 369) had double renal arteries, 1.6% (n = 35) had triple renal arteries, and 0.1% (n = 2) had quadruple renal arteries. The same number of renal arteries were detected by CTA and in laparoscopic donor nephrectomy in 97.9% (n = 2,099) of the donors. In the other 2.1% (n = 45), fewer renal arteries were detected intraoperatively compared to their CTA findings. None of the donors included in the study had a greater number of renal arteries discovered during nephrectomy than by CTA. CTA is a highly accurate method for the evaluation of renovascular variations in donor candidates for living-donor kidney transplantation. However, it must be kept in mind that double or multiple renal artery variations may be detected on CTA in 18.9% of donor candidates.


Engagement With Motivational Interviewing and Cognitive Behavioral Therapy Components of a Web-Based Alcohol Intervention, Elicitation of Change Talk and Sustain Talk, and Impact on Drinking Outcomes: Secondary Data Analysis.
Down Your Drink (DYD) is a widely used unguided web-based alcohol moderation program for the general public based on cognitive behavioral therapy (CBT) and motivational interviewing (MI); it provides users with many opportunities to enter free-text responses. The aim of this study was to assess participants' use of key CBT and MI components, the presence of change talk and sustain talk within their responses, and whether these data are associated with drinking outcomes after 3 months. An exploratory secondary data analysis was conducted on data collected in 2008 from the definitive randomized trial of DYD (N=503). Past week alcohol use at baseline and 3-month follow-up were measured with the TOT-AL. Covariates included baseline alcohol use, age, gender, education level, and word count of the responses. Use of MI and CBT components and presence of change talk and sustain talk were coded by two independent coders (Cohen κ range 0.91-1). Linear model regressions on the subsample of active users (n=410) are presented along with a negative binomial regression. The most commonly used component was the listing of pros and cons of drinking. The number of listed high-risk situations was associated with lower alcohol use at 3-month follow-up (Badj -2.15, 95% CI -3.92 to -0.38, P=.02). Findings on the effects of the percentage of change talk and the number of listed strategies to deal with high-risk situations were inconsistent. An unguided web-based alcohol moderation program can elicit change talk and sustain talk. This secondary analysis suggests that the number of listed high-risk situations can predict alcohol use at 3-month follow-up. Other components show inconsistent findings and should be studied further.


An optimized in vitro model of the respiratory tract wall to study particle cell interactions.
As a part of the respiratory tissue barrier, lung epithelial cells play an important role against the penetration of the body by inhaled particulate foreign materials. In most cell culture models, which are designed to study particle-cell interactions, the cells are immersed in medium. This does not reflect the physiological condition of lung epithelial cells which are exposed to air, separated from it only by a very thin liquid lining layer with a surfactant film at the air-liquid interface. In this study, A549 epithelial cells were grown on microporous membranes in a two chamber system. After the formation of a confluent monolayer the cells were exposed to air. The morphology of the cells and the expression of tight junction proteins were studied with confocal laser scanning and transmission electron microscopy. Air-exposed cells maintained monolayer structure for 2 days, expressed tight junctions and developed transepithelial electrical resistance. Surfactant was produced and released at the apical side of the air-exposed epithelial cells. In order to study particle-cell interactions fluorescent 1 microm polystyrene particles were sprayed over the epithelial surface. After 4 h, 8.8% of particles were found inside the epithelium. This fraction increased to 38% after 24 h. During all observations, particles were always found in the cells but never between them. In this study, we present an in vitro model of the respiratory tract wall consisting of air-exposed lung epithelial cells covered by a liquid lining layer with a surfactant film to study particle-cell interactions.


