Subgingival bacterial burden in relation to clinical and radiographic periodontal parameters.
This cross-sectional study characterizes the association between subgingival bacterial profile and periodontal parameters in patients assigned to coronary angiography because of cardiologic problems, which may affect the oral microbiota. Pooled subgingival bacterial samples were collected from 477 dentate individuals during the oral examinations, along with periodontal probing depth (PD) and assessments of bleeding on probing (BOP) and radiographic alveolar bone loss (ABL). The checkerboard DNA-DNA hybridization assay was used to determine the levels of 29 oral bacteria, which were divided into three bacterial complexes. All bacterial combinations from the etiologic bacterial group and each species from the red complex were significantly associated (P <0.001) with grade of ABL. The prevalence of the etiologic bacterial group and the level of each species were also associated strongly with the proportion of sites with PD 4 to 5 mm and ≥ 6 mm, BOP, and ABL, except Aggregatibacter actinomycetemcomitans. Levels of Gram-negative oral bacteria correlated significantly with those of Gram-positive species (r = 0.840, P <0.001). In multiple logistic regression analysis, the prevalence of the etiologic bacterial group, levels of Gram-negative bacteria and Treponema denticola, and the prevalence of Porphyromonas gingivalis and T. denticola associated significantly with ABL, whereas other bacterial complexes and levels of Gram-positive species did not. Although levels of Gram-negative and -positive species paralleled periodontal parameters, only the species considered etiologic were associated with ABL.


Silymarin inhibits in vitro T-cell proliferation and cytokine production in hepatitis C virus infection.
Silymarin, an extract from the seeds of the milk thistle plant Silybum marianum, has been used for centuries for the treatment of chronic liver diseases. Despite common use by patients with hepatitis C in the United States, its clinical efficacy remains uncertain. The goal of this study was to determine whether silymarin has in vitro effects on immune function that might have implications for its potential effect on hepatitis C virus (HCV)-induced liver disease. Freshly isolated peripheral blood mononuclear cells (PBMC) and T cells from HCV-infected and uninfected subjects were tested in vitro for responses to nonspecific and antigenic stimulation in the presence and absence of a standardized preparation of silymarin (MK001). Minimal MK001 toxicity on PBMC was found at concentrations between 5 and 40 microg/mL. MK001 dose dependently inhibited the proliferation and secretion of tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and interleukin (IL)-2 by PBMC stimulated with anti-CD3. In addition, MK001 inhibited proliferation by CD4(+) T cells to HCV, Candida, and tetanus protein antigens and by HLA-A2/HCV 1406-1415-specific CD8(+) T cells to allogeneic stimulation. MK001 inhibited T-cell TNF-alpha and IFN-gamma cytokine secretion to tetanus and Candida protein antigens. Finally, MK001 inhibited nuclear factor-kappaB transcriptional activation after T-cell receptor-mediated stimulation of Jurkat T cells, consistent with its ability to inhibit Jurkat T-cell proliferation and secretion of IL-2. Silymarin's ability to inhibit the proliferation and proinflammatory cytokine secretion of T cells, combined with its previously described antiviral effect, suggests a possible mechanism of action that could lead to clinical benefit during HCV infection.


Glyceollins, one of the phytoalexins derived from soybeans under fungal stress, enhance insulin sensitivity and exert insulinotropic actions.
Glyceollins are a category of phytoalexins that are produced by soybeans under fungal stress, but their effects on glucose homeostasis remain unknown. We hypothesized that glyceollins play an important role in glucose homeostasis by regulating glucose utilization in adipocytes and improving beta-cell function and survival. Glyceollins improved insulin-stimulated glucose uptake in 3T3-L1 adipocytes without activating the peroxisome proliferator-activated receptor-gamma agonist. They decreased triacylglycerol accumulation in adipocytes. In addition, glyceollins slightly improved glucose-stimulated insulin secretion without palmitate treatment in Min6 cells, and they potentiated insulinotropic actions when 500 microM palmitate was used to induce beta-cell dysfunction. This was associated with decreased beta-cell apoptosis because of the attenuation of endoplasmic reticulum stress, as determined by mRNA levels of XBP-1, ATF-4, ATF-6, and CHOP. Glyceollins also potentiated GLP-1 secretion to enhance insulinotropic actions in enteroendocrine cells. In conclusion, glyceollins help normalize glucose homeostasis by potentiating beta-cell function and survival and improving glucose utilization in adipocytes.


Structural comparison of murine T-cell (B151K12)-derived T-cell-replacing factor (IL-5) with rIL-5: dimer formation is essential for the expression of biological activity.
T-cell-replacing factor (TRF)/IL-5 is a T-cell-derived glycoprotein which has pleiotropic activity on lymphoid and myeloid cells. IL-5 polypeptide translated into Xenopus oocytes are heterogeneous in molecular size (40,000 to 60,000 under nonreducing conditions) and yields a monomeric form (Mr of 25,000 to 30,000) under reducing conditions (J. Immun., 140, 1175-1181, 1988). We purified T-cell-derived TRF and rIL-5 using anti-TRF/IL-5 antibody-coupled affinity column from supernatants of a T-cell hybridoma B151K12 and supernatants of HeLa cells, respectively, which had been transfected with murine IL-5 cDNA, and determined their partial N-terminal amino acid sequence (27 residues for B151-TRF and 13 residues for rIL-5). A single amino acid sequence of each sample obtained beginning from methionine that was identical to that predicted from IL-5 cDNA. This finding supports the notion that secreted B151-TRF polypeptide consists of 113 amino acids. Purified B151-TRF supported eosinophilopoiesis of human bone marrow cells as effective as mouse rIL-5 and human rIL-5. B151-TRF competitively inhibited 35S-labeled rIL-5 binding to target cells to the same extent at rIL-5. Treatment of purified rIL-5 and B151-TRF with reducing reagents such as 2-ME, sodium borohydride or dithiothreitol produced a monomeric form of IL-5 which did not exert a biological activity. Reduction and alkylation of rIL-5 caused the loss of binding to its target cells. These results strongly suggest that B151-TRF exists as a homodimer and its primary structure and secondary structures are identical to those of rIL-5. Moreover, the formation of inter-molecular disulfide bond(s) linked by two pairs of cystein residues is essential for the expression of the biological activity of mouse IL-5.


NaV1.1 channels in axon initial segments of bipolar cells augment input to magnocellular visual pathways in the primate retina.
In the primate visual system, the ganglion cells of the magnocellular pathway underlie motion and flicker detection and are relatively transient, while the more sustained ganglion cells of the parvocellular pathway have comparatively lower temporal resolution, but encode higher spatial frequencies. Although it is presumed that functional differences in bipolar cells contribute to the tuning of the two pathways, the properties of the relevant bipolar cells have not yet been examined in detail. Here, by making patch-clamp recordings in acute slices of macaque retina, we show that the bipolar cells within the magnocellular pathway, but not the parvocellular pathway, exhibit voltage-gated sodium (NaV), T-type calcium (CaV), and hyperpolarization-activated, cyclic nucleotide-gated (HCN) currents, and can generate action potentials. Using immunohistochemistry in macaque and human retinae, we show that NaV1.1 is concentrated in an axon initial segment (AIS)-like region of magnocellular pathway bipolar cells, a specialization not seen in transient bipolar cells of other vertebrates. In contrast, CaV3.1 channels were localized to the somatodendritic compartment and proximal axon, but were excluded from the AIS, while HCN1 channels were concentrated in the axon terminal boutons. Simulations using a compartmental model reproduced physiological results and indicate that magnocellular pathway bipolar cells initiate spikes in the AIS. Finally, we demonstrate that NaV channels in bipolar cells augment excitatory input to parasol ganglion cells of the magnocellular pathway. Overall, the results demonstrate that selective expression of voltage-gated channels contributes to the establishment of parallel processing in the major visual pathways of the primate retina.


Living in biological soil crust communities of African deserts-Physiological traits of green algal Klebsormidium species (Streptophyta) to cope with desiccation, light and temperature gradients.
Green algae of the genus Klebsormidium (Klebsormidiales, Streptophyta) are typical members of biological soil crusts (BSCs) worldwide. The phylogeny and ecophysiology of Klebsormidium has been intensively studied in recent years, and a new lineage called superclade G, which was isolated from BSCs in arid southern Africa and comprising undescribed species, was reported. Three different African strains, that have previously been isolated from hot-desert BSCs and molecular-taxonomically characterized, were comparatively investigated. In addition, Klebsormidium subtilissimum from a cold-desert habitat (Alaska, USA, superclade E) was included in the study as well. Photosynthetic performance was measured under different controlled abiotic conditions, including dehydration and rehydration, as well as under a light and temperature gradient. All Klebsormidium strains exhibited optimum photosynthetic oxygen production at low photon fluence rates, but with no indication of photoinhibition under high light conditions pointing to flexible acclimation mechanisms of the photosynthetic apparatus. Respiration under lower temperatures was generally much less effective than photosynthesis, while the opposite was true for higher temperatures. The Klebsormidium strains tested showed a decrease and inhibition of the effective quantum yield during desiccation, however with different kinetics. While the single celled and small filamentous strains exhibited relatively fast inhibition, the uniserate filament forming isolates desiccated slower. Except one, all other strains fully recovered effective quantum yield after rehydration. The presented data provide an explanation for the regular occurrence of Klebsormidium strains or species in hot and cold deserts, which are characterized by low water availability and other stressful conditions.


Scanning gate microscopy on graphene: charge inhomogeneity and extrinsic doping.
We have performed scanning gate microscopy (SGM) on graphene field effect transistors (GFET) using a biased metallic nanowire coated with a dielectric layer as a contact mode tip and local top gate. Electrical transport through graphene at various back gate voltages is monitored as a function of tip voltage and tip position. Near the Dirac point, the response of graphene resistance to the tip voltage shows significant variation with tip position, and SGM imaging displays mesoscopic domains of electron-doped and hole-doped regions. Our measurements reveal substantial spatial fluctuation in the carrier density in graphene due to extrinsic local doping from sources such as metal contacts, graphene edges, structural defects and resist residues. Our scanning gate measurements also demonstrate graphene's excellent capability to sense the local electric field and charges.


