The microneme proteins EtMIC4 and EtMIC5 of Eimeria tenella form a novel, ultra-high molecular mass protein complex that binds target host cells.
Eimeria tenella, in common with other parasitic protozoa of the phylum Apicomplexa, invades host cells using an actinomyosin-powered "glideosome" complex and requires the secretion of adhesive proteins from the microneme organelles onto the parasite surface. Microneme proteins of E. tenella include EtMIC4, a transmembrane protein that has multiple thrombospondin type I domains and calcium-binding epidermal growth factor-like domains in its extracellular domain, and EtMIC5, a soluble protein composed of 11 tandemly repeated domains that belong to the plasminogen-apple-nematode superfamily. We show here that EtMIC4 and EtMIC5 interact to form an oligomeric, ultrahigh molecular mass protein complex. The complex was purified from lysed parasites by non-denaturing techniques, and the stoichiometry was shown to be [EtMIC4](2):[EtMIC5](1), with an octamer of EtMIC4 bound non-covalently to a tetramer of EtMIC5. The complex is formed within the parasite secretory pathway and is maintained after secretion onto the surface of the parasite. The purified complex binds to a number of epithelial cell lines in culture. Identification and characterization of this complex contributes to an overall understanding of the role of multimolecular protein complexes in specific interactions between pathogens and their hosts during infection.


Prospective evaluation of thyroid function in patients with systemic sclerosis (scleroderma).
A consecutive series of 77 ambulatory, clinically euthyroid patients with systemic sclerosis was evaluated for clinical, chemical and serologic evidence of thyroid disease. Measurements of baseline serum thyroid function tests and the thyroid stimulating hormone response to thyrotropin releasing hormone (TRH) were made. We classified 18 (23%) patients as abnormal, including 8 (10%) who were chemically hypothyroid and 10 (13%) with normal baseline studies but an exaggerated response to TRH injection. The remaining 59 (77%) patients were euthyroid by all measurements. Antithyroid antibodies were present in only 4 of 8 (50%) of the hypothyroid group. There were no differences between the 3 patient groups with regard to the extent of scleroderma, the presence of internal organ involvement, or the frequency of common signs or symptoms of hypothyroidism. Abnormal thyroid function in systemic sclerosis is frequent, often unsuspected clinically, and may occur without markers of autoimmune thyroid disease.


Social circumstances that drive early introduction of formula milk: an exploratory qualitative study in a peri-urban South African community.
Breastfeeding is widely endorsed as the optimal strategy for feeding newborns and young infants, as well as improving child survival and achieving Millennium Development Goal 4. Exclusive breastfeeding (EBF) for the first 6 months of life is rarely practised in South Africa. Following the 2010 World Health Organization (WHO) infant feeding recommendations (EBF for HIV-positive mothers with maternal or infant antiretroviral treatment), South Africa adopted breastfeeding promotion as a National Infant Feeding Strategy and removed free formula milk from the Prevention of Mother-to-Child Transmission of HIV programme. This study aimed to explore the perceptions of mothers and household members at community level regarding the value they placed on formula feeding and circumstances that drive the practice in a peri-urban community. We conducted in-depth interviews with HIV-positive and HIV-negative mothers in a community-randomised trial (Good Start III). Focus group discussions were held with grandmothers, fathers and teenage mothers. Data were analysed using thematic analysis. The following themes were identified; inadequate involvement of teenage mothers; grandmothers who become replacement mothers; fear of failing to practise EBF for 6 months; partners as formula providers and costly formula milk leading to risky feeding practices. The new South African Infant Feeding Strategy needs to address the gaps in key health messages and develop community-orientated programmes with a focus on teenage mothers. These should encourage the involvement of grandmothers and fathers in decision-making about infant feeding so that they can support EBF for optimal child survival.


Cramér-Rao analysis of orientation estimation: influence of target model uncertainties.
We explore the use of Cramér-Rao bound calculations for predicting fundamental limits on the accuracy with which target characteristics can be determined by using imaging sensors. In particular, estimation of satellite orientation from high-resolution sensors is examined. The analysis role that such bounds provide for sensor/experiment design, operation, and upgrade is discussed. Emphasis is placed on the importance of including all relevant target/sensor uncertainties in the analysis. Computer simulations are performed that illustrate that uncertainties in target features (e.g., shape, reflectance, and relative orientation) have a significant impact on the bounds and provide considerable insight as to how details of the three-dimensional target structure may influence the estimation process. The simulations also address the impact that a priori information has on the bounds.