Differential translocation of the fatty acid transporter, FAT/CD36, and the glucose transporter, GLUT4, coordinates changes in cardiac substrate metabolism during ischemia and reperfusion.
Fatty acid and glucose transporters translocate between the sarcolemma and intracellular compartments to regulate substrate metabolism acutely. We hypothesised that during ischemia fatty acid translocase (FAT/CD36) would translocate away from the sarcolemma to limit fatty acid uptake when fatty acid oxidation is inhibited. Wistar rat hearts were perfused during preischemia, low-flow ischemia, and reperfusion, using (3)H-substrates for measurement of metabolic rates, followed by metabolomic analysis and subcellular fractionation. During ischemia, there was a 32% decrease in sarcolemmal FAT/CD36 accompanied by a 95% decrease in fatty acid oxidation rates, with no change in intramyocardial lipids. Concomitantly, the sarcolemmal content of the glucose transporter, GLUT4, increased by 90% during ischemia, associated with an 86% increase in glycolytic rates, 45% decrease in glycogen content, and a 3-fold increase in phosphorylated AMP-activated protein kinase. Following reperfusion, decreased sarcolemmal FAT/CD36 persisted, but fatty acid oxidation rates returned to preischemic levels, resulting in a 35% decrease in myocardial triglyceride content. Elevated sarcolemmal GLUT4 persisted during reperfusion; in contrast, glycolytic rates decreased to 30% of preischemic rates, accompanied by a 5-fold increase in intracellular citrate levels and restoration of glycogen content. During ischemia, FAT/CD36 moved away from the sarcolemma as GLUT4 moved toward the sarcolemma, associated with a shift from fatty acid oxidation to glycolysis, while intramyocardial lipid accumulation was prevented. This relocation was maintained during reperfusion, which was associated with replenishing glycogen stores as a priority, occurring at the expense of glycolysis and mediated by an increase in citrate levels.


Recency effects and lesion effects in delayed non-matching to randomly baited samples by monkeys.
Monkeys' memory for 3-dimensional junk objects was tested in a task which required them to discriminate objects which had recently been presented in an acquisition list from new objects which had not. The accuracy of this discrimination was shown to depend on the recency of presentation of the old object. The discrimination was not significantly affected by lesions of either the foveal pre-striate cortex, the fundus of the superior temporal sulcus, or the anterior inferior temporal area. A substantial impairment was caused by transection of the fornix.


Study protocol for a randomised controlled trial of CBT vs antipsychotics vs both in 14-18-year-olds: Managing Adolescent first episode Psychosis: a feasibility study (MAPS).
Adolescent-onset psychosis is associated with more severe symptoms and poorer outcomes than adult-onset psychosis. The National Institute for Clinical Excellence (NICE) recommend that adolescents with first episode psychosis (FEP) should be offered a combination of antipsychotic medication (APs), cognitive behavioural therapy (CBT) and family intervention (FI). The evidence for APs in treating psychosis is limited in adolescents compared to adults. Nevertheless, it indicates that APs can reduce overall symptoms in adolescents but may cause more severe side effects, including cardiovascular and metabolic effects, than in adults. CBT and FI can improve outcomes in adults, but there are no studies of psychological interventions (PI) in patients under 18 years old. Given this limited evidence base, NICE made a specific research recommendation for determining the clinical and cost effectiveness of APs versus PI versus both treatments for adolescent FEP. The current study aimed to establish the feasibility and acceptability of conducting such a trial by recruiting 14-18-year-olds with a first episode of psychosis into a feasibility prospective randomised open blinded evaluation (PROBE) design, three-arm, randomised controlled trial of APs alone versus PI alone versus a combination of both treatments. We aimed to recruit 90 participants from Early Intervention and Child and Adolescent Mental Health Teams in seven UK sites. APs were prescribed by participants' usual psychiatrists. PI comprised standardised cognitive behavioural therapy and family intervention sessions. This is the first study to compare APs to PI in an adolescent population with FEP. Recruitment finished on 31 October 2018. The study faced difficulties with recruitment across most sites due to factors including clinician and service-user treatment preferences. Current controlled trial with ISRCTN, ISRCTN80567433 . Registered on 27 February 2017.


Background and methodology of the older driver evidence-based systematic literature review.
In response to demands of health care and community-based systems, occupational therapy practitioners are eager to provide effective services that are client centered, supported by evidence, and delivered in an efficient and cost-effective manner. Findings from the scientific literature provide a source of legitimacy and authority for informing and guiding practice in all areas, including driving and community mobility with older adults. A systematic review examined studies designed to enhance the driving ability, performance, and safety of older adults. This article presents an overview of the methodology used to develop the focused questions related to the person, vehicle, infrastructure, and policy and community mobility; conduct the literature review; and establish quality control. It includes a summary of the evidence and implications of the review for clinical practice, education, and research to ultimately identify interventions effective in supporting older adult participation and engagement in occupation.


