A novel class of anti-HIV agents with multiple copies of enfuvirtide enhances inhibition of viral replication and cellular transmission in vitro.
We constructed novel HIV-1 fusion inhibitors that may overcome the current limitations of enfuvirtide, the first such therapeutic in this class. The three prototypes generated by the Dock-and-Lock (DNL) technology to comprise four copies of enfuvirtide tethered site-specifically to the Fc end of different humanized monoclonal antibodies potently neutralize primary isolates (both R5-tropic and X4-tropic), as well as T-cell-adapted strains of HIV-1 in vitro. All three prototypes show EC(50) values in the subnanomolar range, which are 10- to 100-fold lower than enfuvirtide and attainable whether or not the constitutive antibody targets HIV-1. The potential of such conjugates to purge latently infected cells was also demonstrated in a cell-to-cell viral inhibition assay by measuring their efficacy to inhibit the spread of HIV-1(LAI) from infected human peripheral blood mononuclear cells to Jurkat T cells over a period of 30 days following viral activation with 100 nM SAHA (suberoylanilide hydroxamic acid). The IgG-like half-life was not significantly different from that of the parental antibody, as shown by the mean serum concentration of one prototype in mice at 72 h. These encouraging results provide a rationale to develop further novel anti-HIV agents by coupling additional antibodies of interest with alternative HIV-inhibitors via recombinantly-produced, self-assembling, modules.


Oxidative stress index may play a key role in patients with pemphigus vulgaris.
Increased reactive oxygen species (ROS) and lipid peroxidation are seen in many dermatologic disorders, including atopic dermatitis, psoriasis, vitiligo, acne vulgaris, pemphigus vulgaris (PV), lichen planus and alopecia areata. In PV, the increased production of ROS from activated neutrophils reduces the concentrations of antioxidant vitamins and enzymes. The present study aims to determine the oxidative stress index (OSI) by studying serum total oxidant capacity (TOC), lipid hydroperoxide (LOOH) and total antioxidant capacity (TAC) in PV patients. The study included 27 PV patients and a control group consisting of 24 healthy volunteers. Serum TOC, LOOH and TAC levels were examined and OSI was measured in the PV patients and the control group. TOC (P = 0.001) and LOOH (P = 0.001) levels as well as OSI (P = 0.001) were found higher in the PV patients, relative to the control group. Serum TAS (P = 0.221) did not differ between groups. Serum TOC, LOOH and TAC levels and OSI in PV patients with mucosal involvement were not different than those in mucocutaneous PV patients. Serum TOC and LOOH levels and OSI were higher in the PV patients, in comparison with the control group. Serum TAC level was not different.


Stress, burnout, depression and work satisfaction among UK anaesthetic trainees: a qualitative analysis of in-depth participant interviews in the Satisfaction and Wellbeing in Anaesthetic Training study.
Anaesthetists experience unique stressors, and recent evidence suggests a high prevalence of stress and burnout in trainee anaesthetists. There has been no in-depth qualitative analysis to explore this further. We conducted semi-structured interviews to explore contributory and potentially protective factors in the development of perceived stress, burnout, depression and low work satisfaction. We sampled purposively among participants in the Satisfaction and Wellbeing in Anaesthetic Training study, reaching data saturation at 12 interviews. Thematic analysis identified three overarching themes: factors enabling work satisfaction; stressors of being an anaesthetic trainee; and suggestions for improving working conditions. Factors enabling work satisfaction were patient contact; the privilege of enabling good patient outcomes; and strong support at home and work. Stressors were demanding non-clinical work-loads; exhaustion from multiple commitments; a 'love/hate' relationship, as trainees value clinical work but find the training burden immense; feeling 'on edge', even unsafe at work; and the changing way society sees doctors. Nearly all trainees discussed feeling some levels of burnout (which were high and distressing for some) and also high levels of perceived stress. However, trainees also experienced distinct elements of work satisfaction and support. Suggested recommendations for improvement included: allowing contracted hours for non-clinical work; individuals taking responsibility for self-care in and out of work; cultural acceptance that doctors can struggle; and embedding wellbeing support more deeply in organisations and the specialty. Our study provides a foundation for further work to inform organisational and cultural changes, to help translate anaesthetic trainees' passion for their work into a manageable and satisfactory career.


Liver fibrosis progression at autopsy in injecting drug users infected by hepatitis C: a longitudinal long-term cohort study.
There is a paucity of unbiased data on the natural history of hepatitis C virus (HCV) infection in injecting drug users (IDUs). The purpose of this study was to assess the risk of developing advanced fibrosis associated with chronic hepatitis C (CHC) infection among injecting drug users (IDUs) who underwent an autopsy. A longitudinal cohort design was applied, in which the stage of liver fibrosis in anti-HCV positive IDUs with or without chronic HCV infection was assessed in liver tissue from autopsies performed up to 35 years after HCV exposure. The cohort originated from 864 IDUs consecutively admitted for drug abuse treatment 1970-1984. Stored sera, mostly drawn at the time of admission for drug treatment, were available in 635 subjects. 220 out of 523 anti-HCV positive subjects had died before 2009. Liver tissue from autopsies was available from 102/220 subjects, of which 61 were HCV RNA positive. Liver sections were classified according to METAVIR scores for fibrosis. Two pathologists, both blinded for serologic results, scored sections of liver tissue. Among HCV RNA positive subjects 16.4% (10/61) had septal fibrosis (F3) or cirrhosis (F4) compared to 2.4% (1/41) among anti HCV positive/HCV RNA negative subjects (p=0.026). Of 18 HCV RNA positive subjects autopsied <15 years after HCV exposure none had F3 or F4. Among subjects autopsied >25 years after exposure 35% (6/17) had F3-F4. Among IDUs chronically infected by HCV, 1/3 developed septal fibrosis or cirrhosis 25 years or more after exposure.


Responses to a fourth dose of Haemophilus influenzae type B conjugate vaccine in early life.
To describe the immune response of preterm infants, with a reduced response to primary Haemophilus influenzae type B (Hib) immunisation, to a fourth dose of Hib conjugate vaccine given in early life. Prospective observational study. Five Wessex Neonatal Units. Infants born at < 32 weeks and immunised with three doses of combined acellular pertussis-Hib vaccine, with a Hib IgG geometric mean concentration (GMC) < 1.0 microg/ml after these primary immunisations. An additional fourth dose of Hib conjugate vaccine given before 1 year of age. Blood taken to assess Hib IgG concentration and avidity after immunisation. Hib IgG GMC and avidity index. Ninety six infants (mean gestational age at birth 29.1 weeks) received a fourth dose of Hib at a mean age of 7.8 months. Hib IgG GMC after the primary immunisations was 0.17 microg/ml (95% confidence interval (CI) 0.14 to 0.20) rising to 4.68 microg/ml (95% CI 3.36 to 6.57) after the fourth dose (p < 0.0001). The IgG response to the fourth dose correlated positively with the response after the primary immunisations (p < 0.001). Hib IgG geometric mean avidity index (GMAI) after the primary immunisations was 30.87 (95% CI 20.40 to 46.73). This increased to 124.73 (95% CI 109.93 to 141.51) after the fourth dose (p < 0.0001). Preterm infants with very low IgG responses to Hib after primary immunisations with a combined acellular pertussis-Hib vaccine mount a good response to a fourth dose of Hib. This study suggests that all infants will benefit from a fourth dose of Hib, regardless of the age at which it is given.


The molecular biology of memory storage: a dialogue between genes and synapses.
One of the most remarkable aspects of an animal's behavior is the ability to modify that behavior by learning, an ability that reaches its highest form in human beings. For me, learning and memory have proven to be endlessly fascinating mental processes because they address one of the fundamental features of human activity: our ability to acquire new ideas from experience and to retain these ideas over time in memory. Moreover, unlike other mental processes such as thought, language, and consciousness, learning seemed from the outset to be readily accessible to cellular and molecular analysis. I, therefore, have been curious to know: What changes in the brain when we learn? And, once something is learned, how is that information retained in the brain? I have tried to address these questions through a reductionist approach that would allow me to investigate elementary forms of learning and memory at a cellular molecular level-as specific molecular activities within identified nerve cells.


Fertility Awareness-Based Methods for Family Planning and as an Alternative to Hormonal Contraceptives for Therapeutic Reasons.
In current medical practice, many women are prescribed hormonal contraceptives as a method of family planning. Over the years, medical professionals have prescribed hormonal contraceptives to manage numerous health conditions in addition to family planning purposes. A particular question arises in regard to women taking hormonal contraceptives for therapeutic reasons if the drug has a contraceptive effect and abortifacient properties. An important consideration is a definite lack of knowledge among medical professionals and patients about alternatives to hormonal contraceptives. To most lay people and medical professionals, fertility awareness-based methods equate to the outdated calendar rhythm method and therefore tend to be regarded as mostly a matter of chance so that they would have no benefit in helping manage gynecological conditions. In this paper, one will be able to see that modern fertility awareness-based methods are effective as a method of family planning and that there are medical applications that offer an excellent alternative in the treatment of various gynecological conditions, including infertility.


Does Antithrombotic Drug Use Mandate Trauma Team Activation in Awake Geriatric Patients with Intracranial Hemorrhage?
Antithrombotic (anticoagulant [AC] and antiplatelet [AP]) drugs have been associated with mortality in geriatric patients with intracranial hemorrhage (ICH). It is unclear whether trauma team activation (TTA) in this cohort impacts outcome. Patients ≥65 years with a Glasgow Coma Scale of ≥13 and ICH over four years were included and were divided into three groups according to type of drug: group 1, AC with or without AP; group 2, AP only and; group 3, no AC or AP. The Rotterdam score was used to characterize the severity of CT findings. The primary outcome was inhospital mortality or transition to comfort measures. The secondary outcome was need for neurosurgical intervention within 48 hours. Logistic regression analysis was performed to evaluate for predictors of each outcome. Of 419 patients, 20.5, 50.4, and 29.1 per cent belonged to groups 1, 2, and 3, respectively, with TTA occurring in 39.5, 18.0, and 32.0 per cent of the respective groups. Within each group, there were no differences for the primary and secondary outcomes whether or not TTA was triggered. TTA patients had shorter times to CT (median, 20 minutes versus 80 minutes, P < 0.0001) and to administration of reversal agents (median, 105 minutes versus 255 minutes, P < 0.0001). Age, head-Abbreviated Injury Score, and the Rotterdam score were predictors for both outcomes by multivariable analysis, whereas antithrombotic drug use and TTA were not. In awake elderly patients on antithrombotic drugs found to have ICH, TTA expedited evaluation and treatment but was not associated with mortality benefit.