Provider adherence to COPD guidelines: relationship to organizational factors.
A clinical practice guideline for chronic obstructive pulmonary disease (COPD) was implemented in all Veterans Health Administration (VHA) hospitals in the US. The aim of the current analyses is to describe current adherence rates and the organizational factors related to provider adherence to the COPD guideline. We administered a survey to key informants that assessed adherence to the COPD guideline, approaches to disseminating and implementing the COPD guideline, providers' views of the COPD guideline and guidelines in general, and attitudes about the organizational climate. Surveys were returned by 242 key informants (58%) at 130 of the 143 VHA hospitals (91%). Adherence to the COPD clinical practice guideline is perceived by quality managers within the VHA to be good. The final multivariable predictor model identified five measures that were related to provider adherence with the COPD guideline (R(2) = 0.43): responsibilities were changed to support adherence to the COPD guideline, physicians believe that guidelines implemented in the past year were applicable to their practice, patient care providers consistently participate in activities to improve the quality of care, the regional network office monitors the pace at which guidelines are implemented, and there is a system to provide feedback on routinely collected guideline adherence data collected in addition to External Peer Review Program data. Organizations can play an important role in providing a supportive climate to facilitate their providers' adherence to guidelines by implementing processes and culture changes that involve these five measures.


Searching for blood in Chinese lacquerware: zhū xiě huī.
The study gives an overview of the tests and analyses undertaken in the past 20 years to establish the presence of blood in the foundation layers of Chinese lacquer artefacts and also shows the development of analytical methods over that period. When undertaking the conservation of lacquer objects it is crucial to know the type of binding medium as this influences the selection of any consolidants that may be required in the treatment. Microchemical tests to identify blood using benzidine and luminol, various chromatographic and mass spectrometric techniques and DNA analyses were assessed on selected Chinese lacquer objects, and the results gained are summarized.


A Case Study of Controlling Crossover in a Selection Hyper-heuristic Framework Using the Multidimensional Knapsack Problem.
Hyper-heuristics are high-level methodologies for solving complex problems that operate on a search space of heuristics. In a selection hyper-heuristic framework, a heuristic is chosen from an existing set of low-level heuristics and applied to the current solution to produce a new solution at each point in the search. The use of crossover low-level heuristics is possible in an increasing number of general-purpose hyper-heuristic tools such as HyFlex and Hyperion. However, little work has been undertaken to assess how best to utilise it. Since a single-point search hyper-heuristic operates on a single candidate solution, and two candidate solutions are required for crossover, a mechanism is required to control the choice of the other solution. The frameworks we propose maintain a list of potential solutions for use in crossover. We investigate the use of such lists at two conceptual levels. First, crossover is controlled at the hyper-heuristic level where no problem-specific information is required. Second, it is controlled at the problem domain level where problem-specific information is used to produce good-quality solutions to use in crossover. A number of selection hyper-heuristics are compared using these frameworks over three benchmark libraries with varying properties for an NP-hard optimisation problem: the multidimensional 0-1 knapsack problem. It is shown that allowing crossover to be managed at the domain level outperforms managing crossover at the hyper-heuristic level in this problem domain.