Identifying disease mutations in genomic medicine settings: current challenges and how to accelerate progress.
The pace of exome and genome sequencing is accelerating, with the identification of many new disease-causing mutations in research settings, and it is likely that whole exome or genome sequencing could have a major impact in the clinical arena in the relatively near future. However, the human genomics community is currently facing several challenges, including phenotyping, sample collection, sequencing strategies, bioinformatics analysis, biological validation of variant function, clinical interpretation and validity of variant data, and delivery of genomic information to various constituents. Here we review these challenges and summarize the bottlenecks for the clinical application of exome and genome sequencing, and we discuss ways for moving the field forward. In particular, we urge the need for clinical-grade sample collection, high-quality sequencing data acquisition, digitalized phenotyping, rigorous generation of variant calls, and comprehensive functional annotation of variants. Additionally, we suggest that a 'networking of science' model that encourages much more collaboration and online sharing of medical history, genomic data and biological knowledge, including among research participants and consumers/patients, will help establish causation and penetrance for disease causal variants and genes. As we enter this new era of genomic medicine, we envision that consumer-driven and consumer-oriented efforts will take center stage, thus allowing insights from the human genome project to translate directly back into individualized medicine.


Management of non-ST-segment elevation acute myocardial infarction in patients with chronic kidney disease (from the Korea Acute Myocardial Infarction Registry).
The aim of this study was to compare clinical outcomes among early invasive (EI), deferred invasive (DI), and conservative strategies in patients with acute non-ST-segment elevation myocardial infarction (NSTEMI) and chronic kidney disease (CKD). High-risk patients with NSTEMI are believed to fare better with an EI strategy, but the optimal treatment for patients with NSTEMI and CKD is not known. In total 5,185 patients with acute NSTEMI were enrolled from the Korea Acute Myocardial Infarction Registry and followed for 1 year. Patients were divided into EI, DI, and conservative treatment groups and classified into 4 stages using references from the National Kidney Foundation. The invasive EI and DI groups were compared to the conservative groups, and the EI and DI groups were compared according to each renal function stage. At 1-year follow-up, mortality rates in the conservative group were significantly higher than in the invasive groups except for the severe CKD group. The benefit of the EI over the DI strategy, although there were no significant differences between the 2 groups, tended to decrease as renal function decreased. In conclusion, in the management of NSTEMI, an invasive strategy decreased mortality compared to a conservative strategy except for severe CKD. In the timing of an invasive strategy, the EI strategy was observed to be superior to the DI strategy in patients with mild CKD; however, this tendency reversed as renal function decreased. When patients with NSTEMI have severe CKD, a conservative or DI strategy with prescription of cardioprotective medications and prevention of further deterioration in renal function should be considered.


Adherence to standards of quality HIV/AIDS care and antiretroviral therapy in the West Nile Region of Uganda.
Over one million people in Uganda are estimated to be infected with HIV and about 20% of these were already accessing antiretroviral therapy (ART), by 2010. There is a dearth of data on adherence to antiretroviral therapy and yet high client load on a weak and resource constrained health system impacts on provision of quality HIV/AIDS care. We assessed adherence to standards of HIV care among health workers in the West Nile Region of Uganda. We conducted a cross sectional study in nine health facilities. Records of a cohort of 270 HIV clients that enrolled on ART 12 months prior were assessed. The performance of each health facility on the different indicators of standards of HIV/AIDS care was determined and compared with the recommended national guidelines. We found that 94% of HIV clients at all the facilities were assessed for ART eligibility using WHO clinical staging while only two thirds (64.8%) were assessed using CD4. Only 42% and 37% of HIV clients at district hospitals and health centers respectively, received basic laboratory work up prior to ART initiation and about a half (46.7%) of HIV clients at these facilities received the alternative standard 1st line antiretroviral (ARV) regimen. Standards of ART adherence and tuberculosis assessment declined from over 70% to less than 50% and from over 90% to less than 70% respectively, during follow up visits with performance being poorer at the higher level regional referral facility compared to the lower level facilities. Adherence to standards of HIV/AIDS care at facilities was inadequate. Performance was better at the start of ART but declined during the follow up period. Higher level facilities were more likely to adhere to standards like CD4 monitoring and maintaining HIV clients on standard ARV regimen. Efforts geared towards strengthening the health system, including support supervision and provision of care guidelines and job aides are needed, especially for lower level facilities.