A microwave imaging-based technique to localize an in-body RF source for biomedical applications.
In some biomedical applications such as wireless capsule endoscopy, the localization of an in-body radio-frequency (RF) source is important for the positioning of any abnormality inside the gastrointestinal tract. With knowledge of the location, therapeutic operations can be performed precisely at the position of the abnormality. Electrical properties (relative permittivity and conductivity) of the tissues and their distribution are utilized to estimate the position. This paper presents a method for the localization of an in-body RF source based on microwave imaging. The electrical properties of the tissues and their distribution at 403.5 MHz are found from microwave imaging and the position of an RF source is then estimated based on the image. The method is applied on synthetic noisy data, obtained after the addition of white Gaussian noise to simulated data of a simple circular phantom, and a realistic phantom in a 2-D case. The root-mean-square of the error distance between the actual and the estimated position is found to be within 10 and 4 mm for the circular and the realistic phantom, respectively, showing the capability of the proposed algorithm to work with a good accuracy even in the presence of noise for the localization of the in-body RF source.


EI competencies as a related but different characteristic than intelligence.
Amid the swarm of debate about emotional intelligence (EI) among academics are claims that cognitive intelligence, or general mental ability (g), is a stronger predictor of life and work outcomes as well as the counter claims that EI is their strongest predictor. Nested within the tempest in a teapot are scientific questions as to what the relationship is between g and EI. Using a behavioral approach to EI, we examined the relationship of a parametric measure of g as the person's GMAT scores and collected observations from others who live and work with the person as to the frequency of his or her EI behavior, as well as the person's self-assessment. The results show that EI, as seen by others, is slightly related to g, especially for males with assessment from professional relations. Further, we found that cognitive competencies are more strongly related to GMAT than EI competencies. For observations from personal relationships or self-assessment, there is no relationship between EI and GMAT. Observations from professional relations reveal a positive relationship between cognitive competencies and GMAT and EI and GMAT for males, but a negative relationship between EI and GMAT for females.


Tissue-specific transcriptomic changes associated with AmBisome® treatment of BALB/c mice with experimental visceral leishmaniasis.
Background: Liposomal amphotericin B (AmBisome®) as a treatment modality for visceral leishmaniasis (VL) has had significant impact on patient care in some but not all regions where VL is endemic. As the mode of action of AmBisome® in vivo is poorly understood, we compared the tissue-specific transcriptome in drug-treated vs untreated mice with experimental VL. Methods: BALB/c mice infected with L. donovani were treated with 8mg/kg AmBisome®, resulting in parasite elimination from liver and spleen over a 7-day period. At day 1 and day 7 post treatment (R x+1 and R x+7), transcriptomic profiling was performed on spleen and liver tissue from treated and untreated mice and uninfected mice. BALB/c mice infected with M. bovis BCG (an organism resistant to amphotericin B) were analysed to distinguish between direct effects of AmBisome® and those secondary to parasite death. Results: AmBisome® treatment lead to rapid parasitological clearance. At R x+1, spleen and liver displayed only 46 and 88 differentially expressed (DE) genes (P<0.05; 2-fold change) respectively. In liver, significant enrichment was seen for pathways associated with TNF, fatty acids and sterol biosynthesis. At R x+7, the number of DE genes was increased (spleen, 113; liver 400). In spleen, these included many immune related genes known to be involved in anti-leishmanial immunity. In liver, changes in transcriptome were largely accounted for by loss of granulomas. PCA analysis indicated that treatment only partially restored homeostasis. Analysis of BCG-infected mice treated with AmBisome® revealed a pattern of immune modulation mainly targeting macrophage function. Conclusions: Our data indicate that the tissue response to AmBisome® treatment varies between target organs and that full restoration of homeostasis is not achieved at parasitological cure. The pathways required to restore homeostasis deserve fuller attention, to understand mechanisms associated with treatment failure and relapse and to promote more rapid restoration of immune competence.


Evolution of cytokine production capacity in ancient and modern European populations.
As our ancestors migrated throughout different continents, natural selection increased the presence of alleles advantageous in the new environments. Heritable variations that alter the susceptibility to diseases vary with the historical period, the virulence of the infections, and their geographical spread. In this study we built polygenic scores for heritable traits that influence the genetic adaptation in the production of cytokines and immune-mediated disorders, including infectious, inflammatory, and autoimmune diseases, and applied them to the genomes of several ancient European populations. We observed that the advent of the Neolithic was a turning point for immune-mediated traits in Europeans, favoring those alleles linked with the development of tolerance against intracellular pathogens and promoting inflammatory responses against extracellular microbes. These evolutionary patterns are also associated with an increased presence of traits related to inflammatory and auto-immune diseases.


Regional slow waves and spindles in human sleep.
The most prominent EEG events in sleep are slow waves, reflecting a slow (<1 Hz) oscillation between up and down states in cortical neurons. It is unknown whether slow oscillations are synchronous across the majority or the minority of brain regions--are they a global or local phenomenon? To examine this, we recorded simultaneously scalp EEG, intracerebral EEG, and unit firing in multiple brain regions of neurosurgical patients. We find that most sleep slow waves and the underlying active and inactive neuronal states occur locally. Thus, especially in late sleep, some regions can be active while others are silent. We also find that slow waves can propagate, usually from medial prefrontal cortex to the medial temporal lobe and hippocampus. Sleep spindles, the other hallmark of NREM sleep EEG, are likewise predominantly local. Thus, intracerebral communication during sleep is constrained because slow and spindle oscillations often occur out-of-phase in different brain regions.


Expression and secretion of the novel adipokine tartrate-resistant acid phosphatase from adipose tissues of obese and lean women.
Tartrate-resistant acid phosphatase (TRAP) expressed by adipose tissue macrophages (ATMs) induces mice obesity and human adipocyte differentiation in vitro. This study aimed to investigate whether TRAP was secreted differently from human obese versus lean adipose tissues and to identify the cellular source of adipose tissue TRAP. Subcutaneous adipose tissues obtained from healthy subjects. Enzyme-linked immunosorbent assays (ELISAs) for total (5a+5b) and cleaved TRAP (5b) were used. TRAP secretion was determined in adipose tissue biopsies, and mRNA expression was studied in cell types isolated from the same. Results of 24 lean and 24 obese women (in vitro) and 8 subjects (in vivo) were compared. The main outcome measurements were TRAP expression and secretion in vitro and in vivo. In-house total TRAP ELISA showed high sensitivity and a coefficient of variance of 11%. Adipose secretion of total TRAP was linear in vitro with time and was evident in vivo. Total TRAP secretion in vitro was similar in lean and obese women expressed per unit weight of the adipose tissue but correlated positively with the number/size of adipocytes (P ≤ 0.01) and with adipose secretion of tumor necrosis factor-α and interleukin-6 (P<0.01). TRAP 5b was not secreted from the adipose tissue. ATMs displayed highest cellular expression of TRAP mRNA in adipose tissue cells derived from lean or obese women. TRAP is a novel human adipokine produced by macrophages and secreted from the subcutaneous adipose tissue in vivo and in vitro. Secretion is linked to the size and number of adipocytes, as well as to concomitant secretion of inflammatory mediators, suggesting that TRAP is involved in fat accumulation and adipose inflammation.


Activation-Induced Killer Cell Immunoglobulin-like Receptor 3DL2 Binding to HLA-B27 Licenses Pathogenic T Cell Differentiation in Spondyloarthritis.
In the spondyloarthritides (SpA), increased numbers of CD4+ T cells express killer cell immunoglobulin-like receptor 3DL2 (KIR-3DL2). The aim of this study was to determine the factors that induce KIR-3DL2 expression, and to characterize the relationship between HLA-B27 and the phenotype and function of KIR-3DL2-expressing CD4+ T cells in SpA. In total, 34 B27+ patients with SpA, 28 age- and sex-matched healthy controls (20 B27- and 8 B27+), and 9 patients with rheumatoid arthritis were studied. KIR-3DL2 expression and other phenotypic characteristics of peripheral blood and synovial fluid CD4+ T cells were studied by flow cytometry, quantitative polymerase chain reaction, and Western blotting. T cell receptor clonality was determined by template-switch anchored reverse transcription-polymerase chain reaction and sequencing analysis. Cytokines were measured by enzyme-linked immunosorbent assay. Cellular activation induced KIR-3DL2 expression on both naive and effector CD4+ T cells. KIR-3DL2 binding to B27+ cells promoted expression of KIR-3DL2, the Th17-specific transcription factor retinoic acid receptor-related orphan nuclear receptor γt, and the antiapoptotic factor B cell lymphoma 2. KIR-3DL2+CD4+ T cells in patients with ankylosing spondylitis were oligoclonal and enriched for markers of T cell activation and for the gut homing receptor CCR9. In the presence of B27+ antigen-presenting cells, KIR-3DL2+CD4+ T cells produced less interleukin-2 (IL-2) but more IL-17. This effect was blocked by HC10, an antibody that inhibits the binding of KIR-3DL2 to B27 heavy chains. KIR-3DL2 binding to HLA-B27 licenses Th17 cell differentiation in SpA. These findings raise the therapeutic potential of targeting HLA-B27-KIR-3DL2 interactions for the treatment of B27+ patients with SpA.