Pain management in the cirrhotic patient: the clinical challenge.
Pain management in patients with cirrhosis is a difficult clinical challenge for health care professionals, and few prospective studies have offered an evidence-based approach. In patients with end-stage liver disease, adverse events from analgesics are frequent, potentially fatal, and often avoidable. Severe complications from analgesia in these patients include hepatic encephalopathy, hepatorenal syndrome, and gastrointestinal bleeding, which can result in substantial morbidity and even death. In general, acetaminophen at reduced dosing is a safe option. In patients with cirrhosis, nonsteroidal anti-inflammatory drugs should be avoided to avert renal failure, and opiates should be avoided or used sparingly, with low and infrequent dosing, to prevent encephalopathy. For this review, we searched the available literature using PubMed and MEDLINE with no limits.


A coupled physical-computational methodology for the investigation of short fall related infant head impact injury.
Head injury in childhood is the most common cause of death or permanent disability from injury. However, insufficient understanding exists of the response of a child's head to injurious loading scenarios to establish cause and effect relationships to assist forensic and safetly investigations. Largely as a result of a lack of availability of paediatric clinical and Post-Mortem-Human-Surrogate (PMHS) experimental data, a new approach to infant head injury experimentation has been developed. A coupled-methodology, combining a physical infant head surrogate, producing "real world" global, regional and localised impact response data and a computational Finite-Element (FE-head) model was created and validated against available PMHS and physical model global impact response data. Experimental impact simulations were performed to investigate regional and localised injury vulnerability. Different regions of the head produced accelerations significantly greater than those calculated using the currently available method of measuring the global, whole head response. The majority of material strain was produced within the relatively elastic suture and fontanelle regions, rather than the skull bones. A subsequent parametric analysis was conducted to provide a correlation between fall height and areas of maximum-stress-response and fracture-risk-probability. The FE-head was further applied to investigating fracture risk, simulating injurious PMHS impacts and a good qualitative match was observed. The FE-head shows significant potential for the study of infant head injury and is anticipated to be a motivating tool for the improvement of head injury understanding across a range of potentially injurious head loading scenarios.


An improved technique for chromosomal analysis of human ES and iPS cells.
Prolonged in vitro culture of human embryonic stem (hES) cells can result in chromosomal abnormalities believed to confer a selective advantage. This potential occurrence has crucial implications for the appropriate use of hES cells for research and therapeutic purposes. In view of this, time-point karyotypic evaluation to assess genetic stability is recommended as a necessary control test to be carried out during extensive 'passaging'. Standard techniques currently used for the cytogenetic assessment of ES cells include G-banding and/or Fluorescence in situ Hybridization (FISH)-based protocols for karyotype analysis, including M-FISH and SKY. Critical for both banding and FISH techniques are the number and quality of metaphase spreads available for analysis at the microscope. Protocols for chromosome preparation from hES and human induced pluripotent stem (hiPS) cells published so far appear to differ considerably from one laboratory to another. Here we present an optimized technique, in which both the number and the quality of chromosome metaphase spreads were substantially improved when compared to current standard techniques for chromosome preparations. We believe our protocol represents a significant advancement in this line of work, and has the required attributes of simplicity and consistency to be widely accepted as a reference method for high quality, fast chromosomal analysis of human ES and iPS cells.


Using partner notification to address curable sexually transmitted infections in a high HIV prevalence context: a qualitative study about partner notification in Botswana.
Partner notification is an essential component of sexually transmitted infection (STI) management. The process involves identifying exposed sex partner(s), notifying these partner(s) about their exposure to a curable STI, and offering counselling and treatment for the STI as a part of syndromic management or after results from an STI test. When implemented effectively, partner notification services can prevent the index patient from being reinfected with a curable STI from an untreated partner, reduce the community burden of curable STIs, and prevent adverse health outcomes in both the index patient and his or her sex partner(s). However, partner notification and treatment rates are often low. This study seeks to explore experiences and preferences related to partner notification and treatment for curable STIs among pregnant women receiving care in an antenatal clinic with integrated HIV and curable STI testing. Results are intended to inform efforts to improve partner notification and treatment rates in Southern Africa. We conducted qualitative interviews among women diagnosed with Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), and/or Trichomonas vaginalis (TV) infection while seeking antenatal care in Gaborone, Botswana. Semi-structured interviews were used to obtain women's knowledge about STIs and their experiences and preferences regarding partner notification. Fifteen women agreed to participate in the study. The majority of women had never heard of CT, NG, or TV infections prior to testing. Thirteen out of 15 participants had notified partners about the STI diagnosis. The majority of notified partners received some treatment; however, partner treatment was often delayed. Most women expressed a preference for accompanying partners to the clinic for treatment. Experiences and preferences did not differ by HIV infection status. The integration of STI, HIV, and antenatal care services may have contributed to most women's willingness to notify partners. However, logistical barriers to partner treatment remained. More research is needed to identify effective and appropriate strategies for scaling-up partner notification services in order to improve rates of partners successfully contacted and treated, reduce rates of STI reinfection during pregnancy, and ultimately reduce adverse maternal and infant outcomes attributable to antenatal STIs.


Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies.
The propensity score is defined as a subject's probability of treatment selection, conditional on observed baseline covariates. Weighting subjects by the inverse probability of treatment received creates a synthetic sample in which treatment assignment is independent of measured baseline covariates. Inverse probability of treatment weighting (IPTW) using the propensity score allows one to obtain unbiased estimates of average treatment effects. However, these estimates are only valid if there are no residual systematic differences in observed baseline characteristics between treated and control subjects in the sample weighted by the estimated inverse probability of treatment. We report on a systematic literature review, in which we found that the use of IPTW has increased rapidly in recent years, but that in the most recent year, a majority of studies did not formally examine whether weighting balanced measured covariates between treatment groups. We then proceed to describe a suite of quantitative and qualitative methods that allow one to assess whether measured baseline covariates are balanced between treatment groups in the weighted sample. The quantitative methods use the weighted standardized difference to compare means, prevalences, higher-order moments, and interactions. The qualitative methods employ graphical methods to compare the distribution of continuous baseline covariates between treated and control subjects in the weighted sample. Finally, we illustrate the application of these methods in an empirical case study. We propose a formal set of balance diagnostics that contribute towards an evolving concept of 'best practice' when using IPTW to estimate causal treatment effects using observational data.


CCK-A receptors in the rat interpeduncular nucleus: evidence for a presynaptic location.
Using autoradiography, 'peripheral type' or cholecystokinin-A (CCK-A) receptor binding was measured in the interpeduncular nucleus (IPN) of rats which had received electrolytic lesions of the habenular nucleus. Presynaptic GABAB receptor binding was also determined in the IPN in order to verify the loss of input to the nucleus. In animals which showed almost total loss of GABAB receptors. 125I-Bolton Hunter CCK binding in the IPN was reduced from 1.83 +/- 0.28 pmol/g wet weight to 0.87 +/- 0.16 pmol/g wet weight. This was not significantly different from non-specific levels, determined in the same region using 10(-7) M L-365,031 (0.97 +/- 0.14 pmol/g wet weight). These data suggest that CCK-A receptors in rat IPN are localized on presynaptic terminals within the nucleus.


One-stop radiotherapeutic targeting of primary and distant osteosarcoma to inhibit cancer progression and metastasis using 2DG-grafted graphene quantum dots.
The application of radiotherapy (RT) to treat osteosarcoma (OS) has been limited, but this is starting to change as the ability to target radiation energy to niches improves. Furthermore, lung cancer from highly metastatic OS is a major cause of death, so it is critical to explore new strategies to tackle metastasis. In this study, we designed a nanoscale radiosensitizer by grafting 2-deoxy-d-glucose (2DG) onto graphene quantum dots (GQD) to achieve OS targeting and boost RT efficacy. Combining the use of 2DG-grafted GQDs (2DG-g-GQD) with RT produced a significant increase in oxidative stress response and DNA damage in the 143B OS cell line compared with RT alone. Moreover, 2DG-g-GQDs selectively associated with 143B cells, and demonstrated the inhibition of migration in a scratch assay. We also demonstrated remarkable improvement in their ability to inhibit tumour progression and lung metastasis in an OS xenograft mouse model. Our results show that the use of 2DG-g-GQDs as OS-targeting radiosensitizers improves their therapeutic outcome and exhibits potential for use in low-dose precision RT for OS.


Talking delicately: Providing opportunistic weight loss advice to people living with obesity.
Obesity is a major worldwide public health problem. Clinicians are asked to communicate public health messages, including encouraging and supporting weight loss, during consultations with patients living with obesity. However, research shows that talking about weight with patients rarely happens and both parties find it difficult to initiate. Current guidelines on how to have such conversations do not include evidence-based examples of what to say, when to say it and how to avoid causing offence (a key concern for clinicians). To address this gap, we examined 237 audio recorded consultations between clinicians and patients living with obesity in the UK in which weight was discussed opportunistically. Conversation analysis revealed that framing advice as depersonalised generic information was one strategy clinicians used when initiating discussions. This contrasted to clinicians who made advice clearly relevant and personalised to the patient by first appraising their weight. However not all personalised forms of advice worked equally well. Clinicians who spoke delicately when personalising the discussion avoided the types of patient resistance that we found when clinicians were less delicate. More delicate approaches included forecasting upcoming discussion of weight along with delicacy markers in talk (e.g. strategic use of hesitation). Our findings suggest that clinicians should not avoid talking about a patient's weight, but should speak delicately to help maintain good relationships with patients. The findings also demonstrate the need to examine communication practices to develop better and specific guidance for clinicians. Data are in British English.