The economic implications of glaucoma: a literature review.
Glaucoma is a common ophthalmic condition, often associated with elevated intraocular pressure (IOP). It affects >2 million people in the US, and the incidence is expected to exceed 3 million by 2020. However, relatively little is known about the cost of glaucoma compared with costs for other eye conditions. This comprehensive report reviews published literature on costs and cost effectiveness of treatments for glaucoma. Cost-of-illness studies in glaucoma focus on direct medical costs and generally exclude indirect costs. In general, increased costs are associated with increased severity or lack of control over IOP and the distribution of costs (e.g. medication vs procedures) varies with severity. A large number of studies have evaluated the cost of glaucoma medications, assessing the number of drops per bottle and associated cost per drop or per treatment dose. These studies have limited usefulness as they generally evaluate unit medication costs without including differential effectiveness or adverse effects associated with various therapies, and thus provide only one component of real-world costs for glaucoma. Broader comparative cost studies, mainly adopting a cost-minimisation approach, have evaluated the impact of differing treatments and management strategies on all types of medical care resource utilisation and associated costs, but a variety of metrics for success makes interpretation challenging. Studies have generally found beta2-adrenoceptor antagonists to be associated with greater healthcare costs than newer therapies. Among newer treatments such as prostaglandin analogues, no specific treatment has demonstrated a clear cost advantage over other treatments. A number of studies have modelled hypothetical cohorts of glaucoma patients through courses of therapy, projecting costs, outcomes and cost effectiveness. A majority of these cost-effectiveness models compare one of the newer prostaglandin analogues with older medications or with one another. Existing studies suggest that bimatoprost may be more cost effective than other agents. However, the effectiveness outcomes used in these studies vary, including achieving IOP thresholds, IOP-controlled days, percent reduction in IOP and QALYs. Methods used to determine costs also vary substantially between studies. Future evaluations of the burden of glaucoma need to consider the issues of comparability between, and generalisability of, study results. Differences in methods have created barriers to understanding the cost of glaucoma and comparing costs or cost effectiveness between studies. Furthermore, future studies should also consider direct costs of glaucoma generally not covered by health insurance as well as indirect costs of glaucoma. As new screening technologies for early detection of individuals at elevated risk of glaucoma are now in use, more complete estimates of the cost of glaucoma are critical for issues of resource allocation and health policy.


Comparing hospital and telephone follow-up after treatment for breast cancer: randomised equivalence trial.
To compare traditional hospital follow-up with telephone follow-up by specialist nurses after treatment for breast cancer. A two centre randomised equivalence trial in which women remained in the study for a mean of 24 months. Outpatient clinics in two NHS hospital trusts in the north west of England 374 women treated for breast cancer who were at low to moderate risk of recurrence. Participants were randomised to traditional hospital follow-up (consultation, clinical examination, and mammography as per hospital policy) or telephone follow-up by specialist nurses (consultation with structured intervention and mammography according to hospital policy). Psychological morbidity (state-trait anxiety inventory, general health questionnaire (GHQ-12)), participants' needs for information, participants' satisfaction, clinical investigations ordered, and time to detection of recurrent disease. The 95% confidence interval for difference in mean state-trait scores adjusted for treatment received (-3.33 to 2.07) was within the predefined equivalence region (-3.5 to 3.5). The women in the telephone group were no more anxious as a result of foregoing clinic examinations and face-to-face consultations and reported higher levels of satisfaction than those attending hospital clinics (intention to treat P<0.001). The numbers of clinical investigations ordered did not differ between groups. Recurrences were few (4.5%), with no differences between groups for time to detection (median 60.5 (range 37-131) days in hospital group v 39.0 (10-152) days in telephone group; P=0.228). Telephone follow-up was well received by participants, with no physical or psychological disadvantage. It is suitable for women at low to moderate risk of recurrence and those with long travelling distances or mobility problems and decreases the burden on busy hospital clinics. National Cancer Research Institute 1477.


Risk of venous thromboembolism in hospitalized patients with peripherally inserted central catheters.
Peripherally inserted central catheters (PICC) are increasingly used in hospitalized patients. The benefit can be offset by complications such as upper extremity deep vein thrombosis (UEDVT). Retrospective study of patients who received a PICC while hospitalized at the Methodist University Hospital (MUH) in Memphis, TN. All adult consecutive patients who had PICCs inserted during the study period and who did not have a UEDVT at the time of PICC insertion were included in the study. A UEDVT was defined as a symptomatic event in the ipsilateral extremity, leading to the performance of duplex ultrasonography, which confirmed the diagnosis of UEDVT. Pulmonary embolism (PE) was defined as a symptomatic event prompting the performance of ventilation-perfusion lung scan or spiral computed tomography (CT). Among 777 patients, 38 patients experienced 1 or more venous thromboembolisms (VTEs), yielding an incidence of 4.89%. A total of 7444 PICC-days were recorded for 777 patients. This yields a rate of 5.10 VTEs/1000 PICC-days. Compared to patients whose PICC was inserted in the SVC, patients whose PICC was in another location had an increased risk (odds ratio = 2.61 [95% CI = 1.28-5.35]) of VTE. PICC related VTE was significantly more common among patients with a past history of VTE (odds ratio = 10.83 [95% CI = 4.89-23.95]). About 5% of patients undergoing PICC placement in acute care hospitals will develop thromboembolic complications. Thromboembolic complications were especially common among persons with a past history of VTE. Catheter tip location at the time of insertion may be an important modifiable risk factor.