The Influence of Rearing on Behavior, Brain Monoamines, and Gene Expression in Three-Spined Sticklebacks.
The causes of individual variation in behavior are often not well understood, and potential underlying mechanisms include both intrinsic and extrinsic factors, such as early environmental, physiological, and genetic differences. In an exploratory laboratory study, we raised three-spined sticklebacks (Gasterosteus aculeatus) under 4 different environmental conditions (simulated predator environment, complex environment, variable social environment, and control). We investigated how these manipulations related to behavior, brain physiology, and gene expression later in life, with focus on brain dopamine and serotonin levels, turnover rates, and gene expression. The different rearing environments influenced behavior and gene expression, but did not alter monoamine levels or metabolites. Specifically, compared to control fish, fish exposed to a simulated predator environment tended to be less aggressive, more exploratory, and more neophobic; and fish raised in both complex and variable social environments tended to be less neophobic. Exposure to a simulated predator environment tended to lower expression of dopamine receptor DRD4A, a complex environment increased expression of dopamine receptor DRD1B, while a variable social environment tended to increase serotonin receptor 5-HTR2B and serotonin transporter SLC6A4A expression. Despite both behavior and gene expression varying with early environment, there was no evidence that gene expression mediated the relationship between early environment and behavior. Our results confirm that environmental conditions early in life can affect phenotypic variation. However, the mechanistic pathway of the monoaminergic systems translating early environmental variation into observed behavioral responses was not detected.


Lead users' ideas on core features to support physical activity in rheumatoid arthritis: a first step in the development of an internet service using participatory design.
Despite the growing evidence of the benefits of physical activity (PA) in individuals with rheumatoid arthritis (RA), the majority is not physically active enough. An innovative strategy is to engage lead users in the development of PA interventions provided over the internet. The aim was to explore lead users' ideas and prioritization of core features in a future internet service targeting adoption and maintenance of healthy PA in people with RA. Six focus group interviews were performed with a purposively selected sample of 26 individuals with RA. Data were analyzed with qualitative content analysis and quantification of participants' prioritization of most important content. Six categories were identified as core features for a future internet service: up-to-date and evidence-based information and instructions, self-regulation tools, social interaction, personalized set-up, attractive design and content, and access to the internet service. The categories represented four themes, or core aspects, important to consider in the design of the future service: (1) content, (2) customized options, (3) user interface and (4) access and implementation. This is, to the best of our knowledge, the first study involving people with RA in the development of an internet service to support the adoption and maintenance of PA.Participants helped identifying core features and aspects important to consider and further explore during the next phase of development. We hypothesize that involvement of lead users will make transfer from theory to service more adequate and user-friendly and therefore will be an effective mean to facilitate PA behavior change.


The health of prisoners.
More than 10 million people are incarcerated worldwide; this number has increased by about a million in the past decade. Mental disorders and infectious diseases are more common in prisoners than in the general population. High rates of suicide within prison and increased mortality from all causes on release have been documented in many countries. The contribution of prisons to illness is unknown, although shortcomings in treatment and aftercare provision contribute to adverse outcomes. Research has highlighted that women, prisoners aged 55 years and older, and juveniles present with higher rates of many disorders than do other prisoners. The contribution of initiatives to improve the health of prisoners by reducing the burden of infectious and chronic diseases, suicide, other causes of premature mortality and violence, and counteracting the cycle of reoffending should be further examined.


Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia.
Nonalcoholic fatty liver disease (NAFLD) spectrum disorders affect approximately 1 billion individuals worldwide. However, the drivers of progressive steatohepatitis remain incompletely defined. Ketogenesis can dispose of much of the fat that enters the liver, and dysfunction in this pathway could promote the development of NAFLD. Here, we evaluated mice lacking mitochondrial 3-hydroxymethylglutaryl CoA synthase (HMGCS2) to determine the role of ketogenesis in preventing diet-induced steatohepatitis. Antisense oligonucleotide-induced loss of HMGCS2 in chow-fed adult mice caused mild hyperglycemia, increased hepatic gluconeogenesis from pyruvate, and augmented production of hundreds of hepatic metabolites, a suite of which indicated activation of the de novo lipogenesis pathway. High-fat diet feeding of mice with insufficient ketogenesis resulted in extensive hepatocyte injury and inflammation, decreased glycemia, deranged hepatic TCA cycle intermediate concentrations, and impaired hepatic gluconeogenesis due to sequestration of free coenzyme A (CoASH). Supplementation of the CoASH precursors pantothenic acid and cysteine normalized TCA intermediates and gluconeogenesis in the livers of ketogenesis-insufficient animals. Together, these findings indicate that ketogenesis is a critical regulator of hepatic acyl-CoA metabolism, glucose metabolism, and TCA cycle function in the absorptive state and suggest that ketogenesis may modulate fatty liver disease.


Synergetic estrogen receptor-targeting liposome nanocarriers with anti-phagocytic properties for enhanced tumor theranostics.
Multifunctional nanocarriers have been widely applied due to their enhanced effect on tumor therapeutics. Nevertheless, owing to the natural immune clearance mechanisms in living bodies, nanocarriers tend to be eliminated during blood circulation, thereby impeding their effective arrival at the tumor sites. Herein, we constructed a synergetic targeted liposome nanocarrier system named SELS functionalized with both a tumor identification ligand (anti-ER (Estrogen Receptor) antibody) and an immune targeting ligand (Self-Peptide (SP)). The anti-ER antibody could recognize and bind ER-positive breast cancer tissues in a specific way. SP could activate the CD47-SIRPα immune response, which reduced phagocytosis of the nanoparticles by macrophages. Both the enhanced targeting ability and anti-phagocytosis behavior could improve the tumor uptake of the nanocarriers and prevent their immune clearance in living systems. Therefore, drug-loaded SELS enabled improved tumor imaging and therapeutic performance in living systems.


Control, uncertainty, and expectations for the future: a qualitative study of the impact of drought on a rural Australian community.
Many rural Australian communities continue to endure a prolonged drought. The mental health effects of short-term natural disaster are well known; those of a long-term and chronic natural disaster such as drought are less well understood. However, in addition to immediate distress there are likely to be feelings of loss, grief and hopelessness, all of which are implicated in an increased risk of subsequent psychiatric morbidity. Furthermore, rural Australia is at a relative disadvantage for early and effective mental health intervention due to a lack of resources, compared with urban Australia. This qualitative research investigates the experience of drought in two farming communities in the state of New South Wales. Farmers, farm and non-farm businesspeople, and health workers took part in focus group discussions of the effects of drought on themselves, their families and their community. In addition to current distress related to financial and workload problems, people reported experiencing significant distress from the emotional impact of environmental degradation, from loss of hope for the future of their community, and from feelings of being misunderstood by the wider Australian community. The stressors affecting farming communities during times of drought are likely to be associated with increased risk of mental health problems.


Smartphone-Based Cardiac Rehabilitation Program: Feasibility Study.
We introduce a cardiac rehabilitation program (CRP) that utilizes only a smartphone, with no external devices. As an efficient guide for cardiac rehabilitation exercise, we developed an application to automatically indicate the exercise intensity by comparing the estimated heart rate (HR) with the target heart rate zone (THZ). The HR is estimated using video images of a fingertip taken by the smartphone's built-in camera. The introduced CRP app includes pre-exercise, exercise with intensity guidance, and post-exercise. In the pre-exercise period, information such as THZ, exercise type, exercise stage order, and duration of each stage are set up. In the exercise with intensity guidance, the app estimates HR from the pulse obtained using the smartphone's built-in camera and compares the estimated HR with the THZ. Based on this comparison, the app adjusts the exercise intensity to shift the patient's HR to the THZ during exercise. In the post-exercise period, the app manages the ratio of the estimated HR to the THZ and provides a questionnaire on factors such as chest pain, shortness of breath, and leg pain during exercise, as objective and subjective evaluation indicators. As a key issue, HR estimation upon signal corruption due to motion artifacts is also considered. Through the smartphone-based CRP, we estimated the HR accuracy as mean absolute error and root mean squared error of 6.16 and 4.30bpm, respectively, with signal corruption due to motion artifacts being detected by combining the turning point ratio and kurtosis.


Laminar Differences in Responses to Naturalistic Texture in Macaque V1 and V2.
Most single units recorded from macaque secondary visual cortex (V2) respond with higher firing rates to synthetic texture images containing "naturalistic" higher-order statistics than to spectrally matched "noise" images lacking these statistics. In contrast, few single units in V1 show this property. We explored how the strength and dynamics of response vary across the different layers of visual cortex by recording multiunit (defined as high-frequency power in the local field potential) and gamma-band activity evoked by brief presentations of naturalistic and noise images in V1 and V2 of anesthetized macaque monkeys of both sexes. As previously reported, recordings in V2 showed consistently stronger responses to naturalistic texture than to spectrally matched noise. In contrast to single-unit recordings, V1 multiunit activity showed a preference for images with naturalistic statistics, and in gamma-band activity this preference was comparable across V1 and V2. Sensitivity to naturalistic image structure was strongest in the supragranular and infragranular layers of V1, but weak in granular layers, suggesting that it might reflect feedback from V2. Response timing was consistent with this idea. Visual responses appeared first in V1, followed by V2. Sensitivity to naturalistic texture emerged first in V2, followed by the supragranular and infragranular layers of V1, and finally in the granular layers of V1. Our results demonstrate laminar differences in the encoding of higher-order statistics of natural texture, and suggest that this sensitivity first arises in V2 and is fed back to modulate activity in V1.SIGNIFICANCE STATEMENT The circuit mechanisms responsible for visual representations of intermediate complexity are largely unknown. We used a well validated set of synthetic texture stimuli to probe the temporal and laminar profile of sensitivity to the higher-order statistical structure of natural images. We found that this sensitivity emerges first and most strongly in V2 but soon after in V1. However, sensitivity in V1 is higher in the laminae (extragranular) and recording modalities (local field potential) most likely affected by V2 connections, suggesting a feedback origin. Our results show how sensitivity to naturalistic image structure emerges across time and circuitry in the early visual cortex.


Prevalence and predictors of water pipe and cigarette smoking among secondary school students in London.
Water pipe tobacco smoking appears to be an increasing public health concern, with anecdotal reports of higher prevalence than cigarette smoking among young people in some high-income countries. We examined the prevalence and predictors of water pipe and cigarette smoking among students attending secondary schools in a deprived, ethnically diverse part of inner London. We conducted a 96-item, validated smoking habits questionnaire with 2,399 students from Years 8, 10, and 12/13 from 15 secondary schools in Brent, northwest London. Multilevel logistic regression models were used to examine predictors of current and ever cigarette and water pipe smoking. Current water pipe smoking prevalence was more than double that of cigarette smoking prevalence (7.6% vs. 3.4%, p < .001). One in 4 students had tried water pipe compared with 1 in 6 who had tried cigarette smoking (24.0% vs. 15.8%, p < .001). Significant predictors of ever water pipe use include being in a higher age group, South Asian or Middle Eastern ethnicity, and personal, family, or friends tobacco use. Significant predictors of ever cigarette use include being in a higher age group, White ethnicity, and personal, family, or friends tobacco use. Students attending schools with more water pipe cafes within 0.5 miles were more likely to be current water pipe users (AOR = 2.43, 95% CI = 1.33-4.42). Water pipe smoking may be more prevalent than cigarette smoking among young people in some high-income countries. Improved surveillance and dedicated tobacco control interventions are required to better understand the epidemiology of water pipe use and address its growing use.