Identification of N-terminal regions of wheat leaf ferredoxin NADP+ oxidoreductase important for interactions with ferredoxin.
Wheat leaves contain two isoproteins of the photosynthetic ferredoxin:NADP(+) reductase (pFNRI and pFNRII). Truncated forms of both enzymes have been detected in vivo, but only pFNRII displays N-terminal length-dependent changes in activity. To investigate the impact of N-terminal truncation on interaction with ferredoxin (Fd), recombinant pFNRII proteins, differing by deletions of up to 25 amino acids, were generated. During purification of the isoproteins found in vivo, the longer forms of pFNRII bound more strongly to a Fd affinity column than did the shorter forms, pFNRII(ISKK) and pFNRII[N-2](KKQD). Further truncation of the N-termini resulted in a pFNRII protein which failed to bind to a Fd column. Similar k(cat) values (104-140 s(-1)) for cytochrome c reduction were measured for all but the most truncated pFNRII[N-5](DEGV), which had a k(cat) of 38 s(-1). Stopped-flow kinetic studies, examining the impact of truncation on electron flow between mutant pFNRII proteins and Fd, showed there was a variation in k(obs) from 76 to 265 s(-1) dependent on the pFNRII partner. To analyze the sites which contribute to Fd binding at the pFNRII N-terminal, three mutants were generated, in which a single or double lysine residue was changed to glutamine within the in vivo N-terminal truncation region. The mutations affected binding of pFNRII to the Fd column. Based on activity measurements, the double lysine residue change resulted in a pFNRII enzyme with decreased Fd affinity. The results highlight the importance of this flexible N-terminal region of the pFNRII protein in binding the Fd partner.


Radial polarization interferometer.
We propose and demonstrate a new interferometric approach in which a uniform phase difference between the arms of the interferometer manifests itself as spatially varying intensity distribution. The approach is based on interfering two orthogonal spatially varying vector fields, the radially and azimuthally polarized beams, and measuring the projection of the obtained field on an analyzer. This method provides additional spatial information that can be used to improve the smallest detectable phase change as compared with a conventional Michelson interferometer.


Impact of 20-day strike in Polokwane Hospital (18 August - 6 September 2010).
Doctors' strikes have a negative effect on hospital performance indicators. Hospital mortality during such strikes is the most important indicator. To determine the effects of the 2010 strike on Polokwane Hospital. Information was collected from the Hospital Information System, Polokwane Hospital Casualty Department, wards and theatres. During the 20-day strike, a total of 262 patients were admitted to Polokwane Hospital, with 40 patients to the surgical department; 96 operations were performed in the hospital and 40 in the surgical department; and 50 deaths were reported in the hospital (8 deaths in the surgical department). During 20 days of a non-striking period in May 2010, there were 975 admissions to the hospital, with 125 to the surgical department. In the entire hospital, 340 operations were performed, and 79 in the surgical department. For this period, 61 deaths were reported in the hospital and 12 in the surgical department. The total number of patients admitted to the hospital and the surgical department during the strike was significantly lower than during a non-striking situation. Total mortality during the strike in Polokwane Hospital decreased, compared with the normal situation, but it increased when judged against emergency cases. However, when mortality was qualified by the number of admissions, it showed a significant increase. Strikes seriously and significantly affect service delivery.


Estimating 24-hour urine sodium level with spot urine sodium and creatinine.
The 24-hr urine sodium excretion level was estimated based on the spot urine sodium, and the efficacy of the formula was validated to determine the status of low salt intake <100 mEq Na/day. The 24-hr urine samples were collected from 400 patients. The 24-hr urine creatinine level was estimated with the use of three formulas: a newly derived Korean equation (E24UCR_K), and Tanaka (E24UCR_T) and Cockcroft-Gault (E24UCR_CG) equations. The correlation coefficients between the estimated and measured 24-hr urine creatinine for these three equations were 0.863, 0.846, and 0.896, respectively (All P<0.001). After estimating the 24-hr urine sodium levels, the correlation coefficients between the estimated and measured 24-hr urine sodium levels were 0.466, 0.490, and 0.516, respectively (All P<0.001). The sensitivity of three formulas to estimate the measured 24-hr urine sodium≥100 mEq/day using the estimated amount≥100 mEq/day was 84.3%, 87.6%, and 84.8%, respectively. In conclusion, the three equations used to estimate the 24-hr urine sodium content were useful to determine the status of low salt intake.


Microfluidic dose-response platform to track the dynamics of drug response in single mycobacterial cells.
Preclinical analysis of drug efficacy is critical for drug development. However, conventional bulk-cell assays statically assess the mean population behavior, lacking resolution on drug-escaping cells. Inaccurate estimation of efficacy can lead to overestimation of compounds, whose efficacy will not be confirmed in the clinic, or lead to rejection of valuable candidates. Time-lapse microfluidic microscopy is a powerful approach to characterize drugs at high spatiotemporal resolution, but hard to apply on a large scale. Here we report the development of a microfluidic platform based on a pneumatic operating principle, which is scalable and compatible with long-term live-cell imaging and with simultaneous analysis of different drug concentrations. We tested the platform with mycobacterial cells, including the tubercular pathogen, providing the first proof of concept of a single-cell dose-response assay. This dynamic in-vitro model will prove useful to probe the fate of drug-stressed cells, providing improved predictions of drug efficacy in the clinic.


Rapid identification of monospecific monoclonal antibodies using a human proteome microarray.
To broaden the range of tools available for proteomic research, we generated a library of 16,368 unique full-length human ORFs that are expressible as N-terminal GST-His(6) fusion proteins. Following expression in yeast, these proteins were then individually purified and used to construct a human proteome microarray. To demonstrate the usefulness of this reagent, we developed a streamlined strategy for the production of monospecific monoclonal antibodies that used immunization with live human cells and microarray-based analysis of antibody specificity as its central components. We showed that microarray-based analysis of antibody specificity can be performed efficiently using a two-dimensional pooling strategy. We also demonstrated that our immunization and selection strategies result in a large fraction of monospecific monoclonal antibodies that are both immunoblot and immunoprecipitation grade. Our data indicate that the pipeline provides a robust platform for the generation of monoclonal antibodies of exceptional specificity.


Exclusive breastfeeding policy, practice and influences in South Africa, 1980 to 2018: A mixed-methods systematic review.
In 2011, South Africa committed to promoting exclusive breastfeeding (EBF) for six months for all mothers, regardless of HIV status, in line with World Health Organization recommendations. This was a marked shift from earlier policies, and with it, average EBF rates increased from less than 10% in 2011 to 32% by 2016. The aim of this mixed-methods systematic review was to describe EBF practices in South Africa and their multi-level influences over four policy periods. We applied PRISMA guidelines according to a published protocol (Prospero: CRD42014010512). We searched seven databases [Africa-Wide, PubMed, Popline, PsychINFO, CINAHL, Global Health, and The Cochrane Library] and conducted hand searches for eligible articles (all study designs, conducted in South Africa and published between 1980-2018). The quality of articles was assessed using published tools, as appropriate. Separate policy analysis was conducted to delineate four distinct policy periods. We compared EBF rates by these periods. Then, applying a three-level ecological framework, we analysed EBF influences concurrently by method. Finally, the findings were synthesized to compare breastfeeding influences by policy period, maintaining an ecological framework. From an initial sample of 20,226 articles, 72 unique articles were reviewed, three of which contributed to both quantitative and qualitative analysis. Despite the large sample, several provinces were poorly represented (if at all) and many studies were assessed as low to moderate quality. Despite these limitations, our historical lens enabled us to explore why South African progress on increasing EBF practices has been slow. The review reflects a context that increasingly supports EBF, but falls short in accounting for family, community, and workplace influences. The findings also highlight the unintended damage caused by rapidly adopting and introducing global guidelines to an unsupported health workforce. From a South African perspective, we identified geographic and methodological biases, as well as gaps in our understanding and potential explanations of inequities in EBF. Our recommendations relate to policy, programming, and research to inform changes that would be required to further improve EBF practice rates in South Africa. While our review is South Africa-specific, our findings have broader implications for investing in multi-level interventions and limiting how often infant feeding guidelines are changed.


Granulocyte colony-stimulating factor attenuates early ventricular expansion after experimental myocardial infarction.
In the early phase after transmural myocardial infarction (MI), the infarcted myocardium undergoes replacement by scar tissue, which is essential for preserving the structural integrity of the infarcted tissue. Transforming growth factor (TGF)-beta1, which is known as a fibrotic cytokine, plays a pivotal role in the reparative fibrosis after MI. It is reported that granulocyte colony-stimulating factor (G-CSF) can accelerate wound healing. The aim of our study was to investigate the effect of G-CSF on early ventricular expansion after MI. MI was induced by ligation of the left coronary artery in male Wistar rats. G-CSF (20 microg/kg/day, MI-GCSF) or saline (MI-saline) was injected subcutaneously 3 h after MI and every 24 h thereafter for 7 days. Hemodynamic and echocardiographic studies were performed at 14 days. Expression of TGF-beta1 and procollagen type I and type III mRNA in both the infarcted and noninfarcted areas was studied by quantitative RT-PCR at 1, 3, 7, and 14 days after MI. Histological studies were performed at 7 days. MI-GCSF had higher LV max dP/dt, lower LV end-diastolic pressure, and smaller LV end-diastolic and end-systolic dimensions compared to MI-saline. Infarct size was not different between MI-GCSF and MI-saline. Expression of TGF-beta1 mRNA in the infarcted area at 3 days was significantly higher in MI-GCSF than in MI-saline. Expression of procollagen type I and type III mRNA in the infarcted area at 3 days was higher in MI-GCSF compared to MI-saline, and the peak mRNA levels were earlier in MI-GCSF. In the noninfarcted area, there was no difference in TGF-beta1 mRNA expression between MI-GCSF and MI-saline. Histologically, collagen accumulation in the infarcted area at 7 days was more prominent in MI-GCSF than in MI-saline. G-CSF treatment improves early post-infarct ventricular expansion through promotion of reparative collagen synthesis in the infarcted area, suggesting some beneficial effect of G-CSF on the infarct healing process.


Bone disease in primary biliary cirrhosis: increased bone resorption and turnover in the absence of osteoporosis or osteomalacia.
The role of vitamin D in hepatic osteodystrophy was examined. Eleven unselected patients with primary biliary cirrhosis (PBC) were assessed for disorders of mineral and vitamin D metabolism. Six were not receiving supplementary vitamin D, and five were being treated with oral vitamin D (50,000 IU daily). Serum levels of 25-hydroxyvitamin D were normal in all patients receiving oral therapy and in 4 of 6 untreated patients. Levels of serum 1,25-dihydroxyvitamin D and 24,25-dihydroxyvitamin D were normal or near normal in all patients. Studies were repeated after 6 months of therapy with parenteral vitamin D2 (100,000 IU i.m. monthly) in 7 patients. Initial bone histomorphometry revealed no evidence of osteomalacia or osteoporosis. However, the bone resorption surface of trabecular bone was increased. This abnormality was no longer present on repeat bone biopsies obtained after parenteral vitamin D therapy, and bone formation had decreased. In addition, trabecular bone volume remained normal in the face of the lower rate of bone formation. Increased bone resorption surface in the absence of osteoporosis or osteomalacia has not been previously described in PBC. Improvement in this bone parameter, associated with the finding of a decrease in the formation of bone and in hydroxyproline excretion in urine after parenteral vitamin D, suggests that increased turnover may be an early feature of the bone disease which complicates PBC and that parenteral vitamin D may retard the rate at which hepatic osteodystrophy develops in chronic cholestatic liver disease.