Somatostatin receptor subtype expression in human thyroid and thyroid carcinoma cell lines.
Somatostatin (SRIH) analogs can suppress the proliferation of human differentiated thyroid carcinoma cell lines that express SRIH receptors (SSTRs) demonstrated by radioligand binding analysis. Five distinct human SSTR subtypes (hSSTR1-5) that bind native SRIH exhibit diverse affinities to a wide range of SRIH analogs. Reverse transcriptase-PCR amplification of ribonucleic acids (RNAs) obtained from normal thyroid tissues and nine human thyroid carcinoma cell lines, grown as monolayer cultures and xenograft tumors in nude mice, were used to discriminate expression of SSTR subtype messenger RNAs (mRNAs). The cell lines were derived from a follicular adenoma (KAK-1), two follicular carcinomas (MRO-87 and WRO-82), two papillary carcinomas (NPA87 and KAT-10), and four anaplastic thyroid carcinomas (DRO-90, ARO-81, KAT-4, and KAT-18). Most thyroid cancer cell line monolayers and xenografts expressed SSTR3 and SSTR5 mRNAs. SSTR1 expression was more varied between monolayers and xenografts, whereas SSTR2 mRNA was only faintly detectable at the most extreme resolution. SSTR4 mRNA was faintly positive in only one anaplastic carcinoma xenograft. Normal thyroid also expressed SSTR3 and SSTR5 mRNAs, with only faint expression of SSTR1 and SSTR2 mRNAs (in one of five and three of five samples, respectively). SSTR mRNA expression was dependent upon in vitro culture conditions, as xenograft SSTR mRNA expression tended to decrease compared to that in each respective monolayer culture. Characterization of SSTR subtype expression in human thyroid carcinomas may permit targeting of specific SRIH analogs to inhibit proliferation of differentiated and anaplastic thyroid carcinomas in patients.


Conditions for Use and Implementation of Globally-Aligned Versus Local Baseplate Coordinate Systems When Computing Migration Using Radiostereometric Analysis.
Radiostereometric analysis can be used for computing movement of a tibial baseplate relative to the tibia (termed migration) to determine stability of fixation. Quantifying migration in six degrees of freedom requires establishing a coordinate system in which to express the movement. Establishing consistent migration directions among patients and baseplate designs remains challenging. Deviations in imaging alignment (tibia/baseplate alignment during image acquisition) and surgical alignment (baseplate alignment on tibia) will affect computed migrations when using the conventional globally-aligned baseplate coordinate system (BCS) (defined by calibration box). Computing migration using a local BCS (defined by baseplate) may be preferrable. This paper (1) summarizes the migration equations when using a globally-aligned versus local BCS, (2) proposes a method for defining a local BCS, and (3) demonstrates differences in the two BCSs for an example patient whose baseplate has rotational deviations due to imaging or surgical alignments. Differences in migration for the two BCSs ranged from about ±0.5 mm in translations and -0.4 deg to 0.7 deg in rotations. Differences were largest for deviations in internal-external rotation and smallest for deviations in varus-valgus rotation. An example demonstrated that the globally-aligned BCS resulted in migration being quantified as subsidence instead of liftoff, thereby changing fundamental interpretations. Because migrations computed using a local BCS are independent of imaging and surgical alignments and instead characterize migration using baseplate features, a local BCS enhances consistency in migration directions among patients and baseplate designs relative to the interface in which fixation may be compromised.