Ene cyclization reaction in heterocycle synthesis.
The ene cyclization has evolved to become an indispensable tool for the synthesis of various ring size heterocyclic compounds. In the past and recent years, many exciting reports have demonstrated the broad scope and synthetic utility of ene cyclization and the versatility of oxonium ion, iminium ion and thionium ion intermediates. Moreover, the ease of regio- and stereoselectivity of ene cyclization has led to the development of new types of heterocyclic compounds. This article aims at reviewing the utilities of ene cyclization reactions for the synthesis of various ring sizes of oxygen, nitrogen and sulfur heterocycles. It also covers some applications in natural product synthesis. The mechanism of the reactions is discussed wherever necessary. The review article covers the time period from 1986 to 2017.


DNMT3B interacts with hSNF2H chromatin remodeling enzyme, HDACs 1 and 2, and components of the histone methylation system.
The non-random pattern of genome-wide DNA methylation in mammalian cells is established and maintained by DNA methyltransferases DNMT1, 3A, and 3B. De novo DNA methyltransferase DNMT3B is critical for embryonic development and is mutated in ICF syndrome. Despite its importance in normal cellular functioning, little is known about how DNMT3B operates in the context of chromatin. Here we demonstrate that DNMT3B associates with four chromatin-associated enzymatic activities common to transcriptionally repressed, heterochromatic regions of the genome: DNA methyltransferase, histone deacetylase, ATPase, and histone methylase activities. By immunoprecipitation and GST pull-down, we show that DNMT3B interacts with HDAC1, HDAC2, HP1 proteins, Suv39h1, and the ATP-dependent chromatin remodeling enzyme hSNF2H. Endogenous hSNF2H is also associated with DNA methyltransferase activity. These proteins co-localize extensively with DNMT3B in heterochromatic regions. Our results therefore link DNMT3B to three other components of the epigenetic machinery and provide important insights into how DNA methylation patterns may be established within the chromatin environment.


Transcranial magnetic stimulation induces increases in extracellular levels of dopamine and glutamate in the nucleus accumbens.
Transcranial magnetic stimulation (TMS) is a non-invasive approach used for stimulating the human brain. Repetitive stimulation over the prefrontal cortex has proven effective in the treatment of major depression, however the mechanism of the antidepressant action is unknown. Since the nucleus accumbens is a major region implicated in reward circuitry and depressive disorders, we used the microdialysis technique to study some of the neurochemical changes induced in that region during and after acute TMS. Magnetic stimulation was applied over the frontal or the caudal cortex of the rat brain using a special coil design and microdialysis samples were collected before, during and after the stimulation session. The extracellular levels of both dopamine and glutamate in the nucleus accumbens were increased during the stimulation while the extracellular levels of acetylcholine were not affected. Stimulation over the caudal cortex caused a greater increase in dopamine levels than the stimulation over the frontal cortex, while such difference was not observed for glutamate levels. The changes in dopamine and glutamate extracellular levels in the nucleus accumbens may play a role in the antidepressant effect of TMS and it is therefore suggested that the effect of stimulation over caudal cortical sites on depressive patients will be examined.


ActRIIB blockade increases force-generating capacity and preserves energy supply in exercising mdx mouse muscle in vivo.
Postnatal blockade of the activin type IIB receptor (ActRIIB) represents a promising therapeutic strategy for counteracting dystrophic muscle wasting. However, its impact on muscle function and bioenergetics remains poorly documented in physiologic conditions. We have investigated totally noninvasively the effect of 8-wk administration of either soluble ActRIIB signaling inhibitor (sActRIIB-Fc) or vehicle PBS (control) on gastrocnemius muscle force-generating capacity, energy metabolism, and anatomy in dystrophic mdx mice using magnetic resonance (MR) imaging and dynamic [31P]-MR spectroscopy ([31P]-MRS) in vivo ActRIIB inhibition increased muscle volume (+33%) without changing fiber-type distribution, and increased basal animal oxygen consumption (+22%) and energy expenditure (+23%). During an in vivo standardized fatiguing exercise, maximum and total absolute contractile forces were larger (+40 and 24%, respectively) in sActRIIB-Fc treated animals, whereas specific force-generating capacity and fatigue resistance remained unaffected. Furthermore, sActRIIB-Fc administration did not alter metabolic fluxes, ATP homeostasis, or contractile efficiency during the fatiguing bout of exercise, although it dramatically reduced the intrinsic mitochondrial capacity for producing ATP. Overall, sActRIIB-Fc treatment increased muscle mass and strength without altering the fundamental weakness characteristic of dystrophic mdx muscle. These data support the clinical interest of ActRIIB blockade for reversing dystrophic muscle wasting.-Béchir, N., Pecchi, E., Vilmen, C., Le Fur, Y., Amthor, H., Bernard, M., Bendahan, D., Giannesini, B. ActRIIB blockade increases force-generating capacity and preserves energy supply in exercising mdx mouse muscle in vivo.


Online Patient Education for Chronic Disease Management: Consumer Perspectives.
Patient education plays an important role in chronic disease management. The aim of this study is to identify patients' preferences in regard to the design features of effective online patient education (OPE) and the benefits. A review of the existing literature was conducted in order to identify the benefits of OPE and its essential design features. These design features were empirically tested by conducting survey with patients and caregivers. Reliability analysis, construct validity and regression analysis were performed for data analysis. The results identified patient-tailored information, interactivity, content credibility, clear presentation of content, use of multimedia and interpretability as the essential design features of online patient education websites for chronic disease management.


Relationship between granular cytoplasm of oocytes and pregnancy outcome following intracytoplasmic sperm injection.
Couples undergoing intracytoplasmic sperm injection (ICSI) for male infertility using oocytes with centrally located granular cytoplasm (CLCG) were evaluated for fertilization, embryo development, implantation and pregnancy rate. CLCG is a rare morphological feature of the oocyte, that is diagnosed as a larger, dark, spongy granular area in the cytoplasm. Severity is based on both the diameter of granular area and the depth of the lesion. Twenty-seven couples with 39 cycles presenting CLCG in >50% of retrieved oocytes were evaluated. A total of 489 oocytes was retrieved, out of which 392 were at MII. CLCG was observed in 258 of the MII oocytes (65. 8%); 66.7% of these oocytes had slight and 33.3% had severe CLCG. The overall fertilization rate was 72.2% and no statistical significant difference was found between normal and CLCG oocytes and between the oocytes representing slight and severe CLCG. The development and quality of embryos was the same in normal and CLCG oocytes. In nine cycles, preimplantation genetic diagnosis was executed to evaluate a possible accompanying chromosomal abnormality. Out of 44 blastomeres biopsied, 23 had chromosomal abnormality (52. 3%). Eleven pregnancies were achieved in 39 cycles (28.2%), six pregnancies resulted in abortion (54.5%). The implantation rate was found to be 4.2%. Only five ongoing pregnancies were achieved in 39 cycles (12.8%). Couples with CLCG oocytes should be informed about poor on-going pregnancy rates even if fertilization, embryo quality and total pregnancy rates are normal. Furthermore, a high aneuploidy rate may be linked to a high abortion rate.


Cancers with increasing incidence trends in the United States: 1999 through 2008.
Despite declines in incidence rates for the most common cancers, the incidence of several cancers has increased in the past decade, including cancers of the pancreas, liver, thyroid, and kidney and melanoma of the skin, as well as esophageal adenocarcinoma and certain subsites of oropharyngeal cancer associated with human papillomavirus (HPV) infection. Population-based incidence data compiled by the North American Association of Central Cancer Registries were used to examine trends in incidence rates from 1999 through 2008 for the 7 cancers listed by sex, age group, race/ethnicity, and stage at diagnosis. Joinpoint regression was used to calculate average annual percent changes in incidence rates (1999-2008). Rates for HPV-related oropharyngeal cancer, esophageal adenocarcinoma, cancer of the pancreas, and melanoma of the skin increased only in whites, except for esophageal adenocarcinoma, which also increased in Hispanic men. Liver cancer rates increased in white, black, and Hispanic men and in black women only. In contrast, incidence rates for thyroid and kidney cancers increased in all racial/ethnic groups, except American Indian/Alaska Native men. Increases in incidence rates by age were steepest for liver and HPV-related oropharyngeal cancers among those aged 55 [corrected] to 64 years and for melanoma of the skin in those aged 65 years and older. Notably, for HPV-related oropharyngeal cancer in men and thyroid cancer in women, incidence rates were higher in those aged 55 to 64 years than in those aged 65 years and older. Rates increased for both local and advanced stage diseases for most cancer sites. The reasons for these increasing trends are not entirely known. Part of the increase (for esophageal adenocarcinoma and cancers of the pancreas, liver, and kidney) may be linked to the increasing prevalence of obesity as well as increases in early detection practices for some cancers. These rising trends will exacerbate the growing cancer burden associated with population expansion and aging. Additional research is needed to determine the underlying reasons for these increasing trends.