The vocal repertoire in a solitary foraging carnivore, Cynictis penicillata, may reflect facultative sociality.
We describe the vocal repertoire of a facultatively social carnivore, the yellow mongoose, Cynictis penicillata. Using a combination of close-range observations, recordings and experiments with simulated predators, we were able to obtain clear descriptions of call structure and function for a wide range of calls used by this herpestid. The vocal repertoire of the yellow mongooses comprised ten call types, half of which were used in appeasing or fearful contexts and half in aggressive interactions. Data from this study suggest that the yellow mongoose uses an urgency-based alarm calling system, indicating high and low urgency through two distinct call types. Compared to solitary mongooses, the yellow mongoose has a large proportion of 'friendly' vocalisations that enhance group cohesion, but its vocal repertoire is smaller and less context-specific than those of obligate social species. This study of the vocal repertoire of the yellow mongoose is, to our knowledge, the most complete to have been conducted on a facultatively social species in its natural habitat.


The influence of neuroticism in terms of E-cigarette dependence and beliefs about use and quitting among dual users of combustible and electronic cigarettes.
Dual use of combustible and electronic cigarettes (e-cigarettes) is increasing in prevalence and may be related to an increased risk for health problems. Accordingly, dual users represent a particularly vulnerable group. Neuroticism is an individual difference factor that demonstrates robust relations to combustible cigarette use. Yet, no work has examined neuroticism in relation to e-cigarette dependence or cognitions among dual users. To address this limitation, the present study examined neuroticism in relation to e-cigarette dependence, expectancies about the negative effects of e-cigarettes, and perceived barriers for quitting e-cigarettes. The present study analyzed data collected from a cross-sectional survey of 437 dual combustible cigarette and e-cigarette users (49.9% female, Mage = 35.12 years, SD = 10.04). Results indicated that neuroticism was significantly, positively related to e-cigarette dependence (ΔR2 = 0.02, p < .001), expectancies about the negative effects of e-cigarettes (ΔR2 = 0.03, p < .001), and perceived barriers for quitting e-cigarettes (ΔR2 = 0.10, p < .001). These novel findings suggest there may be merit in further exploring the role of neuroticism in the maintenance of concurrent combustible cigarette and e-cigarette use.


A comparison of the effects of differences in temporal gating and ear of presentation on profile discrimination.
The aim of the study was to examine the effects of differences in temporal gating and ear of presentation (both separately and in combination) on listeners' ability to detect an increment in the level of a 1 kHz component (the target) relative to that of four spectrally flanking components. The flanking components were always presented to the listeners' right ear, while the target component was either presented to the same ear (monaural presentation) or to the left ear (dichotic presentation). Similarly, the target and flanking components were either gated on and off at the same time (synchronous presentation), or else the target component began 100 ms before and terminated 100 ms after the four flanking components (asynchronous presentation). On average, thresholds were lowest in the synchronous, monaural condition, and highest in the two asynchronous conditions. Ear differences alone did result in elevated thresholds for most listeners. However, combining differences in gating and ear of presentation produced thresholds that were indistinguishable from those obtained when gating differences alone were employed. These results are consistent with the suggestion that differences in temporal gating lead to more complete segregation of concurrent frequency components than differences in spatial location.


Auricular acupressure as a treatment for anxiety in prehospital transport settings.
Auricular acupuncture at the relaxation point has been previously shown to be an effective treatment for anxiety in the preoperative setting. The purpose of this prospective, randomized, blinded study was to determine whether auricular acupressure can reduce stress and anxiety during ambulance transport. Patients who required ambulance transport secondary to medical conditions were randomized to receive auricular acupressure at the relaxation point (n = 17) or at a sham point (n = 19). A visual analog scale was used to assess state anxiety as well as patient anticipation of hospital medical treatment (estimated waiting period for treatment, anticipated pain during treatment, attitude toward the physicians, and treatment outcomes). These variables were assessed at baseline and on arrival to the hospital. Patients in the relaxation group reported significantly less anxiety than patients in the sham group on arrival to the hospital (visual analog scale mean +/- SD: 37.6 +/- 20.6 to 12.4 +/- 7.8 mm vs. 42.5 +/- 29.9 to 46.7 +/- 25.9 mm, respectively; P = 0.002). Similarly, patient perception of pain during treatment (mean visual analog scale +/- SD: 32.7 +/- 27.7 to 14.5 +/- 8.1 mm vs. 17.2 +/- 26.1 to 28.8 +/- 21.9 mm, respectively; P = 0.006) and treatment outcomes of their illnesses (mean visual analog scale +/- SD: 46.7 +/- 29.4 to 19.1 +/- 10.4 mm vs. 35.0 +/- 25.7 to 31.5 +/- 20.5 mm, respectively; P = 0.014) were significantly more positive in the relaxation group than in the sham group. No differences were found in the other variables assessed. It was concluded that auricular acupressure is an effective treatment for anxiety in prehospital emergency settings.