Type VI secretion apparatus and phage tail-associated protein complexes share a common evolutionary origin.
Protein secretion is a common property of pathogenic microbes. Gram-negative bacterial pathogens use at least 6 distinct extracellular protein secretion systems to export proteins through their multilayered cell envelope and in some cases into host cells. Among the most widespread is the newly recognized Type VI secretion system (T6SS) which is composed of 15-20 proteins whose biochemical functions are not well understood. Using crystallographic, biochemical, and bioinformatic analyses, we identified 3 T6SS components, which are homologous to bacteriophage tail proteins. These include the tail tube protein; the membrane-penetrating needle, situated at the distal end of the tube; and another protein associated with the needle and tube. We propose that T6SS is a multicomponent structure whose extracellular part resembles both structurally and functionally a bacteriophage tail, an efficient machine that translocates proteins and DNA across lipid membranes into cells.


Magnetic Field Observations near Venus: Preliminary Results from Mariner 10.
The NASA-GSFC magnetic field experiment on Mariner 10 is the first flight of a dual magnetometer system conceived to permit accurate measurements of weak magnetic fields in space in the presence of a significant and variable spacecraft magnetic field. Results from a preliminary analysis of a limted data set are summarized in this report, which is restricted primarily to Venus encounter. A detached bow shock wave that develops as the super Alfvénic solar wind interacts with the Venusian atmosphere has been observed. However, the unique coincidence of trajectory position and interplanetary field orientation at the time of bow shock crossing led to a very disturbed shock profile with considerably enhanced upstream magnetic fluctuations. At present it is not possible to ascertain the nature and characteristics of the obstacle responsible for deflecting the solar wind flow. Far downstream disturbances associated with the solar wind wake have been observed.


Adaptive calibration of imaging array detectors.
We present two methods for nonuniformity correlation of imaging array detectors based on neural networks; both exploit image properties to supply lack of calibrations and maximize the entropy of the output. The first method uses a self-organizing net that produces a linear correction of the raw data with coefficients that adapt continuously. The second method employs a kind of contrast equalization curve to match pixel distributions. Our work originates from silicon detectors, but the treatment is general enough to be applicable to many kinds of array detectors like those used in infrared imaging or in high-energy physics.


Carbazole derivatives: a promising scenario for breast cancer treatment.
Chemotherapeutics used in cancer treatment may elicit pleiotropic effects interfering, for instance, directly on DNA metabolism or on endoplasmic organelles functions. Recently there has been a trend towards the use of molecular-targeted therapies as alternative treatments of cancer, arising from the need to overcome the onset of undesired side effects or drug-resistance. Thus, a major challenge is the design and synthesis of new agents able to interact with specific cellular components, often over-expressed or altered in cancerous cells, such as telomerase and topoisomerase or protein kinases, with reduced toxicity at effective doses. The main molecular targets for the development of new anticancer drugs include: cell surface receptors, signal transduction pathways, enzymes, gene transcription, ubiquitin-proteasome/heat shock proteins, and anti-angiogenic agents. Several natural or synthetic polycyclic molecules with carbazolic nucleus, which show attractive drug-like properties, were identified with the aim to increase their biological activities and their specificity, obtaining cytotoxic agents effective in a panel of cancer cell lines. The cytotoxic profile of these compounds has been assessed using several in vitro assays as, for instance, MTT, colony formation, and flow cytometry assays and some of these compounds showed an interesting profile at sub-micromolar concentrations. The usefulness of some carbazole derivatives has been demonstrated, as well, in preclinical studies.


Efficiency performance of China's health care delivery system.
Improving efficiency performance of the health care delivery system has been on the agenda for the health system reform that China initiated in 2009. This study examines the changes in efficiency performance and determinants of efficiency after the reform to provide evidence to assess the progress of the reform from the perspective of efficiency. Descriptive analysis, Data Envelopment Analysis, the Malmquist Index, and multilevel regressions are used with data from multiple sources, including the World Bank, the China Health Statistical Yearbook, and routine reports. The results indicate that over the last decade, health outcomes compared with health investment were relatively higher in China than in most other countries worldwide, and the trend was stable. The overall efficiency and total factor productivity increased after the reform, indicating that the reform was likely to have had a positive impact on the efficiency performance of the health care delivery system. However, the health care delivery structure showed low system efficiency, mainly attributed to the weakened primary health care system. Strengthening the primary health care system is central to enhancing the future performance of China's health care delivery system.


Creatine supplementation: can it improve quality of life in the elderly without associated resistance training?
Ageing is associated with decreased muscle mass, strength, power and function, and reduction in bone density and mineral content, leading to reduced independence and increased risk of falls. Creatine supplementation is reported to improve muscular strength and performance with training in younger athletes, and therefore could benefit older individuals. This review critically appraises the current literature on whether creatine supplementation enhances muscular performance and function, body composition, bone mineral density and content in older adults without the addition of resistance training, and thus determines whether creatine supplementation can lead to an improved lifestyle for the sedentary elderly population. There is conflicting evidence regarding the usefulness of creatine supplementation in older subjects. Generally, however, creatine supplementation, without associated resistance training, seems to enhance muscular strength, power and endurance, increase lean body mass (LBM) and improve the functional capacity of the elderly. Furthermore, it has been demonstrated that increased muscle mass due to creatine supplementation can result in increased local bone density. It appears that the effect of creatine supplementation is more beneficial in larger muscles and less effective in smaller muscles, however there are exceptions. The mechanism by which creatine supplementation works requires further research, however it is likely that the effects of creatine are related to creatine kinase activity, providing enhanced energy production for greater muscular contraction. These data indicate that creatine supplementation without associated training in the elderly could potentially delay atrophy of muscle mass, improve endurance and strength, and increase bone strength, and thus may be a safe therapeutic strategy to help decrease loss in functional performance of everyday tasks.


Patient-derived xenografts of triple-negative breast cancer reproduce molecular features of patient tumors and respond to mTOR inhibition.
Triple-negative breast cancer (TNBC) is aggressive and lacks targeted therapies. Phosphatidylinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways are frequently activated in TNBC patient tumors at the genome, gene expression and protein levels, and mTOR inhibitors have been shown to inhibit growth in TNBC cell lines. We describe a panel of patient-derived xenografts representing multiple TNBC subtypes and use them to test preclinical drug efficacy of two mTOR inhibitors, sirolimus (rapamycin) and temsirolimus (CCI-779). We generated a panel of seven patient-derived orthotopic xenografts from six primary TNBC tumors and one metastasis. Patient tumors and corresponding xenografts were compared by histology, immunohistochemistry, array comparative genomic hybridization (aCGH) and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) sequencing; TNBC subtypes were determined. Using a previously published logistic regression approach, we generated a rapamycin response signature from Connectivity Map gene expression data and used it to predict rapamycin sensitivity in 1,401 human breast cancers of different intrinsic subtypes, prompting in vivo testing of mTOR inhibitors and doxorubicin in our TNBC xenografts. Patient-derived xenografts recapitulated histology, biomarker expression and global genomic features of patient tumors. Two primary tumors had PIK3CA coding mutations, and five of six primary tumors showed flanking intron single nucleotide polymorphisms (SNPs) with conservation of sequence variations between primary tumors and xenografts, even on subsequent xenograft passages. Gene expression profiling showed that our models represent at least four of six TNBC subtypes. The rapamycin response signature predicted sensitivity for 94% of basal-like breast cancers in a large dataset. Drug testing of mTOR inhibitors in our xenografts showed 77 to 99% growth inhibition, significantly more than doxorubicin; protein phosphorylation studies indicated constitutive activation of the mTOR pathway that decreased with treatment. However, no tumor was completely eradicated. A panel of patient-derived xenograft models covering a spectrum of TNBC subtypes was generated that histologically and genomically matched original patient tumors. Consistent with in silico predictions, mTOR inhibitor testing in our TNBC xenografts showed significant tumor growth inhibition in all, suggesting that mTOR inhibitors can be effective in TNBC, but will require use with additional therapies, warranting investigation of optimal drug combinations.


Norepinephrine modulates the effect of neuropeptides in coeliac ganglion on ovarian hormones release: its relationship with ovarian nitric oxide and nerve growth factor.
Ovarian steroids are modulated by neural influences. In this work we investigate whether norepinephrine (NE) modifies the vasoactive intestinal peptide (VIP) or neuropeptide Y (NPY) actions in coeliac ganglion (CG) on the ovarian hormone release, and evaluate the participation of nitric oxide (NO), measured as nitrite, and of inducible nitric oxide synthetase (iNOS) protein, nerve growth factor (NGF) and its trkA receptor gene expression in the ovarian response. The study was performed in the ex vivo CG-superior ovarian nerve (SON)-ovary system of rats on diestrus day 2 (D2). CG and ovary were placed in separate compartments connected by the SON and incubated with Krebs-Ringer buffer. After addition of 50 ng/ml VIP, 50 ng/ml NPY, 10-6 M NE, or a mix of VIP+NE or NPY+NE in ganglion, samples from the ovarian compartment were taken at different times throughout 180 minutes to measure progesterone, androstenedione and nitrite levels. VIP and NPY in ganglion induced an increase of progesterone release that was associated for VIP, but not NPY, with a decrease of ovarian nitrite levels, iNOS protein, and NGF/trkA receptor mRNA expression. By contrast, NE in ganglion decreased progesterone, an effect that was suppressed by addition of propranolol in ganglion, and increased nitrites/iNOS and NGF/trkA receptor expression in ovary. GABA A receptor antagonist bicuculline (20 muM) added in ovarian compartment prevented the inhibitory effect on progesterone caused by NE in CG. Androstenedione was not modified under neuropeptides or NE ganglionic stimulation. Finally, results from VIP+NE or NPY+NE in ganglion showed that ovarian response on D2 induced by VIP or NPY alone is moderated by the opposite action of NE, and occurs only on progesterone, the most sensitive steroid to neural action.