Population genetic diversity of the NAT2 gene supports a role of acetylation in human adaptation to farming in Central Asia.
The arylamine N-acetyltransferase 2 (NAT2) enzyme detoxifies a wide spectrum of naturally occurring xenobiotics including carcinogens and drugs. Variation at the NAT2 gene has been linked to the human acetylation capacity, either 'slow' or 'fast', which modifies susceptibility to cancer and adverse drug reactions. We investigated the possible influence of natural selection in shaping the acetylation phenotype and the NAT2 gene variability in six Central Asian populations, who are either long-term sedentary agriculturalists (two Tajik populations), recent sedentary agriculturalists (Kazakhs, Uzbeks) or nomad pastoralists (two Kirghiz populations). To this end, we sequenced the entire NAT2 coding exon, as well as genotyping nine intergenic SNPs covering a 200-kb region. Our results revealed that the two Tajik populations exhibited significantly higher proportions of slow acetylators than the nomadic populations. In addition, sequence-based neutrality tests yielded significantly positive values in Central Asian populations following an agriculturalist lifestyle, due to an excess of haplotypes at intermediate frequencies. Taken together, our data suggest that balancing selection, and/or directional selection on standing low-frequency alleles, have shaped NAT2 genetic diversity and the human acetylation phenotype in Central Asian agriculturalists. These results further support the hypothesis that a major transition in human lifestyle, such as the emergence of farming has dramatically changed human chemical environments and the selective pressures they imposed.


Feasibility and safety of regional myocardial hypothermia during myocardial ischemia and infarction in pigs.
Mild systemic hypothermia has been shown to be feasible and safe in patients during acute myocardial infarction (AMI). Regional myocardial hypothermia of the ischemic myocardium only may be more effective in myocardial salvage with fewer side effects compared with systemic hypothermia. The purpose of this study was to evaluate the feasibility and safety of regional myocardial hypothermia in pigs. Open-chest pigs with (n=5) or without (n=4) myocardial infarction underwent left anterior descending coronary artery (LAD) ligation followed by intracoronary infusion of lactated Ringer's solution (at room temperature and at 15 degrees C between 20-35 ml/min for 3 min) via the central lumen of a specially designed balloon catheter at the time of reperfusion. Intramyocardial temperatures via thermocouples at the ischemic zone (LAD territory) and non-ischemic zone (circumflex territory) as well as systemic temperature were constantly recorded, as were the hemodynamics. Each pig acted as its control regarding the myocardial temperature response to both solutions. In addition, intracoronary versus intramyocardial temperatures were compared with thermocouples in both territories during infusion. There was no hemodynamic compromise or arrhythmia seen during the intracoronary infusion of either temperature solution. There was a linear relationship between the infusion solution temperature and infusion rate versus intramyocardial temperature response, with the cooled solution providing 2 degrees C lower temperature and faster infusion resulting in lower intramyocardial temperature. There was no change in the non-ischemic zone or systemic temperature. On average, 6-8 degrees C reduction in tissue temperature, potential target temperature range for hypothermic therapy, was achieved in all animals. In addition, intracoronary temperature in distal LAD measured by intracoronary thermocouples correlated with the intramyocardial temperature (2 degrees C lower temperature in the coronary artery). It is feasible and safe to achieve regional myocardial hypothermia by intracoronary infusion of cooled solution in pigs.


Bench-Top Fabrication of Single-Molecule Nanoarrays by DNA Origami Placement.
Large-scale nanoarrays of single biomolecules enable high-throughput assays while unmasking the underlying heterogeneity within ensemble populations. Until recently, creating such grids which combine the advantages of microarrays and single-molecule experiments (SMEs) has been particularly challenging due to the mismatch between the size of these molecules and the resolution of top-down fabrication techniques. DNA origami placement (DOP) combines two powerful techniques to address this issue: (i) DNA origami, which provides a ∼100 nm self-assembled template for single-molecule organization with 5 nm resolution and (ii) top-down lithography, which patterns these DNA nanostructures, transforming them into functional nanodevices via large-scale integration with arbitrary substrates. Presently, this technique relies on state-of-the-art infrastructure and highly trained personnel, making it prohibitively expensive for researchers. Here, we introduce a cleanroom-free, $1 benchtop technique to create meso-to-macro-scale DNA origami nanoarrays using self-assembled colloidal nanoparticles, thereby circumventing the need for top-down fabrication. We report a maximum yield of 74%, 2-fold higher than the statistical limit of 37% imposed on non-specific molecular loading alternatives. Furthermore, we provide a proof-of-principle for the ability of this nanoarray platform to transform traditionally low-throughput, stochastic, single-molecule assays into high-throughput, deterministic ones, without compromising data quality. Our approach has the potential to democratize single-molecule nanoarrays and demonstrates their utility as a tool for biophysical assays and diagnostics.


Influence of a veterinary curriculum on the approaches and study skills of veterinary medical students.
The objectives of the present study were to evaluate first-, second-, third-, and fourth-year veterinary medical students' approaches to studying and learning as well as the factors within the curriculum that may influence these approaches. A questionnaire consisting of the short version of the Approaches and Study Skills Inventory for Students (ASSIST) was completed by 405 students, and it included questions relating to conceptions about learning, approaches to studying, and preferences for different types of courses and teaching. Descriptive statistics, factor analysis, Cronbach's alpha analysis, and log-linear analysis were performed on the data. Deep, strategic, and surface learning approaches emerged. There were a few differences between our findings and those presented in previous studies in terms of the correlation of the subscale monitoring effectiveness, which showed loading with both the deep and strategic learning approaches. In addition, the subscale alertness to assessment demands showed correlation with the surface learning approach. The perception of high workloads, the use of previous test files as a method for studying, and examinations that are based only on material provided in lecture notes were positively associated with the surface learning approach. Focusing on improving specific teaching and assessment methods that enhance deep learning is anticipated to enhance students' positive learning experience. These teaching methods include instructors who encourage students to be critical thinkers, the integration of course material in other disciplines, courses that encourage thinking and reading about the learning material, and books and articles that challenge students while providing explanations beyond lecture material.


Mutator phenotype of BCR--ABL transfected Ba/F3 cell lines and its association with enhanced expression of DNA polymerase beta.
Chronic myelogenous leukemia (CML) is characterized by the Philadelphia chromosome resulting from the translocation t(9-22) producing the chimeric 190 and 210 kDa BCR-ABL fusion proteins. Evolution of the CML to the more agressive acute myelogenous leukemia (AML) is accompanied by increased cellular proliferation and genomic instability at the cytogenetic level. We hypothezised that genomic instability at the nucleotide level and spontaneous error in DNA replication may also contribute to the evolution of CML to AML. Murine Ba/F3 cell line was transfected with the p190 and p210-encoding BCR-ABL oncogenes, and spontaneous mutation frequency at the Na-K-ATPase and the hypoxanthine guanine phosphoribosyl transferase (HPRT) loci were measured. A significant 3-5-fold increase in mutation frequency for the transfected cells relative to the untransfected control cells was found. Furthermore, we observed that BCR-ABL transfection induced an overexpression of DNA polymerase beta, the most inaccurate of the mammalian DNA polymerases, as well as an increase in its activity, suggesting that inaccuracy of DNA replication may account for the observed mutator phenotype. These data suggest that the Philadelphia abnormality confers a mutator phenotype and may have implications for the potential role of DNA polymerase beta in this process.


Delivering bad news: an approach according to jewish scriptures.
Despite a preoccupation in the medical literature with developing an effective approach for breaking bad news, the sources are based on personal opinion alone and only in some instances on qualitative research. Recognizing the gravity of this topic coupled with respect for the wisdom of the written and oral Jewish scriptures, this work is an attempt to delve into the diverse ancient writings to draw conclusions regarding a recommended methodology to guide and inform this task. It is interesting to learn that most elements related to this topic have previously been raised in various forms in the scriptures. The issues range from where, when, and how the bearer of bad news should undertake this duty, to details such as the environment, the format, the speed, and depth of the details to be disclosed. The essence of this paper is to enrich the reader using both positive and negative examples found in the Jewish heritage. Adopting these principles will hopefully provide an effective method for performing this unpleasant obligation, with the goal of limiting harmful consequences as much as possible.


Ultrasound credentialing in North American emergency department systems with ultrasound fellowships: a cross-sectional survey.
To describe the credentialing systems of North American emergency department systems (EDS) with emergency ultrasound (EUS) fellowship programmes. This is a prospective, cross-sectional, survey-based study of North American EUS fellowships using a 62-item, pilot-tested, web-based survey instrument assessing credentialing and training systems. The American College of Emergency Physicians (ACEP) distributed the surveys using SNAP survey (Snap Surveys Ltd, Portsmouth, New Hampshire, USA). Over 6 months, 75 eligible programmes were surveyed, 55 responded (73% response rate); 1 declined to participate leaving 54 participating programmes. Less than 20% of EDS credential nurses, physician assistants, nurse practitioners and students in EUS. Respondent EDS reported having an average of 4.2 ± 3.3 ultrasound faculty members (faculty identifying their career focus as EUS). The median number of annual point-of-care ultrasounds reported was 5000 (IQR 3000-8000). 30 EDS (56%) credential each examination individually and 48 EDS (89%) use ACEP credentialing criteria. 61% of fellowship leadership believe their credentialing system is either satisfactory or very satisfactory (Cronbach's coefficient α=0.84). The data show heterogeneity among North American EDS with EUS fellowship programmes with regard to credentialing systems despite published guidelines from the ACEP and Canadian Emergency Ultrasound Society.


Associations Between Speech Perception, Vocabulary, and Phonological Awareness Skill in School-Aged Children With Speech Sound Disorders.
Purpose Prior studies report conflicting descriptions of the relationships between phonological awareness (PA), vocabulary, and speech perception in preschoolers with speech disorders. This study sought to determine the nature of these relationships in a sample of school-aged children with residual speech sound errors affecting /ɹ/. Method Participants included 110 children aged 7;0-17;4 (years;months) with residual errors impacting /ɹ/. Data on perceptual acuity and perceptual bias in an /ɹ/ identification task, receptive vocabulary, and PA were obtained. A theoretically and empirically motivated path model was constructed with vocabulary mediating the relationship between two measures of speech perception and PA. Model parameters were determined through maximum likelihood estimation with standard errors that were robust to nonnormality. Monte Carlo simulation was used to examine achieved power at the current sample size. Results The saturated path model explained 19% of the variance in PA. The direct path between age-adjusted perceptual acuity and PA was significant, as was the direct path between vocabulary and PA. Contrary to our hypothesis, there was no evidence in the current sample that vocabulary skill mediated the relationship between speech perception and PA. Each individual path was adequately powered at the current sample size. Conclusions The overall model provided evidence for a continued relationship between speech perception, measured by perceptual acuity of the sound in error, and PA in school-aged children with residual speech errors. Thus, measures of speech perception remain relevant to the assessment of school-aged children and adolescents in this population. Supplemental Material https://doi.org/10.23641/asha.13641275.