In vitro Antimicrobial Activity of Ocimum sanctum (Tulsi) Extract on Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis.
Aim: The present study was conducted with an aim to assess the antimicrobial activity of Ocimum sanctum (tulsi) extract on Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis.Materials and methods: Tulsi extract with ethanol was prepared using cold extraction method in the present in vitro study. Various concentrations (2, 4, 6, and 8%) were then obtained by dilution with dimethylformamide. A 0.2% chlorhexidine served as the positive control, whereas the negative control was dimeth-ylformamide. Zones of inhibition were measured, each for A. actinomycetemcomitans and P. gingivalis. For comparison within the group and between the study groups, one-way analysis of variance (ANOVA) and Tukey's post hoc tests were used. A statistical significance level of p < 0.05 was established. Results: The 8% concentration of the tulsi extract showed maximum zone of inhibition against A. actinomycetemcomitans and P. gingivalis (40.10 ± 0.90, 33.79 ± 1.82 mm), followed by the 6, 4, and 2% concentrations. The 0.2% chlorhexidine, which was the positive control, had 39.80 ± 1.24 and 32.28 ± 1.28 mm zones of inhibition; dimethylformamide showed 13.55 ± 1.92 and 10.21 ± 2.16 mm zones of inhibition against both the microorganisms. The ANOVA showed highly statistically significant (p < 0.0001) results between and within the groups. The antimicrobial activity of tulsi extract at 6 and 8% concentrations, and 0.2% chlorhexidine against A. actinomycetemcomitans showed statistically significant differences between the groups. The concentration of tulsi extract at 8 and 0.2% chlorhexidine on P. gingivalis showed statistically significant differences between the groups. Conclusion: It was concluded that 8% concentration of O. sanctum (tulsi) extract showed the maximum antimicrobial activity against A. actinomycetemcomitans and P. gingivalis. It is thus recommended that this may be useful as an adjunc-tive to mechanical therapy in the prevention and treatment of periodontal diseases. Clinical significance:O. sanctum (tulsi) is a herb that is abundantly available, easily accessible, economically feasible, and culturally acceptable. Therefore, it is very useful in the management of oral diseases and also for overcoming many barriers that exist for the utilization of dental services, such as affordability, accessibility, availability, and acceptability. Keywords:Aggregatibacter actinomycetemcomitans, Antimicrobial, Ocimum sanctum, Porphyromonas gingivalis.


Major life events and development of major depression in Parkinson's disease patients.
Non-motor symptoms including depression are important features of Parkinson's disease (PD). We aim to address the relationship between major life events and depression amongst PD patients free of depressive symptoms at baseline. New-onset PD patients from California were recruited in 2001-2007 and followed up for 3-4 years. The participants (n=221) were examined by neurologists and responded to comprehensive interviews that included major life events, social support, and coping measures from validated scales. Major depression was assessed using the Structured Clinical Interview for the DSM-IV depression module (SCID). More than half of all patients had experienced major life events since diagnosed with PD, and 22 patients developed a major depression. The number of life events was associated with risk of depression in an exposure-dependent manner, with each additional event being associated with a 56% higher risk of depression (95% CI: 1.23-1.98). Most individual life events were associated with a two- to eight-fold higher risk of depression. Patients with low social support or coping capacities seemed to be particularly susceptible to developing depression after experiencing major life events. Life events play an important role for onset of depression in patients with PD; an effect that seems to be modulated by social support and coping capacities and these factors may therefore be important to assess in order to identify patients with PD at high risk of depression and provide effective interventions.