Somatic inactivation of Pkd2 results in polycystic kidney disease.
Germline mutations in PKD2 cause autosomal dominant polycystic kidney disease. We have introduced a mutant exon 1 in tandem with the wild-type exon 1 at the mouse Pkd2 locus. This is an unstable allele that undergoes somatic inactivation by intragenic homologous recombination to produce a true null allele. Mice heterozygous and homozygous for this mutation, as well as Pkd+/- mice, develop polycystic kidney and liver lesions that are indistinguishable from the human phenotype. In all cases, renal cysts arise from renal tubular cells that lose the capacity to produce Pkd2 protein. Somatic loss of Pkd2 expression is both necessary and sufficient for renal cyst formation in ADPKD, suggesting that PKD2 occurs by a cellular recessive mechanism.


Early antibiotic exposure and development of asthma and allergic rhinitis in childhood.
The prevalence of pediatric allergic diseases has increased rapidly in the United States over the past few decades. Recent studies suggest an association between the increase in allergic disease and early disturbances to the gut microbiome. The gut microbiome is a set of intestinal microorganisms that begins to form during birth and is highly susceptible to disturbance during the first year of life. Early antibiotic exposure may negatively impact the gut microbiota by altering the bacterial composition and causing dysbiosis, thus increasing the risk for developing childhood allergic disease. We performed a retrospective chart review of data in Loyola University Medical Center's (LUMC) Epic system from 2007 to 2016. We defined antibiotic exposure as orders in both the outpatient and inpatient settings. Inclusion criteria were being born at LUMC with at least two follow up visits. Asthma and allergic rhinitis diagnoses were obtained using ICD 9 and ICD 10 codes. We controlled for multiple confounding factors. Using Stata, bivariate logistic regression was performed between antibiotics from 0 to 12 months of life and development of disease. This analysis was repeated for total lifetime antibiotics. We defined statistically significant as p < .05. The administration of antibiotics within the first 12 months of life was significantly associated with lifetime asthma (OR 2.66; C. I 1.11-6.40) but not allergic rhinitis. There was a significant association between lifetime antibiotics and asthma (OR 3.54; C. I 1.99-6.30) and allergic rhinitis (OR 2.43; C. I 1.43-4.11). Antibiotic administration in the first year of life and throughout lifetime is significantly associated with developing asthma and allergic rhinitis. These results provide support for a conservative approach regarding antibiotic use in early childhood.


Secretome analysis of Aspergillus fumigatus reveals Asp-hemolysin as a major secreted protein.
Surface-associated and secreted proteins represent primarily exposed components of Aspergillus fumigatus during host infection. Several secreted proteins are known to be involved in defense mechanisms or immune evasion, thus, probably contributing to pathogenicity. Furthermore, several secreted antigens were identified as possible biomarkers for the verification of diseases caused by Aspergillus species. Nevertheless, there is only limited knowledge about the composition of the secretome and about molecular functions of particular proteins. To identify secreted proteins potentially essential for virulence, the core secretome of A. fumigatus grown in minimal medium was determined. Two-dimensional gel electrophoretic separation and subsequent MALDI-TOF-MS/MS analyses resulted in the identification of 64 different proteins. Additionally, secretome analyses of A. fumigatus utilizing elastin, collagen or keratin as main carbon and nitrogen source were performed. Thereby, the alkaline serine protease Alp1 was identified as the most abundant protein and hence presumably represents an important protease during host infection. Interestingly, the Asp-hemolysin (Asp-HS), which belongs to the protein family of aegerolysins and which was often suggested to be involved in fungal virulence, was present in the secretome under all growth conditions tested. In addition, a second, non-secreted protein with an aegerolysin domain annotated as Asp-hemolysin-like (HS-like) protein can be found to be encoded in the genome of A. fumigatus. Generation and analysis of Asp-HS and HS-like deletion strains revealed no differences in phenotype compared to the corresponding wild-type strain. Furthermore, hemolysis and cytotoxicity was not altered in both single-deletion and double-deletion mutants lacking both aegerolysin genes. All mutant strains showed no attenuation in virulence in a mouse infection model for invasive pulmonary aspergillosis. Overall, this study provides a comprehensive analysis of secreted proteins of A. fumigatus and a detailed characterization of hemolysin mutants.


Effect of Rocuronium vs Succinylcholine on Endotracheal Intubation Success Rate Among Patients Undergoing Out-of-Hospital Rapid Sequence Intubation: A Randomized Clinical Trial.
Rocuronium and succinylcholine are often used for rapid sequence intubation, although the comparative efficacy of these paralytic agents for achieving successful intubation in an emergency setting has not been evaluated in clinical trials. Succinylcholine use has been associated with several adverse events not reported with rocuronium. To assess the noninferiority of rocuronium vs succinylcholine for tracheal intubation in out-of-hospital emergency situations. Multicenter, single-blind, noninferiority randomized clinical trial comparing rocuronium (1.2 mg/kg) with succinylcholine (1 mg/kg) for rapid sequence intubation in 1248 adult patients needing out-of-hospital tracheal intubation. Enrollment occurred from January 2014 to August 2016 in 17 French out-of-hospital emergency medical units. The date of final follow-up was August 31, 2016. Patients were randomly assigned to undergo tracheal intubation facilitated by rocuronium (n = 624) or succinylcholine (n = 624). The primary outcome was the intubation success rate on first attempt. A noninferiority margin of 7% was chosen. A per-protocol analysis was prespecified as the primary analysis. Among 1248 patients who were randomized (mean age, 56 years; 501 [40.1%] women), 1230 (98.6%) completed the trial and 1226 (98.2%) were included in the per-protocol analysis. The number of patients with successful first-attempt intubation was 455 of 610 (74.6%) in the rocuronium group vs 489 of 616 (79.4%) in the succinylcholine group, with a between-group difference of -4.8% (1-sided 97.5% CI, -9% to ∞), which did not meet criteria for noninferiority. The most common intubation-related adverse events were hypoxemia (55 of 610 patients [9.0%]) and hypotension (39 of 610 patients [6.4%]) in the rocuronium group and hypoxemia (61 of 616 [9.9%]) and hypotension (62 of 616 patients [10.1%]) in the succinylcholine group. Among patients undergoing endotracheal intubation in an out-of-hospital emergency setting, rocuronium, compared with succinylcholine, failed to demonstrate noninferiority with regard to first-attempt intubation success rate. ClinicalTrials.gov Identifier: NCT02000674.


Prediction of restraints among youth in a psychiatric hospital: application of translational action research.
This study extends a translational action research program by applying a theoretically based measure of risk in predicting incidents of restraint among children and adolescents in a secure psychiatric hospital. Youth inpatients (N = 149, aged 5-17 years) were assessed at intake for the presence of selected individual and contextual risk factors, and their involvement in critical incidents was tracked (i.e., number of episodes in which restraint was applied) for the remainder of their hospitalization. Models including history of aggression or history of previous placements as well as combined models including several individual and contextual factors significantly predicted the likelihood of a youth becoming involved in at least one restraint. Unique predictors of restraint involvement included history of aggression against adults and history of previous psychiatric hospitalizations. None of the variables assessed predicted the extent of a youth's restraint involvement. The implications of these findings are discussed with respect to future research and empirically informed practice with high-risk youth.


Impact of male fertility status on the transcriptome of the bovine epididymis.
Can region-specific transcriptional profiling of the epididymis from fertile and sub-fertile bulls predict the etiology of fertility/sub-fertility in males? The highly regulated gene expression along the bovine epididymis is affected by the fertility status of bulls used for artificial insemination. In mammals, sperm maturation and storage occur in the epididymis. Each epididymal segment has his own transcriptomic signature that modulates the intraluminal composition and consequently governs sequential modifications of the maturing male gamete. Epididymides from six Holstein bulls with documented fertility were used. These bulls were divided into two groups: high fertility (n = 3), and medium-low fertility (n = 3) and their epididymal transcriptomic profiles were analyzed. Bovine cDNA microarray probing and bioinformatic tools were used to identify genes that are differentially expressed in caput, corpus and cauda epididymidal tissues of bulls with the documented fertility index. Hierarchical clustering and principal component analysis revealed a clear separation between caput, corpus and cauda epididymides. Some transcripts characterize a particular anatomical segment, whereas others are expressed in two out of three epididymal segments. Gene ontology analysis allowed deduction of specific functions played by each epididymal segment. The transcriptional profiles between fertile versus sub-fertile conditions clustered most closely in the corpus and cauda segments, whereas the profiles in the caput segment were distinct between fertile and sub-fertile bulls. Of the differently expressed genes, 10 (AKAP4, SMCP, SPATA3, TCP11, ODF1, CTCFL, SPATA18, ADAM28, SORD and FAM161A) were found to exert functions related to reproductive systems and 5 genes (DEAD, CYST11, DEFB119, DEFB124 and MX1) were found to be associated with the defense response. The GEO number for public access of bovine epididymis microarray data is GSE96602. Further work is required to link these modulations of epididymal functions with sperm fertilizing ability in order to understand the etiology of certain cases of idiopathic infertility in livestock and men. As fertility can be quantified in bulls used for artificial insemination, this species is a unique model to aid in the understanding of male fertility/sub-fertility in man. Our data provide a molecular characterization that will facilitate advances in understanding the involvement of epididymal physiology in sub/infertility etiology. This work was supported by a grant to R.S. from the Natural Sciences and Engineering Research Council (NSERC) of Canada. C.L., A.A., E.C. and R.S. have no conflict of interest to declare. P.B. is R&D director at Alliance Boviteq Inc., a bovine artificial insemination company.