Dispersal, Infectivity and Sex Ratio of Early- or Late-Emerging Infective Juveniles of the Entomopathogenic Nematode Steinernema carpocapsae.
Differences in activity between infective juveniles (IJ) of the entomopathogenic nematode Steinernema carpocapsae that emerged directly from cadavers onto either a sand or agar substrate compared with those emerging from a cadaver into water and then being placed on the same substrate are known to occur. Differences between S. carpocapsae IJ that emerged directly from a cadaver vs. those that emerged from a cadaver and held in water were further elucidated. Dispersed and non-dispersed IJ from a cadaver were compared with those held in water between two time periods designated as early- (first two days) or late-emerging IJ (seventh day). A significantly greater proportion of early-emerging IJ from the cadaver treatment dispersed, compared with late-emerging IJ from a cadaver or either group of emerging IJ held in aqueous suspension. Moreover, IJ from cadavers were more infectious than those from the aqueous suspensions, and IJ that dispersed were less infectious than those that did not disperse. IJ that emerged early were mostly males, whereas those that emerged late were mostly females. For the non-dispersed IJ, most that emerged early were males, and those that emerged later were females, but among dispersing IJ, there was no difference in sex ratio between early- and late-emerging nematodes.


Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial.
Infection with Clostridium difficile is the primary infective cause of antibiotic-associated diarrhoea. We aimed to compare efficacy and safety of fidaxomicin and vancomycin to treat patients with C difficile infection in Europe, Canada, and the USA. In this multicentre, double-blind, randomised, non-inferiority trial, we enrolled patients from 45 sites in Europe and 41 sites in the USA and Canada between April 19, 2007, and Dec 11, 2009. Eligible patients were aged 16 years or older with acute, toxin-positive C difficile infection. Patients were randomly allocated (1:1) to receive oral fidaxomicin (200 mg every 12 h) or oral vancomycin (125 mg every 6 h) for 10 days. The primary endpoint was clinical cure, defined as resolution of diarrhoea and no further need for treatment. An interactive voice-response system and computer-generated randomisation schedule gave a randomisation number and medication kit number for each patient. Participants and investigators were masked to treatment allocation. Non-inferiority was prespecified with a margin of 10%. Modified intention-to-treat and per-protocol populations were analysed. This study is registered with ClinicalTrials.gov, number NCT00468728. Of 535 patients enrolled, 270 were assigned fidaxomicin and 265 vancomycin. After 26 patients were excluded, 509 were included in the modified intention-to-treat (mITT) population. 198 (91·7%) of 216 patients in the per-protocol population given fidaxomicin achieved clinical cure, compared with 213 (90·6%) of 235 given vancomycin, meeting the criterion for non-inferiority (one-sided 97·5% CI -4·3%). Non-inferiority was also shown for clinical cure in the mITT population, with 221 (87·7%) of 252 patients given fidaxomicin and 223 (86·8%) of 257 given vancomycin cured (one-sided 97·5% CI -4·9%). In most subgroup analyses of the primary endpoint in the mITT population, outcomes in the two treatment groups did not differ significantly; although patients receiving concomitant antibiotics for other infections had a higher cure rate with fidaxomicin (46 [90·2%] of 51) than with vancomycin (33 [73·3%] of 45; p=0·031). Occurrence of treatment-emergent adverse events did not differ between groups. 20 (7·6%) of 264 patients given at least one dose of fidaxomicin and 17 (6·5%) of 260 given vancomycin died. Fidaxomicin could be an alternative treatment for infection with C difficile, with similar efficacy and safety to vancomycin. Optimer Pharmaceuticals.


Hypothetical performance of syndrome-based management of acute paediatric admissions of children aged more than 60 days in a Kenyan district hospital.
To investigate whether the outpatient, syndrome-based approach of the Integrated Management of Childhood Illness (IMCI) protocol could be extended to the inpatient arena to give clear and simple minimum standards of care for poorly resourced facilities. A prospective, one-year admission cohort retrospectively compared hypothetical performance of syndrome-based management with paediatrician-defined final diagnosis. Admission syndrome definitions were based on local adaptations to the IMCI protocol that encompassed 20 clinical features, measurement of oxygen saturation, and malaria microscopy. After 315 children with clinically obvious diagnoses (e.g. sickle cell disease and burns) were excluded, 3705 admission episodes were studied. Of these, 2334 (63%) met criteria for at least one severe syndrome (mortality 8% vs <1% for "non-severe" cases), and half of these had features of two or more severe syndromes. No cases of measles were seen. Syndrome-based treatment would have been appropriate (sensitivity >95%) for severe pneumonia, severe malaria, and diarrhoea with severe dehydration, and probably for severe malnutrition (sensitivity 71%). Syndrome-directed treatment suggested the use of broad-spectrum antibiotics in 75/133 (56% sensitivity) children with bacteraemic and 63/71 (89% sensitivity) children with meningitis. Twenty clinical features, oxygen saturation measurements, and results of malaria blood slides could be used for inpatient, syndrome-based management of acute paediatric admissions. The addition of microscopy of the cerebrospinal fluid and haemoglobin measurements would improve syndrome-directed treatment considerably. This approach might rationalize admission policy and standardize inpatient paediatric care in resource-poor countries, although the clinical detection of bacteraemia remains a problem.


Evaluation of kasugamycin for fire blight management, effect on nontarget bacteria, and assessment of kasugamycin resistance potential in Erwinia amylovora.
The emergence and spread of streptomycin-resistant strains of Erwinia amylovora in Michigan has necessitated the evaluation of new compounds effective for fire blight control. The aminoglycoside antibiotic kasugamycin (Ks) targets the bacterial ribosome and is particularly active against E. amylovora. The efficacy of Ks formulated as Kasumin 2L for control of fire blight was evaluated in six experiments conducted over four field seasons in our experimental orchards in East Lansing, MI. Blossom blight control was statistically equivalent to the industry standard streptomycin in all experiments. E. amylovora populations remained constant on apple flower stigmas pretreated with Kasumin and were ≈100-fold lower than on stigmas treated with water. Kasumin applied to apple trees in the field also resulted in a 100-fold reduced total culturable bacterial population compared with trees treated with water. We performed a prospective analysis of the potential for kasugamycin resistance (Ks(R)) development in E. amylovora which focused on spontaneous resistance development and acquisition of a transferrable Ks(R) gene. In replicated lab experiments, the development of spontaneous resistance in E. amylovora to Ks at 250 or 500 ppm was not observed when cells were directly plated on medium containing high concentrations of the antibiotic. However, exposure to increasing concentrations of Ks in media (initial concentration 25 μg ml(-1)) resulted in the selection of Ks resistance (at 150 μg ml(-1)) in the E. amylovora strains Ea110, Ea273, and Ea1189. Analysis of mutants indicated that they harbored mutations in the kasugamycin target ksgA gene and that all mutants were impacted in relative fitness observable through a reduced growth rate in vitro and decreased virulence in immature pear fruit. The possible occurrence of a reservoir of Ks(R) genes in orchard environments was also examined. Culturable gram-negative bacteria were surveyed from six experimental apple orchards that had received at least one Kasumin application. In total, 401 Ks(R) isolates (42 different species) were recovered from apple flowers and leaves and orchard soil samples. Although we have not established the presence of a transferrable Ks(R) gene in orchard bacteria, the frequency, number of species, and presence of Ks(R) enterobacterial species in orchard samples suggests the possible role of nontarget bacteria in the future transfer of a Ks(R) gene to E. amylovora. Our data confirm the importance of kasugamycin as an alternate antibiotic for fire blight management and lay the groundwork for the development and incorporation of resistance management strategies.


The effect of perspective on presence and space perception.
In this paper we report two experiments in which the effect of perspective projection on presence and space perception was investigated. In Experiment 1, participants were asked to score a presence questionnaire when looking at a virtual classroom. We manipulated the vantage point, the viewing mode (binocular versus monocular viewing), the display device/screen size (projector versus TV) and the center of projection. At the end of each session of Experiment 1, participants were asked to set their preferred center of projection such that the image seemed most natural to them. In Experiment 2, participants were asked to draw a floor plan of the virtual classroom. The results show that field of view, viewing mode, the center of projection and display all significantly affect presence and the perceived layout of the virtual environment. We found a significant linear relationship between presence and perceived layout of the virtual classroom, and between the preferred center of projection and perceived layout. The results indicate that the way in which virtual worlds are presented is critical for the level of experienced presence. The results also suggest that people ignore veridicality and they experience a higher level of presence while viewing elongated virtual environments compared to viewing the original intended shape.


B-cell development and functions and therapeutic options in adenosine deaminase-deficient patients.
Adenosine deaminase (ADA) deficiency causes severe cellular and humoral immune defects and dysregulation because of metabolic toxicity. Alterations in B-cell development and function have been poorly studied. Enzyme replacement therapy (ERT) and hematopoietic stem cell (HSC) gene therapy (GT) are therapeutic options for patients lacking a suitable bone marrow (BM) transplant donor. We sought to study alterations in B-cell development in ADA-deficient patients and investigate the ability of ERT and HSC-GT to restore normal B-cell differentiation and function. Flow cytometry was used to characterize B-cell development in BM and the periphery. The percentage of gene-corrected B cells was measured by using quantitative PCR. B cells were assessed for their capacity to proliferate and release IgM after stimulation. Despite the severe peripheral B-cell lymphopenia, patients with ADA-deficient severe combined immunodeficiency showed a partial block in central BM development. Treatment with ERT or HSC-GT reverted most BM alterations, but ERT led to immature B-cell expansion. In the periphery transitional B cells accumulated under ERT, and the defect in maturation persisted long-term. HSC-GT led to a progressive improvement in B-cell numbers and development, along with increased levels of gene correction. The strongest selective advantage for ADA-transduced cells occurred at the transition from immature to naive cells. B-cell proliferative responses and differentiation to immunoglobulin secreting IgM after B-cell receptor and Toll-like receptor triggering were severely impaired after ERT and improved significantly after HSC-GT. ADA-deficient patients show specific defects in B-cell development and functions that are differently corrected after ERT and HSC-GT.