Clonal spread and interspecies transmission of clinically relevant ESBL-producing Escherichia coli of ST410--another successful pandemic clone?
Clinically relevant extended-spectrum beta-lactamase (ESBL)-producing multi-resistant Escherichia coli have been on the rise for years. Initially restricted to mostly a clinical context, recent findings prove their prevalence in extraclinical settings independent of the original occurrence of antimicrobial resistance in the environment. To get further insights into the complex ecology of potentially clinically relevant ESBL-producing E. coli, 24 isolates from wild birds in Berlin, Germany, and 40 ESBL-producing human clinical E. coli isolates were comparatively analyzed. Isolates of ST410 occurred in both sample groups (six). In addition, three ESBL-producing E. coli isolates of ST410 from environmental dog feces and one clinical dog isolate were included. All 10 isolates were clonally analyzed showing almost identical macrorestriction patterns. They were chosen for whole-genome sequencing revealing that the whole-genome content of these 10 E. coli isolates showed a very high genetic similarity, differing by low numbers of single nucleotide polymorphisms only. This study gives initial evidence for a recent interspecies transmission of a new successful clone of ST410 E. coli between wildlife, humans, companion animals and the environment. The results underline the zoonotic potential of clinically relevant multi-resistant bacteria found in the environment as well as the mandatory nature of the 'One Health' approach.


Adaptive management of ecosystem services across different land use regimes.
Using adaptive management to manage desired flows of ecosystem services may seem on the surface to be a good fit, but many social, economic, environmental, legal, and political factors influence how good a fit. One strongly influential factor is the land use regime within which the profile of ecosystem services is being managed. Shaped largely by legal mandates, market forces, and social and cultural practices, different land use regimes present different opportunities for and constraints on goals for ecosystem services and pose different decision making environments. Even where all other conditions appear amenable to using adaptive management, therefore, it is essential to consider the constraining (or liberating) effects of different land use regimes when deciding whether to adopt adaptive management to achieve those goals and, if so, how to implement it.


Enriched conditioning expands the regenerative ability of sensory neurons after spinal cord injury via neuronal intrinsic redox signaling.
Overcoming the restricted axonal regenerative ability that limits functional repair following a central nervous system injury remains a challenge. Here we report a regenerative paradigm that we call enriched conditioning, which combines environmental enrichment (EE) followed by a conditioning sciatic nerve axotomy that precedes a spinal cord injury (SCI). Enriched conditioning significantly increases the regenerative ability of dorsal root ganglia (DRG) sensory neurons compared to EE or a conditioning injury alone, propelling axon growth well beyond the spinal injury site. Mechanistically, we established that enriched conditioning relies on the unique neuronal intrinsic signaling axis PKC-STAT3-NADPH oxidase 2 (NOX2), enhancing redox signaling as shown by redox proteomics in DRG. Finally, NOX2 conditional deletion or overexpression respectively blocked or phenocopied enriched conditioning-dependent axon regeneration after SCI leading to improved functional recovery. These studies provide a paradigm that drives the regenerative ability of sensory neurons offering a potential redox-dependent regenerative model for mechanistic and therapeutic discoveries.


Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumorigenesis.
The mechanisms by which deregulated nuclear factor erythroid-2-related factor 2 (NRF2) and kelch-like ECH-associated protein 1 (KEAP1) signaling promote cellular proliferation and tumorigenesis are poorly understood. Using an integrated genomics and ¹³C-based targeted tracer fate association (TTFA) study, we found that NRF2 regulates miR-1 and miR-206 to direct carbon flux toward the pentose phosphate pathway (PPP) and the tricarboxylic acid (TCA) cycle, reprogramming glucose metabolism. Sustained activation of NRF2 signaling in cancer cells attenuated miR-1 and miR-206 expression, leading to enhanced expression of PPP genes. Conversely, overexpression of miR-1 and miR-206 decreased the expression of metabolic genes and dramatically impaired NADPH production, ribose synthesis, and in vivo tumor growth in mice. Loss of NRF2 decreased the expression of the redox-sensitive histone deacetylase, HDAC4, resulting in increased expression of miR-1 and miR-206, and not only inhibiting PPP expression and activity but functioning as a regulatory feedback loop that repressed HDAC4 expression. In primary tumor samples, the expression of miR-1 and miR-206 was inversely correlated with PPP gene expression, and increased expression of NRF2-dependent genes was associated with poor prognosis. Our results demonstrate that microRNA-dependent (miRNA-dependent) regulation of the PPP via NRF2 and HDAC4 represents a novel link between miRNA regulation, glucose metabolism, and ROS homeostasis in cancer cells.