Design of an ultra-compact electro-absorption modulator comprised of a deposited TiN/HfO₂/ITO/Cu stack for CMOS backend integration.
An ultra-compact electro-absorption (EA) modulator operating around 1.55-μm telecom wavelengths is proposed and theoretically investigated. The modulator is comprised of a stack of TiN/HfO2</ITO/Cu conformally deposited on a single-mode stripe waveguide to form a hybrid plasmonic waveguide (HPW). Since the thin ITO layer can behave as a semiconductor, the stack itself forms a MOS capacitor. A voltage is applied between the Cu and TiN layers to change the electron concentration of ITO (NITO), which in turn changes its permittivity as well as the propagation loss of HPW. For a HPW comprised of a Cu/3-nm-ITO/5-nm-HfO2/5-nm-TiN stack on a 400-nm × 340-nm-Si stripe waveguide, the propagation loss for the 1.55-μm TE (TM) mode increases from 1.6 (1.4) to 23.2 (23.9) dB/μm when the average NITO in the 3-nm ITO layer increases from 2 × 10(20) to 7 × 10(20) cm(-3), which is achieved by varying the voltage from -2 to 4 V if the initial NITO is 3.5 × 10(20) cm(-3). As a result, a 1-μm-long EA modulator inserted in the 400-nm × 340-nm-Si stripe waveguide exhibits insertion loss of 2.9 (3.2) dB and modulation depth of 19.9 (15.2) dB for the TE (TM) mode. The modulation speed is ~11 GHz, limited by the RC delay, and the energy consumption is ~0.4 pJ/bit. The stack can also be deposited on a low-index-contrast waveguide such as Si3N4. For example, a 4-μm-long EA modulator inserted in an 800-nm × 600-nm-Si3N4 stripe waveguide exhibits insertion loss of 6.3 (3.5) dB and modulation depth of 16.5 (15.8) dB for the TE (TM) mode. The influences of the ITO, TiN, HfO2 layers and the beneath dielectric core, as well as the processing tolerance, on the performance of the proposed EA modulator are systematically investigated.


Cross-sectional and longitudinal associations between objectively measured sedentary time and metabolic disease: the Coronary Artery Risk Development in Young Adults (CARDIA) study.
Prolonged sedentary time (ST) might be contributing to the diabetes epidemic, but most studies have been cross-sectional and few have objectively measured ST. The purpose of this study was to evaluate cross-sectional and 5-year longitudinal relationships between ST and metabolic parameters and outcomes. This was an analysis of 2,027 Coronary Artery Risk Development in Young Adults (CARDIA) study participants (aged 38-50 years, 57% female, and mean BMI of 29.0 ± 7.0 kg/m(2)) with accelerometry data (≥4 days with ≥10 h/day) measured at the year 20 follow-up exam (2005-2006). Metabolic variables (fasting glucose, fasting insulin, 2-h postchallenge glucose, HOMA of insulin resistance [HOMA-IR], and HbA1c) and outcomes (impaired fasting glucose [IFG], impaired glucose tolerance [IGT], prediabetes by HbA1c, and diabetes) were assessed concurrently and 5 years later. Average ST was 8.1 ± 1.7 h/day or 55 ± 10% of wear time. Each additional hour per day of ST was cross-sectionally associated with a 3% higher fasting insulin and HOMA-IR (both P < 0.01) but not 5-year changes in metabolic parameters. Having ≥10 h/day vs. <6 h/day of ST was associated with an odds ratio (OR) = 2.74 (95% CI 1.13, 6.62) for IGT and an OR = 3.80 (95% CI 1.39, 10.35) for diabetes. ST was not associated with prevalent IFG, prevalent prediabetes by HbA1c, or 5-year incidence of any metabolic outcomes (all P > 0.05). ST was independently related to insulin, HOMA-IR, and prevalent diabetes and IGT but did not predict 5-year changes in metabolic parameters or incidence of metabolic outcomes. These results suggest that higher ST may not be a risk factor for future metabolic outcomes, but more research with repeated ST measurement and longer follow-up is needed.


Multi-spatial-mode single-beam quadrature squeezed states of light from four-wave mixing in hot rubidium vapor.
We present experimental results on the generation of multi-spatial-mode, single-beam, quadrature squeezed light using four-wave mixing in hot Rb vapor. Squeezing and phase-sensitive deamplification are observed over a range of powers and detunings near the (85)Rb D1 atomic transition. We observe -3 dB of vacuum quadrature squeezing, comparable to the best single-spatial mode results previously reported using atomic vapors, however, produced here in multiple spatial modes. We confirm that the squeezing is present in more than one transverse mode by studying the spatial distribution of the noise properties of the field.


Chimeric PD-1:28 Receptor Upgrades Low-Avidity T cells and Restores Effector Function of Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy.
Inherent intermediate- to low-affinity T-cell receptors (TCR) that develop during the natural course of immune responses may not allow sufficient activation for tumor elimination, making the majority of T cells suboptimal for adoptive T-cell therapy (ATT). TCR affinity enhancement has been implemented to provide stronger T-cell activity but carries the risk of creating undesired cross-reactivity leading to potential serious adverse effects in clinical application. We demonstrate here that engineering of low-avidity T cells recognizing a naturally processed and presented tumor-associated antigen with a chimeric PD-1:28 receptor increases effector function to levels seen with high-avidity T cells of identical specificity. Upgrading the function of low-avidity T cells without changing the TCR affinity will allow a large arsenal of low-avidity T cells previously thought to be therapeutically inefficient to be considered for ATT. PD-1:28 engineering reinstated Th1 function in tumor-infiltrating lymphocytes that had been functionally disabled in the human renal cell carcinoma environment without unleashing undesired Th2 cytokines or IL10. Involved mechanisms may be correlated to restoration of ERK and AKT signaling pathways. In mouse tumor models of ATT, PD-1:28 engineering enabled low-avidity T cells to proliferate stronger and prevented PD-L1 upregulation and Th2 polarization in the tumor milieu. Engineered T cells combined with checkpoint blockade secreted significantly more IFNγ compared with T cells without PD-1:28, suggesting a beneficial combination with checkpoint blockade therapy or other therapeutic strategies. Altogether, the supportive effects of PD-1:28 engineering on T-cell function make it an attractive tool for ATT. Cancer Res; 77(13); 3577-90. ©2017 AACR.


Targeted nanoparticles that mimic immune cells in pain control inducing analgesic and anti-inflammatory actions: a potential novel treatment of acute and chronic pain condition.
The peripheral immune-derived opioid analgesic pathway has been well established as a novel target in the clinical pain management of a number of painful pathologies, including acute inflammatory pain, neuropathic pain, and rheumatoid arthritis. Our objective was to engineer targeted nanoparticles that mimic immune cells in peripheral pain control to deliver opioids, in particular loperamide HCl, specifically to peripheral opioid receptors to induce analgesic and anti-inflammatory actions for use in painful inflammatory conditions. This peripheral analgesic system is devoid of central opioid mediated side effects (e.g., respiratory depression, sedation, dependence, tolerance). A randomized, double blind, controlled animal trial. Thirty-six adult male Wistar rats (200 - 250 g) were randomly divided into 6 groups: loperamide HCl-encapsulated anti-ICAM-1 immunoliposomes, naloxone methiodide + loperamide HCl-encapsulated anti-ICAM-1 immunoliposomes, loperamide HCl-encapsulated liposomes, empty anti-ICAM-1 immunoliposomes, empty liposomes, and loperamide solution. Animals received an intraplantar injection of 150 μL Complete Freund's Adjuvant (CFA) into the right hindpaw and experiments were performed 5 days post-CFA injection, which corresponded to the peak inflammatory response. All formulations were administered intravenously via tail vein injection. The dose administered was 200 μL, which equated to 0.8 mg of loperamide HCl for the loperamide HCl treatment groups (sub-therapeutic dose). Naloxone methiodide (1 mg/kg) was administered via intraplantar injection, 15 minutes prior to loperamide-encapsulated anti-ICAM-1 immunoliposomes. An investigator blinded to the treatment administered assessed the time course of the antinociceptive and anti-inflammatory effects using a paw pressure analgesiometer and plethysmometer, respectively. Biodistribution studies were performed 5 days post-CFA injection with anti-ICAM-1 immunoliposomes and control liposomes via tail vein injection using liquid scintillation counting (LSC). Administration of liposomes loaded with loperamide HCl, and conjugated with antibody to intercellular adhesion molecule-1 (anti-ICAM-1), exerted analgesic and anti-inflammatory effects exclusively in peripheral painful inflamed tissue. These targeted nanoparticles produced highly significant analgesic and anti-inflammatory effects over the 48 hour time course studied following intravenous administration in rats with Complete Freund's Adjuvant-induced inflammation of the paw. All control groups showed no significant antinociceptive or anti-inflammatory effects. Our biodistribution study demonstrated specific localization of the targeted nanoparticles to peripheral inflammatory tissue and no significant uptake into the brain. In vivo studies were performed in the well-established rodent model of acute inflammatory pain. We are currently studying this approach in chronic pain models known to have clinical activation of the peripheral immune-derived opioid response. The study presents a novel approach of opioid delivery specifically to injured tissues for pain control. The study also highlights a novel anti-inflammatory role for peripheral opioid targeting, which is of clinical relevance. The potential also exists for the modification of these targeted nanoparticles with other therapeutic compounds for use in other painful conditions.


Do Psychosocial Interventions Improve Quality of Life and Wellbeing in Adults with Neuromuscular Disorders? A Systematic Review and Narrative Synthesis.
Quality of life and well-being are frequently restricted in adults with neuromuscular disorders. As such, identification of appropriate interventions is imperative. The objective of this paper was to systematically review and critically appraise quantitative studies (RCTs, controlled trials and cohort studies) of psychosocial interventions designed to improve quality of life and well-being in adults with neuromuscular disorders. A systematic review of the published and unpublished literature was conducted. Studies meeting inclusion criteria were appraised using a validated quality assessment tool and results presented in a narrative synthesis. Out of 3,136 studies identified, ten studies met criteria for inclusion within the review. Included studies comprised a range of interventions including: cognitive behavioural therapy, dignity therapy, hypnosis, expressive disclosure, gratitude lists, group psychoeducation and psychologically informed rehabilitation. Five of the interventions were for patients with Amyotrophic Lateral Sclerosis (ALS). The remainder were for patients with post-polio syndrome, muscular dystrophies and mixed disorders, such as Charcot-Marie-Tooth disease, myasthenia gravis and myotonic dystrophy. Across varied interventions and neuromuscular disorders, seven studies reported a short-term beneficial effect of intervention on quality of life and well-being. Whilst such findings are encouraging, widespread issues with the methodological quality of these studies significantly compromised the results. There is no strong evidence that psychosocial interventions improve quality of life and well-being in adults with neuromuscular disorders, due to a paucity of high quality research in this field. Multi-site, randomised controlled trials with active controls, standardised outcome measurement and longer term follow-ups are urgently required.