Gifts, exchanges and the political economy of health care. Part I: should blood be bought and sold?
Should blood be bought and sold is in crude terms the question asked and answered by Richard Titmuss in his recent book The Gift Relationship. Dr Raymond Plant, a lecturer in philosophy at Manchester University, analyses Titmuss' arguments in a paper which we are printing in two parts. Titmuss has taken the provision of blood as his example of the gift relationship--and by extension that of health care generally. Dr Plant considers in turn each of Titmuss' arguments that blood should not be a marketable commodity, the moral objections to which seem to be the erosion of freedom and of truth telling, the separation of society through the cash nexus, and its converse that the provision of health care is a means for the integration of society. Dr Plant also examines the views of other commentators on the Titmuss' theory of the value of a 'free' blood transfusion service and other medical care as a means of integration in society, and ends with his promise that in the second part of his paper he will examine Titmuss' principles not in terms of the market but rather as related to the principle of social justice.


Tissue-specific functions of the Caenorhabditis elegans p120 Ras GTPase activating protein GAP-3.
All metazoan genomes encode multiple RAS GTPase activating proteins (RasGAPs) that negatively regulate the conserved RAS/MAPK signaling pathway. In mammals, several RasGAPs exhibit tumor suppressor activity by preventing excess RAS signal transduction. We have identified gap-3 as the to date missing Caenorhabditiselegans member of the p120 RasGAP family. By studying the genetic interaction of gap-3 with the two previously identified RasGAPs gap-1 and gap-2, we find that different combinations of RasGAPs are used to repress LET-60 RAS signaling depending on the cellular context. GAP-3 is the predominant negative regulator of RAS during meiotic progression of the germ cells, while GAP-1 is the key inhibitor of RAS during vulval induction. In other tissues such as the sex myoblasts or the chemosensory neurons, all three RasGAPs act in concert. The C. elegans RasGAPs have thus undergone partial specialization after gene duplication to allow the differential regulation of the RAS/MAPK signaling pathway in different cell types. A similar tissue specialization of the human tumor suppressor genes may explain the strong bias in the type of cancer they promote when mutated.


Classification and longitudinal examination of callused teat ends in dairy cows.
To examine the development of teat end callosity thickness and roughness in early lactation and to quantify cow factors of interest, a system to classify teat end condition was developed. A distinction was made between rough and smooth rings around the teat orifice. In addition, a classification of the degree of callosity was developed. Kappa coefficients for the repeatability of scoring by this classification system by different workers were 0.71 for teat end callosity thickness and 0.86 for teat end callosity roughness. The teat end callosity classification system was used for a longitudinal study with 40 cows during the first 14 wk of lactation. Models were built to predict teat end callosity thickness and roughness, machine-on time, and milk yield. For the response variables, teat end callosity thickness, machine-on time, and milk yield, the consecutive measurements appeared to follow a lactation curve model with a subject-specific general slope and intercept. Teat end callosity increased rapidly the first 8 wk. Cow factors such as days in milk, parity, machine-on time, and teat end shape were associated with the degree of teat end callosity, and the probability of the callosity ring to become rough. Teat end callosity thickness did not decrease within the 14-wk trial period for most teats. Pointed or round teat ends showed more callus than inverted teat ends. Longer machine-on time resulted in a higher probability of the callosity ring to become rough. Rear teats showed less callosity than front teats in this study.


Towards a DNA Barcode Reference Database for Spiders and Harvestmen of Germany.
As part of the German Barcode of Life campaign, over 3500 arachnid specimens have been collected and analyzed: ca. 3300 Araneae and 200 Opiliones, belonging to almost 600 species (median: 4 individuals/species). This covers about 60% of the spider fauna and more than 70% of the harvestmen fauna recorded for Germany. The overwhelming majority of species could be readily identified through DNA barcoding: median distances between closest species lay around 9% in spiders and 13% in harvestmen, while in 95% of the cases, intraspecific distances were below 2.5% and 8% respectively, with intraspecific medians at 0.3% and 0.2%. However, almost 20 spider species, most notably in the family Lycosidae, could not be separated through DNA barcoding (although many of them present discrete morphological differences). Conspicuously high interspecific distances were found in even more cases, hinting at cryptic species in some instances. A new program is presented: DiStats calculates the statistics needed to meet DNA barcode release criteria. Furthermore, new generic COI primers useful for a wide range of taxa (also other than arachnids) are introduced.


Isolation and characterization of anti-T-antigen single chain antibodies from a phage library.
T-antigen (Galbeta1-3GalNAc-Thr/Ser) also known as Thomsen-Friedenreich (TF) antigen is the core 1 structure of O-linked mucin type glycans. In normal epithelium, the disaccharide structure is masked by terminal carbohydrate moieties, but is uncovered in most primary and metastatic epithelial malignant tumors. For the purpose of establishing cancer diagnosis and therapeutics, anti-T-antigen antibodies were isolated from a phage library displaying human single chain antibodies. A strategy similar to the previously published method (Sakai et al. Biochemistry. 2007; 46:253-262) was used to screen T-antigen specific antibodies, except that a different type of glycolipid was used for panning and screening. Eleven phage clones were isolated and characterized by DNA sequencing and ELISA, which revealed 4 groups of clones with T-antigen binding activity. One single chain antibody (scFv) protein, derived from phage clone 1G11, was expressed in Escherichia coli and purified to near homogeneity by two column chromatographies. ELISA and surface plasmon resonance analyses revealed that the purified 1G11 scFv bound to the T-antigen moiety of the neoglycolipid used. This study not only demonstrated the validity of our previously introduced strategy employing the phage display technology in constructing human scFvs against various carbohydrate antigens, but also provided us with various scFv genes that can lead to future development of antibody-based therapeutics.


A common solution to group 2 influenza virus neutralization.
The discovery and characterization of broadly neutralizing antibodies (bnAbs) against influenza viruses have raised hopes for the development of monoclonal antibody (mAb)-based immunotherapy and the design of universal influenza vaccines. Only one human bnAb (CR8020) specifically recognizing group 2 influenza A viruses has been previously characterized that binds to a highly conserved epitope at the base of the hemagglutinin (HA) stem and has neutralizing activity against H3, H7, and H10 viruses. Here, we report a second group 2 bnAb, CR8043, which was derived from a different germ-line gene encoding a highly divergent amino acid sequence. CR8043 has in vitro neutralizing activity against H3 and H10 viruses and protects mice against challenge with a lethal dose of H3N2 and H7N7 viruses. The crystal structure and EM reconstructions of the CR8043-H3 HA complex revealed that CR8043 binds to a site similar to the CR8020 epitope but uses an alternative angle of approach and a distinct set of interactions. The identification of another antibody against the group 2 stem epitope suggests that this conserved site of vulnerability has great potential for design of therapeutics and vaccines.


The prescription of oral contraceptives and its relation to the incidence of chlamydia and abortion in Sweden 1997-2005.
The aim of this study is to examine the association between the prescription of oral contraceptives and the incidence of chlamydia, and between the prescription of oral contraceptives and the number of abortions in a population-based ecological study. For this study we used register data from the Swedish Institute for Infectious Disease Control (chlamydia incidence), the Swedish National Board of Health and Welfare (number of abortions), Statistics Sweden (population data), and Apoteket (Swedish pharmacy) (prescriptions for oral contraceptives). We conducted ordinary least squares regression analysis of the association between chlamydia or abortions and the prescription of oral contraceptives. The prescription of oral contraceptives has a positive association on both the incidence of chlamydia and the numbers of abortion. Our best model predicts that prescription of 100 yearly doses of oral contraceptives increase the abortions by 3.3 cases among 16-year-old women and 0.7 cases among 29-year-old women, while cases of chlamydia increase by 6.7 among 16-year-old women and 1.5 among 29-year-old women. Our findings indicate that the use of oral contraceptives among young people and young adults is positively associated with the chlamydia incidence and the abortion rate in these populations in Sweden.


Insulin, thyroid hormone, and heart function of diabetic spontaneously hypertensive rat.
Diabetes impairs cardiac performance more extensively in hypertensive rats than it does in nonhypertensive strains. A "low thyroid state" may contribute to the adverse cardiovascular effects of diabetes in spontaneously hypertensive rats (SHR). We tested this hypothesis by comparing the effects of thyroid hormone with those of insulin treatment on cardiac performance of diabetic SHR. Diabetes was induced with streptozotocin (45 mg/kg). Subsets of diabetic rats were treated with either insulin (10-20 units/kg/day) or triiodothyronine (8-10 micrograms/kg/day). Heart rate and systolic arterial pressure were obtained at weekly intervals. After 8 weeks, cardiac function was assessed using an isolated working heart preparation. Diabetes reduced arterial pressure and heart rate in vivo and markedly depressed cardiac performance under volume and pressure loading conditions ex vivo, confirming previous observations. As expected, insulin treatment prevented the bradycardia and depressor effect in vivo and the impairment of cardiac performance ex vivo caused by diabetes. The triiodothyronine treatment duplicated the effects of insulin on the hemodynamic measurements in vivo, and corrected nearly all depressed indexes of performance of diabetic SHR hearts ex vivo. Both treatment regimens successfully reduced 8-week mortality when compared with the untreated diabetic group. The results support the hypothesis that a low thyroid state may contribute to the cardiovascular dysfunction in diabetic SHR. Left ventricular hypertrophy may be an important factor in this phenomenon.


Amino acids are compatible osmolytes for volume recovery after hypertonic shrinkage in vascular endothelial cells.
The response to chronic hypertonic stress has been studied in human endothelial cells derived from saphenous veins. In complete growth medium the full recovery of cell volume requires several hours and is neither associated with an increase in cell K+ nor hindered by bumetanide but depends on an increased intracellular pool of amino acids. The highest increase is exhibited by neutral amino acid substrates of transport system A, such as glutamine and proline, and by the anionic amino acid glutamate. Transport system A is markedly stimulated on hypertonic stress, with an increase in activity roughly proportional to the extent and the duration of the osmotic shrinkage. Cycloheximide prevents the increase in transport activity of system A and the recovery of cell volume. It is concluded that human endothelial cells counteract hypertonic stress through the stimulation of transport system A and the consequent expansion of the intracellular amino acid pool.