Activation of metabotropic glutamate receptor 5 in the amygdala modulates pain-like behavior.
The central nucleus of the amygdala (CeA) has been identified as a site of nociceptive processing important for sensitization induced by peripheral injury. However, the cellular signaling components underlying this function remain unknown. Here, we identify metabotropic glutamate receptor 5 (mGluR5) as an integral component of nociceptive processing in the CeA. Pharmacological activation of mGluRs with (R,S)-3,5-dihydroxyphenylglycine (DHPG) in the CeA of mice is sufficient to induce peripheral hypersensitivity in the absence of injury. DHPG-induced peripheral hypersensitivity is reduced via pharmacological blockade of mGluR5 or genetic disruption of mGluR5. Furthermore, pharmacological blockade or conditional deletion of mGluR5 in the CeA abrogates inflammation-induced hypersensitivity, demonstrating the necessity of mGluR5 in CeA-mediated pain modulation. Moreover, we demonstrate that phosphorylation of extracellular-signal regulated kinase 1/2 (ERK1/2) is downstream of mGluR5 activation in the CeA and is necessary for the full expression of peripheral inflammation-induced behavioral sensitization. Finally, we present evidence of right hemispheric lateralization of mGluR5 modulation of amygdalar nociceptive processing. We demonstrate that unilateral pharmacological activation of mGluR5 in the CeA produces distinct behavioral responses depending on whether the right or left amygdala is injected. We also demonstrate significantly higher levels of mGluR5 expression in the right amygdala compared with the left under baseline conditions, suggesting a potential mechanism for right hemispheric lateralization of amygdala function in pain processing. Together, these results establish an integral role for mGluR5 and ERK1/2 in nociceptive processing in the CeA.


Childhood deprivation, health and development: associations with adult health in the 1958 and 1970 British prospective birth cohort studies.
To examine the associations between childhood socioeconomic and family circumstances, health and behavioural and cognitive development, and health and mental well-being outcomes in adulthood; exploring whether associations are different for cohorts born in 1958 and 1970, or for men and women. Pooled analysis of two prospective, population-based, British birth cohort studies. 11 327 men and women born in 1958 and 11 177 men and women born in 1970 who responded in the adult follow-up investigations at ages 33 and 30 respectively. Self-rated general health, Rutter malaise scale indicating mental well-being, and presence of a long-standing illness limiting daily activities; assessed at ages 33 and 30 for the 1958 and 1970 birth cohorts respectively. A diversity of family background (socioeconomic deprivation, housing tenure, family disruption and parental interest), health and development (cognition and behaviour) measures each provided powerful independent indications for general health and mental well-being. Indications for limiting long-standing illness in adulthood were focused most strongly upon health difficulties in childhood. Few interactions between either birth cohort or gender and childhood measures were observed, and excepting these interactions consistency in associations between the childhood measures and the outcomes by gender and cohort was observable. This study emphasises the importance of cognitive and behavioural development in childhood, as well as deprivation, family background and childhood health in indicating future adult health and mental well-being, emphasising time-persistent effects and important indications for men and women.


The Immediate and Long-Term Impact of Preeclampsia on Offspring Vascular and Cardiac Physiology in the Preterm Infant.
Hypertensive disorders of pregnancy, including preeclampsia, affect nearly 10% of all pregnancies and are associated with significant long-term detrimental effects on both maternal and offspring cardiovascular health. Current management of preeclampsia involves timely delivery with the more severe form of disease requiring iatrogenic preterm birth. The effects on the maternal cardiovascular system have been studied extensively; however, less is known about the short- and long-term impacts on offspring cardiovascular health. There is a growing body of evidence suggesting that the offspring of pre-eclamptic pregnancies have an altered cardiac structure and function, along with a unique vascular physiology driven by lower endothelial function. Many of these changes can also be seen in those born preterm even in the absence of pregnancy hypertension. It is difficult to determine the relative contribution of pre-maturity and preeclampsia to the cardiovascular phenotype of those exposed to these pregnancy complications as they are, in many cases, inextricably linked. This review, therefore, focuses specifically on the evidence from clinical studies showing a negative cardiovascular impact of preeclampsia in preterm-born offspring, investigating phenotypic similarities and differences between offspring born preterm to normotensive vs. pre-eclamptic pregnancies. We explore the unique cardiac and vascular alterations in pre-eclamptic offspring born preterm, highlighting knowledge gaps, and potential areas of further research in the field.