Symptoms, personality traits, and stress in people with mobile phone-related symptoms and electromagnetic hypersensitivity.
Some people report symptoms that they associate with electromagnetic field (EMF) exposure. These symptoms may be related to specific EMF sources or to electrical equipment in general (perceived electromagnetic hypersensitivity, EHS). Research and clinical observations suggest a difference between mobile phone (MP)-related symptoms and EHS with respect to symptom prevalence, psychological factors, and health prognosis. This study assessed prevalence of EMF-related and EMF-nonrelated symptoms, anxiety, depression, somatization, exhaustion, and stress in people with MP-related symptoms or EHS versus a population-based sample and a control sample without EMF-related symptoms. Forty-five participants with MP-related symptoms and 71 with EHS were compared with a population-based sample (n=106) and a control group (n=63) using self-report questionnaires. The EHS group reported more symptoms than the MP group, both EMF-related and EMF-nonrelated. The MP group reported a high prevalence of somatosensory symptoms, whereas the EHS group reported more neurasthenic symptoms. As to self-reported personality traits and stress, the case groups differed only on somatization and listlessness in a direct comparison. In comparison with the reference groups, the MP group showed increased levels of exhaustion and depression but not of anxiety, somatization, and stress; the EHS group showed increased levels for all of the conditions except for stress. The findings support the idea of a difference between people with symptoms related to specific EMF sources and people with general EHS with respect to symptoms and anxiety, depression, somatization, exhaustion, and stress. The differences are likely to be important in the management of patients.


[Bioethical principles in public health: limitations and proposals].
We propose to analyze the specificity of ethical problems in public health issues and to elucidate the applicability of principlism as a problem-solving strategy in this realm. Although well-established in clinical ethics, principlism is not an adequate model to be used in public health, since it is basically intended to serve as a moral guide in the physician-patient encounter. We discuss the possible adequacy of principles like "solidarity", "ontic responsibility" (as proposed by Jonas), and "caring or diaconal responsibility" as presented by Lévinas. Solidarity appears to be insufficiently specified, whereas the other two perspectives may be adapted to public health issues by bringing together Jonas' ontological and Lévinas' transcendental concerns to form a principle of protection that might better serve the purposes of such an ethics. This principle would help to identify more clearly the goals and agents involved in the implementation of public policies that are expected to be both morally correct and pragmatically effective.


Breastfeeding and smoking among low-income women: results of a longitudinal qualitative study.
The benefits of breastfeeding for infants and mothers have been well established, yet rates of breastfeeding remain well below national recommendations in the United States and even lower for women who smoke during pregnancy. Primary goals of this study were to explore contextual factors that contribute to breastfeeding intentions and behavior and to examine how smoking status affected women's decision making about breastfeeding. This paper is based on a longitudinal qualitative study of smoking, pregnancy, and breastfeeding among 44 low-income women in the southwest U.S. who smoked during pregnancy. Each woman was interviewed 9 times; 6 times during pregnancy and 3 times postpartum using semistructured questionnaires. Interviews lasted 1 to 3 hours and were tape-recorded, transcribed, and analyzed. Despite 36 (82%) respondents stating that they intended to breastfeed for an average duration of 8 months, rates of breastfeeding initiation and duration were much lower than intentions. By 6 months postpartum, only two women were breastfeeding exclusively. Women perceived that a strong risk of harming the baby was posed by smoking while breastfeeding and received little encouragement to continue breastfeeding despite an inability to stop smoking. The perceptions of the toxic, addictive, and harmful effects of smoking on breastmilk constitution and quantity factored into reasons why women weaned their infants from breastfeeding much earlier than the recommended 6 months. The results indicate a need for more consistency and routine in educating women on the relationship between smoking and breastfeeding and in promoting breastfeeding in spite of smoking postpartum.


Retinoic acid controls the bilateral symmetry of somite formation in the mouse embryo.
A striking characteristic of vertebrate embryos is their bilaterally symmetric body plan, which is particularly obvious at the level of the somites and their derivatives such as the vertebral column. Segmentation of the presomitic mesoderm must therefore be tightly coordinated along the left and right embryonic sides. We show that mutant mice defective for retinoic acid synthesis exhibit delayed somite formation on the right side. Asymmetric somite formation correlates with a left-right desynchronization of the segmentation clock oscillations. These data implicate retinoic acid as an endogenous signal that maintains the bilateral synchrony of mesoderm segmentation, and therefore controls bilateral symmetry, in vertebrate embryos.


The Development of Evidence Briefs to Transfer Knowledge About Advanced Practice Nursing Roles to Providers, Policymakers and Administrators.
The transfer of health-related research knowledge between producers and users is a complex, dynamic and iterative process. There has been little research describing the preferred knowledge transfer strategies used by different stakeholder groups, including healthcare providers, policymakers and administrators. The purpose of the survey was to gain an understanding of the content and preferred dissemination strategies of knowledge users of briefing notes about the effectiveness of advanced practice nursing (APN) roles in Canada. An on-line cross-sectional survey was conducted from December 2011 to January 2012. Purposeful sampling was used to identify the target audience. The questionnaire included six items. The response rate was 44% (n=75/170). Participants identified that the briefing note should concisely summarize definitions for APN roles and information about the safety, effectiveness, cost savings and effective role implementation strategies. Multiple approaches were favoured to disseminate the information. Preferred dissemination strategies included personalized emails, meeting with briefing note recipients, engaging nurse practitioners and clinical nurse specialists in organizations where APN roles have been successfully implemented, engaging the media and using social media. The use of briefing notes has shown promise. More research is needed to evaluate the effectiveness of tailored briefing notes.


Thyroid Function and the Risk of Fibrosis of the Liver, Heart, and Lung in Humans: A Systematic Review and Meta-Analysis.
Background: Fibrotic diseases have an unclear etiology and poor prognosis. Fluctuations in thyroid function may play a role in the development of fibrosis, but evidence is fragmented and inconclusive. This systematic review and meta-analysis aimed to investigate the association of thyroid function with fibrotic diseases of the liver, heart, and lung in humans. Methods: We searched PubMed, Medline Ovid, Embase Ovid, and Web-of-Science for studies published from inception to 14 June 2019, to identify observational studies that investigated the association of thyroid function with fibrosis of the liver, heart, and lung in humans. Study quality was evaluated by the Newcastle-Ottawa Scale. The Mantel-Haenszel method was used to pool the odds ratios (ORs) of studies investigating the association of hypothyroidism with liver fibrosis. Results: Of the 2196 identified articles, 18 studies were included in the systematic review, of which 11 studies reported on liver fibrosis, 4 on myocardial fibrosis, and 3 on pulmonary fibrosis. The population sample size ranged from 36 to 7259 subjects, with median mean age 51 years (range, 36-69) and median percentage of women 53 (range, 17-100). The risk of bias of studies was low to moderate to high. Higher serum thyrotropin and lower thyroid hormone levels were generally associated with higher likelihood of fibrosis. Compared with euthyroidism, overt and subclinical hypothyroidism was associated with a higher likelihood of fibrosis in the liver (six of seven studies), heart (three of three studies), and lung (three of three studies). Based on the results of the seven studies included in the meta-analysis, overt and subclinical hypothyroidism was associated with an increased risk of liver fibrosis (pooled OR, 2.81; 95% confidence interval [CI], 1.74-4.53; heterogeneity, I2 31.4%; pooled OR, 2.12; CI, 1.45-3.12; heterogeneity, I2 0%; respectively), without evidence of publication bias. Conclusions: This study suggests that low thyroid function is associated with increased likelihood of chronic fibrotic diseases of the liver, heart, and lung. However, the evidence is mainly based on cross-sectional data. Prospective studies and randomized clinical trials are needed to investigate the potential efficacy of thyroid hormone and its analogs on the occurrence and progression of fibrosis.


Quantification of Modified Tyrosines in Healthy and Diabetic Human Urine using Liquid Chromatography/Tandem Mass Spectrometry.
The quantification of urinary oxidized tyrosines, dityrosine (DiY), nitrotyrosine (NY), bromotyrosine (BrY), and dibromotyrosine (DiBrY), was accomplished by quadruple liquid chromatography-tandem mass spectrometry (LC/MS/MS). The sample was partially purified by solid phase extraction, and was then applied to the LC/MS/MS using multiple-reaction monitoring (MRM) methods. The analysis for the DiY quantification was done first. The residual samples were further butylated with n-butanol/HCl, and the other modified tyrosines were then quantified with isotopic dilution methods. MRM peaks of the modified tyrosines (DiY, NY, BrY, and DiBrY) from human urine were measured and the elution times coincided with the authentic and isotopic standards. The amounts of modified tyrosines in healthy human urine (n = 23) were 8.8 +/- 0.6 (DiY), 1.4 +/- 0.4 (NY), 3.8 +/- 0.3 (BrY), and 0.7 +/- 0.1 (DiBrY) micromol/mol of creatinine, respectively. A comparison of the modified tyrosines with urinary 8-oxo-deoxyguanosine, pentosidine, and N(epsilon)-(hexanoyl)lysine was also performed. Almost all products, except for NY, showed good correlations with each other. The amounts of the modified tyrosines (NY, BrY, and DiBrY) in the diabetic urine were higher than those in the urine from healthy people.


Fracture of a Y-TZP ceramic femoral head. Analysis of a fault.
We studied factors contributing to the initiation of fracture and failure of a zirconia ceramic femoral head. The materials retrieved during a revision total hip replacement were submitted to either visual, stereomicroscopic and scanning electron microscopy (SEM) or SEM and energy-dispersive X-ray analysis. X-ray diffraction was performed in order to investigate the extent of tetragonal to monoclinic phase transition. Histological examination was performed on the periprosthetic tissues. The results showed that failure was due to the propagation during clinical use of defects which may have been introduced into the material during the processing of the ceramic, rather than those intrinsic to zirconia. The literature relating to previous failures of zirconia components is reviewed.