Machine learning for automated quality assurance in radiotherapy: A proof of principle using EPID data description.
Developing automated methods to identify task-driven quality assurance (QA) procedures is key toward increasing safety, efficacy, and efficiency. We investigate the use of machine learning (ML) methods for possible visualization, automation, and targeting of QA, and assess its performance using multi-institutional data. To enable automated analysis of QA data given its higher dimensional nature, we used nonlinear kernel mapping with support vector data description (SVDD) driven approaches. Instead of using labeled data as in typical support vector machine (SVM) applications, which requires exhaustive annotation, we applied a clustering extension of SVDD, which identifies the minimal enclosing hypersphere in the feature space defined by a kernel function separating normal operations from possible failures (i.e., outliers). In our case, QA test data are mapped by a Gaussian kernel to a higher dimensional feature space and then the minimal enclosing sphere was identified. This sphere, when mapped back to the input data space along the principal components, can separate the data into several components, each enclosing a separate cluster of QA points that could be used to evaluate tolerance boundaries and test reliability. We evaluated this approach for gantry sag, radiation field shift, and [multileaf collimator (MLC)] offset data acquired using electronic portal imaging devices (EPID), as representative examples. Data from eight LINACS and seven institutions (n = 119) were collected. A standardized EPID image of a phantom with fiducials provided deviation estimates between the radiation field and phantom center at four cardinal gantry angles. Deviation measurements in the horizontal direction (0°, 180°) were used to determine the gantry sag and deviations in the vertical direction (90°, 270°) were used to determine the field shift. These measurements were fed into the SVDD clustering algorithm with varying hypersphere radii (Gaussian widths). For gantry sag analysis, two clusters were identified one of which contained 2.5% of the outliers and also exceeded the 1 mm tolerance set by TG-142. In the case of field shifts, SVM clustering identified two distinct classes of measurements primarily driven by variations in the second principal component at 270°. Results from MLC analysis identified one outlier cluster (0.34%) along Leaf offset Constancy (LoC) axis that coincided with TG-142 limits. Machine learning methods based on SVDD clustering are promising for developing automated QA tools and providing insights into their reliability and reproducibility.


Abnormalities in hyperpolarized (129)Xe magnetic resonance imaging and spectroscopy in two patients with pulmonary vascular disease.
The diagnosis of pulmonary vascular disease (PVD) is usually based on hemodynamic and/or clinical criteria. Noninvasive imaging of the heart and proximal vasculature can also provide useful information. An alternate approach to such criteria in the diagnosis of PVD is to image the vascular abnormalities in the lungs themselves. Hyperpolarized (HP) (129)Xe magnetic resonance imaging (MRI) is a novel technique for assessing abnormalities in ventilation and gas exchange in the lungs. We applied this technique to two patients for whom there was clinical suspicion of PVD. Two patients who had significant hypoxemia and dyspnea with no significant abnormalities on computed tomography imaging or ventilation-perfusion scan and only mild or borderline pulmonary arterial hypertension at catheterization were evaluated. They underwent HP (129)Xe imaging and subsequently had tissue diagnosis obtained from lung pathology. In both patients, HP (129)Xe imaging demonstrated normal ventilation but markedly decreased gas transfer to red blood cells with focal defects on imaging, a pattern distinct from those previously described for idiopathic pulmonary fibrosis or obstructive lung disease. Pathology on both patients later demonstrated severe PVD. These findings suggest that HP (129)Xe MRI may be useful in the diagnosis of PVD and monitoring response to therapy. Further studies are required to determine its sensitivity and specificity in these settings.


Fluticasone furoate nasal spray reduces symptoms of uncomplicated acute rhinosinusitis: a randomised placebo-controlled study.
Uncomplicated acute rhinosinusitis (ARS) is usually a self-limiting inflammatory condition often treated with antibiotics. To assess the safety and efficacy of fluticasone furoate nasal spray (FFNS) compared with placebo for symptomatic relief of uncomplicated ARS. A randomised, double-blind, placebo-controlled, parallel-group, multicentre, 2-week treatment study of FFNS 110 μg once and twice daily was undertaken in adults/adolescents. A statistically significant reduction was seen in the daily major symptoms score, a composite score of three individual symptoms (nasal congestion/stuffiness, sinus headache/pressure or facial pain/pressure, and postnasal drip on a 0-3 scale) by both FFNS doses compared with placebo (least square mean differences vs. placebo of -0.386 (p=0.008) and -0.357 (p=0.014) for once daily and twice daily FFNS, respectively). The differences in median times to symptom improvement were not statistically significant between each dose of FFNS (7 days) and placebo (8 days). There were no treatment differences in antibiotic use for possible fulminant bacterial rhinosinusitis (3% in each group). The safety profile of FFNS was similar to placebo. FFNS reduces symptoms of uncomplicated ARS compared with placebo and is well tolerated, providing support for withholding antibiotics in selected patients.


Using an anesthesia information management system as a cost containment tool. Description and validation.
Medical informatics provide a new way to evaluate the practice of medicine. Anesthesia automated record keepers have introduced anesthesiologists to computerized medical records. To derive useful information from the stored data requires programming that is not currently commercially available. The authors describe how they custom-programmed an automated record keeper's database to perform cost calculations, how they validated the programming, and how they used the data in a successful pharmaceutical cost-containment program. The Arkive (San Diego, CA) automated record keeper database was programmed at Duke University Medical Center as an independent noncommercial project to calculate costs according to standard formulae and to follow adherence to Duke University Department of Anesthesiology's prescribing guidelines for anesthetic drugs. Validation of that programming (including analysis of discarded drugs) was accomplished by comparing database calculated costs with actual pharmacy distribution of drugs during a 1-month period. Validation data demonstrated a 99% accuracy rate for total costs of the drugs studied (atracurium, vecuronium, rocuronium, propofol, midazolam, fentanyl, and isoflurane). The study drugs represented approximately 67% of all drug costs for the period studied. Programming of an anesthesia automated record keeper's database yields essential information for management of an anesthetic practice. Accurate economic evaluation of anesthetic drug use is now possible. In the future, as definitive identification of best anesthetic practices that yield optimal patient outcomes and higher measures of patient satisfaction is pursued, large numbers of patients should be studied. This is only possible through database analysis and complete computerization of the perioperative medical record.


Abruptly autofocusing terahertz waves with meta-hologram.
An abruptly autofocusing ring-Airy beam is demonstrated in the terahertz (THz) waveband with a meta-hologram. The designed meta-hologram is composed of gold C-shaped slot antennas, which can realize both phase and amplitude modulation of the incident THz wave. A THz holographic imaging system is utilized to measure the generated ring-Airy beam; an abrupt focus following a parabolic trajectory is subsequently observed. THz ring-Airy beams with different parameters are also generated and investigated. This method can be expanded to other wavebands, such as the visible band, for which the meta-hologram can replace traditional computer-generated holography to avoid undesirable multiple diffraction orders.


Zafirlukast improves pulmonary function in patients with moderate persistent asthma receiving regular inhaled steroids: a prospective randomized control study.
Zafirlukast is a leukotriene receptor antagonist that was invented to treat patients with chronic asthma. To evaluate whether the zafirlukast improved the peak expiratory flow rate (PEFR) and clinical symptoms, 31 asthmatic patients with moderate persistent asthma who received regular inhaled corticosteroid were randomly divided into the study group (N = 17). They received the zafirlukast 20 mg bid for 4 weeks, and the control group (N = 14) received a placebo. Daily morning and evening PEFR and St. George's Respiratory Questionnaire (SGRQ) scoring were recorded respectively. The levels of serum IgE and urine leukotriene E4 before and after treatment were measured using enzyme linked immunosorbent assay and enzyme immunoassay kits. In the zafirlukast treated group, the morning PEFR was significantly improved from 314.4 +/- 20.6 to 340.6 +/- 18.3 L/min (N = 17, p < 0.05) after 4 weeks of treatment, while the control group did not show any significant changes. The zafirlukast group had significant improvement in their symptom scores of SGRQ from 48.6 +/- 4.6 to 33.8 +/- 4.7 (N = 17, p < 0.05). However, the placebo did not improve the symptom scores. Leukotriene receptor antagonists effectively improved symptoms and benefited lung function for moderate persistent asthmatic patients who had received regular treatments with inhaled steroids.


Fully automated chemiluminescence detection using an electrified-Lab-on-a-Disc (eLoaD) platform.
Typical Lab-on-a-Disc (LoaD) platforms cannot make a continuous measurement while the disc is spinning; this drawback means that the disc usually must be stopped and aligned with a sensor. This can result in measurement errors in time-dependent assays along with inaccuracies due to liquid displacement and bubble formation in the absence of a stabilising centrifugal field. This paper presents a novel concept for a wirelessly electrified-Lab-on-a-Disc (eLoaD) platform that allows continuous measurement of experimental parameters while the disc is spinning. This platform incorporates all the components needed for measurement within the rotating frame of reference, and bidirectional transmission of data outside this reference frame, thus allowing for online measurement independent of the rotation of the disc. The eLoaD platform is conceived in a modular manner whereby an interchangeable and non-disposable 'Application Disc' can be fitted to the eLoaD platform and so the system can be adapted for a range of optical, electrochemical and other measurement types. As an application example, optical readout, using the Application Disc fitted with a silicon photomultiplier, is demonstrated using a tagged chemiluminescent antibody, which is commonly used, for instance, in ELISA assays. The precision of the eLoaD platform is >94%, while its accuracy, when compared to a commercial benchtop luminometer, is higher than 96%. The modular design of this platform will permit extension of this technology to many other LoaD applications.


Role of the gastrointestinal tract in burn sepsis.
During the last 50 years, our understanding of the role of the gastrointestinal tract as a first-line defense against the development of postburn sepsis has increased dramatically. Starting with the concept of that gut-derived bacteria cause distant injury, investigators have delineated a complex series of physical changes in the barrier of the gastrointestinal tract. Along with an understanding of these physical changes has come an appreciation of the role of the immune system in modulating postburn organ failure. Importantly, recent investigations into the role of mesenteric lymph have fundamentally changed the paradigm of organ failure and have implicated the gut as a cytokine-secreting organ. This article traces the development of key concepts in the study of burn sepsis and their clinical implications.