The role of tomato products and lycopene in the prevention of gastric cancer: a meta-analysis of epidemiologic studies.
Gastric cancer is the second most common cause of death from cancer worldwide. Epidemiologic studies have examined the possible association between tomato products consumption and gastric cancer, but the relationship between tomato products and the risk of gastric cancer is controversial. We performed a meta-analysis of cohort and case-control studies to analyze this association. We systematically searched MEDLINE and EMBASE and contacted authors to identify potential studies published from January 1966 to June 2012. We pooled the relative risks from individual studies using a random-effects model and performed heterogeneity and publication bias analyses. Twenty-one studies were eligible for our inclusion criteria, in a pooled analysis of all studies, consumption of large amounts of tomato products (in a comparison of the highest and lowest consumption groups) reduced the risk for gastric cancer (odds ratio, 0.73; 95% confidence interval, 0.60-0.90). The pooled OR of lycopene consumption and serum lycopene was 0.88 (95% CI=0.67-1.16) and 0.79 (95% CI=0.59-1.07), respectively. Consumption of large amounts of tomato products is associated with a reduced risk of gastric cancer. However, because of potential confounding factors and exposure misclassification, further studies are required to establish these findings.


PFAS concentration during pregnancy in relation to cardiometabolic health and birth outcomes.
Poly- and perfluoroalkyl substances (PFAS) are persistent organic pollutants with pervasive exposure and suspected associations with metabolic abnormalities and adverse pregnancy outcomes. The goal of the present study was to examine the relationship between serum-PFAS concentrations measured in late pregnancy with relevant outcomes. The study sample included 433 pregnant women enrolled in the Vanguard Pilot Study of the National Children's Study. Six PFAS were measured in primarily third trimester serum, as well as fasting insulin, total cholesterol, and triglycerides. The PFAS were examined in quartiles in relation to serum biomarkers, gestational age at birth and birth weight standardized for gestational age using multivariable-adjusted regression models. Over 98% of the study population had detectable concentrations of four of the PFAS, and concentrations varied by race/ethnicity. Total cholesterol was positively associated with PFDA, PFNA, and PFOS, and triglycerides with PFDA, PFNA, PFOS, and PFOA, but PFAS were not associated with fasting insulin in adjusted models. Only PFNA was associated with an increased odds of birth at <37 weeks gestation. PFAS were generally not associated with birth weight, though PFHxS was associated with the first quartile of birth weight among males only. This study of pregnant U.S. women supports the ubiquitous exposure to PFAS and positive associations between PFAS exposure with serum-lipid concentrations. PFAS were largely unassociated with gestational age at birth and birth weight, though PFNA was associated with preterm birth. The results support the vulnerability to PFAS exposure of pregnancy.


Perceived difficulty and appropriateness of decision making by General Practitioners: a systematic review of scenario studies.
Health-care quality in primary care depends largely on the appropriateness of General Practitioners' (GPs; Primary Care or Family Physicians) decisions, which may be influenced by how difficult they perceive decisions to be. Patient scenarios (clinical or case vignettes) are widely used to investigate GPs' decision making. This review aimed to identify the extent to which perceived decision difficulty, decision appropriateness, and their relationship have been assessed in scenario studies of GPs' decision making; identify possible determinants of difficulty and appropriateness; and investigate the relationship between difficulty and appropriateness. MEDLINE, EMBASE, PsycINFO, the Cochrane Library and Web of Science were searched for scenario studies of GPs' decision making. One author completed article screening. Ten percent of titles and abstracts were checked by an independent volunteer, resulting in 91% agreement. Data on decision difficulty and appropriateness were extracted by one author and descriptively synthesised. Chi-squared tests were used to explore associations between decision appropriateness, decision type and decision appropriateness assessment method. Of 152 included studies, 66 assessed decision appropriateness and five assessed perceived difficulty. While no studies assessed the relationship between perceived difficulty and appropriateness, one study objectively varied the difficulty of the scenarios and assessed the relationship between a measure of objective difficulty and appropriateness. Across 38 studies where calculations were possible, 62% of the decisions were appropriate as defined by the appropriateness standard used. Chi-squared tests identified statistically significant associations between decision appropriateness, decision type and decision appropriateness assessment method. Findings suggested a negative relationship between decision difficulty and appropriateness, while interventions may have the potential to reduce perceived difficulty. Scenario-based research into GPs' decisions rarely considers the relationship between perceived decision difficulty and decision appropriateness. The links between these decisional components require further investigation.