New oral anticoagulants-TURKey (NOAC-TURK): Multicenter cross-sectional study.
New oral anticoagulants (NOACs) are increasingly used both for prevention of stroke in non-valvular atrial fibrillation (NVAF) and the treatment of venous thromboembolism (VTE). In this study, we aimed to evaluate the current patterns of NOACs treatment in Turkey. Moreover, demographic and clinical parameters and bleeding and/or embolic events under NOACs treatment were analyzed. The New Oral Anticoagulants-TURKey (NOAC-TURK) study was designed as a multicenter cross-sectional study. A total of 2,862 patients from 21 different centers of Turkey under the treatment of NOACs for at least three months were included in this study. Demographic, clinical, and laboratory characteristics of study participants with their medications used were obtained through the NOAC-TURK survey database. Additional necessary medical records were obtained from electronic health records of participating centers. Of the 2. 862 patients, 1.131 (39.5%) were male and the mean age was 70.3±10.2 years. Hypertension was found as the most frequent comorbidity (81%). The most common indication for NOACs was permanent atrial fibrillation (83.3%). NOACs were mainly preferred because of inadequate therapeutic range or overdose during warfarin usage. The most frequent complication was bleeding (n=217, 7.6%), and major bleeding was observed in 1.1% of the patients. Embolic events were observed in 37 patients (1.3%). Rivaroxaban and dabigatran were both more preferred than apixaban. Almost half of the patients (47.6%) were using lower doses of NOACs, which is definitely much more than expected. The NOAC-TURK study showed an important overview of the current NOACs treatment regimens in Turkey. Although embolic and bleeding complications were lower than or similar to previous studies, increased utilization of low-dose NOACs in this study should be considered carefully. According to the results of this study, NOACs treatment should be guided through CHA2DS2-VASc and HASBLED scores to ensure more benefit and less adverse effects in NVAF patients.


Predicting crystal structures of organic compounds.
Currently, organic crystal structure prediction (CSP) methods are based on searching for the most thermodynamically stable crystal structure, making various approximations in evaluating the crystal energy. The most stable (global minimum) structure provides a prediction of an experimental crystal structure. However, depending on the specific molecule, there may be other structures which are very close in energy. In this case, the other structures on the crystal energy landscape may be polymorphs, components of static or dynamic disorder in observed structures, or there may be no route to nucleating and growing these structures. A major reason for performing CSP studies is as a complement to solid form screening to see which alternative packings to the known polymorphs are thermodynamically feasible.


[Determination of the efficiency of single-photon emission computed tomography with 99mTc-HMPAO-labelled leukocytes in the diagnosis of myocarditis: Comparison of scintigraphic and histological data].
to determine the efficiency of single-photon emission computed tomography (SPECT) with 99mTc-HMPAO- labelled leukocytes in diagnosing myocarditis, by comparing scintigraphic and histological data. The investigation enrolled 35 patients with suspected myocarditis, who were planned to undergo coronaroventriculography or intervention with endomyocardial biopsy. Prior to endomyocardial biopsy, all the patients underwent myocardial scintigraphy using 99mTC-exametazime-labelled leukocytes. The results of myocardial scintigraphic and histological examinations were compared. Abnormal myocardial 99mTc-HMPAO-labelled leukocyte accumulation was detected in 7 (20%) examinees. Myocarditis was histologically verified in 9 (25.7%) persons. Our findings showed that the sensitivity of 99mTc-HMPAO-labelled leukocyte SPECT in diagnosing myocardial inflammatory changes was 62%; its specificity and diagnostic accuracy were 92% and 85%, respectively. Conclusion. 99mTc- HMPAO-labelled leukocyte scintigraphy is today one of a few procedures for the primary noninvasive diagnosis of myocardial inflammation. However, in view of its sufficiently low sensitivity and laboriousness and the sigh cost of consumables, the technique is irrationally used in routine clinical practice.


Trajectory-Based Flow Feature Tracking in Joint Particle/Volume Datasets.
Studying the dynamic evolution of time-varying volumetric data is essential in countless scientific endeavors. The ability to isolate and track features of interest allows domain scientists to better manage large complex datasets both in terms of visual understanding and computational efficiency. This work presents a new trajectory-based feature tracking technique for use in joint particle/volume datasets. While traditional feature tracking approaches generally require a high temporal resolution, this method utilizes the indexed trajectories of corresponding Lagrangian particle data to efficiently track features over large jumps in time. Such a technique is especially useful for situations where the volume dataset is either temporally sparse or too large to efficiently track a feature through all intermediate timesteps. In addition, this paper presents a few other applications of this approach, such as the ability to efficiently track the internal properties of volumetric features using variables from the particle data. We demonstrate the effectiveness of this technique using real world combustion and atmospheric datasets and compare it to existing tracking methods to justify its advantages and accuracy.


Problem list completeness in electronic health records: A multi-site study and assessment of success factors.
To assess problem list completeness using an objective measure across a range of sites, and to identify success factors for problem list completeness. We conducted a retrospective analysis of electronic health record data and interviews at ten healthcare organizations within the United States, United Kingdom, and Argentina who use a variety of electronic health record systems: four self-developed and six commercial. At each site, we assessed the proportion of patients who have diabetes recorded on their problem list out of all patients with a hemoglobin A1c elevation>=7.0%, which is diagnostic of diabetes. We then conducted interviews with informatics leaders at the four highest performing sites to determine factors associated with success. Finally, we surveyed all the sites about common practices implemented at the top performing sites to determine whether there was an association between problem list management practices and problem list completeness. Problem list completeness across the ten sites ranged from 60.2% to 99.4%, with a mean of 78.2%. Financial incentives, problem-oriented charting, gap reporting, shared responsibility, links to billing codes, and organizational culture were identified as success factors at the four hospitals with problem list completeness at or near 90.0%. Incomplete problem lists represent a global data integrity problem that could compromise quality of care and put patients at risk. There was a wide range of problem list completeness across the healthcare facilities. Nevertheless, some facilities have achieved high levels of problem list completeness, and it is important to better understand the factors that contribute to success to improve patient safety. Problem list completeness varies substantially across healthcare facilities. In our review of EHR systems at ten healthcare facilities, we identified six success factors which may be useful for healthcare organizations seeking to improve the quality of their problem list documentation: financial incentives, problem oriented charting, gap reporting, shared responsibility, links to billing codes, and organizational culture.


Acute dim light at night increases body mass, alters metabolism, and shifts core body temperature circadian rhythms.
The circadian system is primarily entrained by the ambient light environment and is fundamentally linked to metabolism. Mounting evidence suggests a causal relationship among aberrant light exposure, shift work, and metabolic disease. Previous research has demonstrated deleterious metabolic phenotypes elicited by chronic (>4 weeks) exposure to dim light at night (DLAN) (∼ 5 lux). However, the metabolic effects of short-term (<2 weeks) exposure to DLAN are unspecified. We hypothesized that metabolic alterations would arise in response to just 2 weeks of DLAN. Specifically, we predicted that mice exposed to dim light would gain more body mass, alter whole body metabolism, and display altered body temperature (Tb) and activity rhythms compared to mice maintained in dark nights. Our data largely support these predictions; DLAN mice gained significantly more mass, reduced whole body energy expenditure, increased carbohydrate over fat oxidation, and altered temperature circadian rhythms. Importantly, these alterations occurred despite similar activity locomotor levels (and rhythms) and total food intake between groups. Peripheral clocks are potently entrained by body temperature rhythms, and the deregulation of body temperature we observed may contribute to metabolic problems due to "internal desynchrony" between the central circadian oscillator and temperature sensitive peripheral clocks. We conclude that even relatively short-term exposure to low levels of nighttime light can influence metabolism to increase mass gain.


Microbial Profiling of Cultural Systems for Suppression of Phytophthora Root Rot in Fraser Fir.
Phytophthora root rot of Fraser fir, caused by several Phytophthora spp., is a severe problem in Christmas tree production. Since fungicides are not economically viable for disease management in field plantings and host resistance is not available, cultural control methods were investigated. Mulches, dairy compost, and soil pH adjustment were tested at five field sites in North Carolina. Treatments included wood chips, wood chips plus compost, or pine bark as raised beds, and compost or sulfur tilled into soil. Soil and mulch microbial populations were characterized by dilution plating and calculation of a log series diversity index, and by enzyme analyses at 5, 12, 17, and 24 months after planting. Bacterial and fungal counts, microbial activity, and cellulase activity were higher in mulch than in soil at all sites and times (P < 0.01), and generally did not differ among mulch types or among soils. Treatments significantly affected disease ratings and tree survival at three of five sites, with one or more mulch treatments yielding lower disease ratings and greater survival than controls. Tree mortality at each time point varied significantly with cellulase activity in the upper root zone (P = 0.005). Other biological variables did not show significant relationships with disease ratings or mortality.


The energy-diversity relationship of complex bacterial communities in Arctic deep-sea sediments.
The availability of nutrients and energy is a main driver of biodiversity for plant and animal communities in terrestrial and marine ecosystems, but we are only beginning to understand whether and how energy-diversity relationships may be extended to complex natural bacterial communities. Here, we analyzed the link between phytodetritus input, diversity and activity of bacterial communities of the Siberian continental margin (37-3427 m water depth). Community structure and functions, such as enzymatic activity, oxygen consumption and carbon remineralization rates, were highly related to each other, and with energy availability. Bacterial richness substantially increased with increasing sediment pigment content, suggesting a positive energy-diversity relationship in oligotrophic regions. Richness leveled off, forming a plateau, when mesotrophic sites were included, suggesting that bacterial communities and other benthic fauna may be structured by similar mechanisms. Dominant bacterial taxa showed strong positive or negative relationships with phytodetritus input and allowed us to identify candidate bioindicator taxa. Contrasting responses of individual taxa to changes in phytodetritus input also suggest varying ecological strategies among bacterial groups along the energy gradient. Our results imply that environmental changes affecting primary productivity and particle export from the surface ocean will not only affect bacterial community structure but also bacterial functions in Arctic deep-sea sediment, and that sediment bacterial communities can record shifts in the whole ocean ecosystem functioning.