A case for tobacco content regulation by the U.S. Food and Drug Administration.
Although many people welcome the recent move by the United States to give its Food and Drug Administration (FDA) the authority to regulate the content of tobacco, some worry that such regulation constitutes unwarranted interference with the freedom of competent adult tobacco consumers. The concern for protecting the autonomy of individuals is valuable indeed, but given the highly addictive nature of tobacco products (and especially the nicotine in tobacco products), the continued use of tobacco by smokers cannot -without straining credulity-be said to be autonomous. This fact, combined with a proper construal of the FDA's role and an appreciation of the substantial morbidity and mortality associated with tobacco use, makes a strong case for content regulation.


The Inflammatory Cytokine Profile of Patients with Malignant Pleural Effusion Treated with Pleurodesis.
Patients with malignant pleural effusion (MPE) who underwent successful pleurodesis survive longer than those for whom it fails. We hypothesize that the therapy-induced inflammatory responses inhibit the cancer progression, and thereby lead to a longer survival. Thirty-three consecutive patients with MPE that were eligible for bleomycin pleurodesis between September 2015 and December 2017 were recruited prospectively. Nineteen patients (57.6%) achieved fully or partially successful pleurodesis, while 14 patients either failed or survived less than 30 days after pleurodesis. Two patients without successful pleurodesis were excluded because of missing data. Interleukin (IL)-1 beta, IL-6, IL-10, transforming growth factor beta, tumor necrosis factor alpha (TNF-α), and vascular endothelial growth factor in the pleural fluid were measured before, and after 3 and 24 h of pleurodesis. Their pleurodesis outcome and survival were monitored and analyzed. Patients who underwent successful pleurodesis had a longer survival rate. Patients without successful pleurodesis had significantly higher TNF-α and IL-10 levels in their pleural fluid than in the successful patients before pleurodesis. Following pleurodesis, there was a significant increment of IL-10 in the first three hours in the successful patients. In contrast, significant increments of TNF-α and IL-10 were found in the unsuccessful patients between 3 and 24 h after pleurodesis. The ability to produce specific cytokines in the pleural space following pleurodesis may be decisive for the patient's outcome and survival. Serial measurement of cytokines can help allocate the patients to adequate treatment strategies. Further study of the underlying mechanism may shed light on cytokine therapies as novel approaches.


Comparative analysis of Japanese three-spined stickleback clades reveals the Pacific Ocean lineage has adapted to freshwater environments while the Japan Sea has not.
Divergent selection and adaptive divergence can increase phenotypic diversification amongst populations and lineages. Yet adaptive divergence between different environments, habitats or niches does not occur in all lineages. For example, the colonization of freshwater environments by ancestral marine species has triggered adaptive radiation and phenotypic diversification in some taxa but not in others. Studying closely related lineages differing in their ability to diversify is an excellent means of understanding the factors promoting and constraining adaptive evolution. A well-known example of the evolution of increased phenotypic diversification following freshwater colonization is the three-spined stickleback. Two closely related stickleback lineages, the Pacific Ocean and the Japan Sea occur in Japan. However, Japanese freshwater stickleback populations are derived from the Pacific Ocean lineage only, suggesting the Japan Sea lineage is unable to colonize freshwater. Using stable isotope data and trophic morphology, we first show higher rates of phenotypic and ecological diversification between marine and freshwater populations within the Pacific Ocean lineage, confirming adaptive divergence has occurred between the two lineages and within the Pacific Ocean lineage but not in the Japan Sea lineage. We further identified consistent divergence in diet and foraging behaviour between marine forms from each lineage, confirming Pacific Ocean marine sticklebacks, from which all Japanese freshwater populations are derived, are better adapted to freshwater environments than Japan Sea sticklebacks. We suggest adaptive divergence between ancestral marine populations may have played a role in constraining phenotypic diversification and adaptive evolution in Japanese sticklebacks.


Supervised learning in multilayer spiking neural networks.
We introduce a supervised learning algorithm for multilayer spiking neural networks. The algorithm overcomes a limitation of existing learning algorithms: it can be applied to neurons firing multiple spikes in artificial neural networks with hidden layers. It can also, in principle, be used with any linearizable neuron model and allows different coding schemes of spike train patterns. The algorithm is applied successfully to classic linearly nonseparable benchmarks such as the XOR problem and the Iris data set, as well as to more complex classification and mapping problems. The algorithm has been successfully tested in the presence of noise, requires smaller networks than reservoir computing, and results in faster convergence than existing algorithms for similar tasks such as SpikeProp.