Consensus recommendations for a standardized brain tumor imaging protocol for clinical trials in brain metastases.
A recent meeting was held on March 22, 2019, among the FDA, clinical scientists, pharmaceutical and biotech companies, clinical trials cooperative groups, and patient advocacy groups to discuss challenges and potential solutions for increasing development of therapeutics for central nervous system metastases. A key issue identified at this meeting was the need for consistent tumor measurement for reliable tumor response assessment, including the first step of standardized image acquisition with an MRI protocol that could be implemented in multicenter studies aimed at testing new therapeutics. This document builds upon previous consensus recommendations for a standardized brain tumor imaging protocol (BTIP) in high-grade gliomas and defines a protocol for brain metastases (BTIP-BM) that addresses unique challenges associated with assessment of CNS metastases. The "minimum standard" recommended pulse sequences include: (i) parameter matched pre- and post-contrast inversion recovery (IR)-prepared, isotropic 3D T1-weighted gradient echo (IR-GRE); (ii) axial 2D T2-weighted turbo spin echo acquired after injection of gadolinium-based contrast agent and before post-contrast 3D T1-weighted images; (iii) axial 2D or 3D T2-weighted fluid attenuated inversion recovery; (iv) axial 2D, 3-directional diffusion-weighted images; and (v) post-contrast 2D T1-weighted spin echo images for increased lesion conspicuity. Recommended sequence parameters are provided for both 1.5T and 3T MR systems. An "ideal" protocol is also provided, which replaces IR-GRE with 3D TSE T1-weighted imaging pre- and post-gadolinium, and is best performed at 3T, for which dynamic susceptibility contrast perfusion is included. Recommended perfusion parameters are given.


The Terroir of Cannabis: Terpene Metabolomics as a Tool to Understand Cannabis sativa Selections.
The phytochemical diversity of Cannabis chemovars is not well understood, and many chemovars were created in informal breeding programs without records of parentage or the criteria for selection. Key criteria for selection sometimes included aroma notes and visual cues, which some breeders associated with pharmacological activity. We hypothesized that the process of selection for scents believed to be related to specific tetrahydrocannabinol levels has resulted in modified terpene biosynthesis in these chemovars. Thirty-two cannabinoids, 29 monoterpenes and 38 sesquiterpenes were measured in 33 chemovars from 5 licensed producers. A classification system based on cannabinoid content was used with targeted metabolomic tools to determine relationships in the phytochemistry. Three monoterpenes, limonene, β-myrcene, and α-pinene, and two sesquiterpenes, caryophyllene and humulene, were abundant in the majority of chemovars. Nine terpenes were present in tetrahydrocannabinol-dominant chemovars. Three monoterpenes and four sesquiterpenes were predominantly found in cannabidiol-containing chemovars. Low abundance terpenes may have been the aromatic cues identified by breeders. The medicinal activity of some of the terpenes is likely to contribute to the pharmacological effect of specific chemovars. Together, these data demonstrate the synergy of compounds in Cannabis chemovars and point to the need for additional research to understand the phytochemical complexity.


Direct binding of the EGF-like domain of neuregulin-1 to integrins ({alpha}v{beta}3 and {alpha}6{beta}4) is involved in neuregulin-1/ErbB signaling.
Integrin-growth factor receptor cross-talk plays a role in growth factor signaling, but the specifics are unclear. In a current model, integrins and growth factor receptors independently bind to their ligands (extracellular matrix and growth factors, respectively). We discovered that neuregulin-1 (NRG1), either as an isolated EGF-like domain or as a native multi-domain form, binds to integrins αvβ3 (with a K(D) of 1.36 × 10(-7) m) and α6β4. Docking simulation predicted that three Lys residues at positions 180, 184, and 186 of the EGF-like domain are involved in integrin binding. Mutating these residues to Glu individually or in combination markedly suppressed integrin binding and ErbB3 phosphorylation. Mutating all three Lys residues to Glu (the 3KE mutation) did not affect the ability of NRG1 to bind to ErbB3 but markedly reduced the ability of NRG1 to induce ErbB3 phosphorylation and AKT and Erk1/2 activation in MCF-7 and T47D human breast cancer cells. This suggests that direct integrin binding to NRG1 is critical for NRG1/ErbB signaling. Notably, stimulation of cells with WT NRG1 induced co-precipitation of ErbB3 with α6β4 and with αvβ3 to a much lower extent. This suggests that WT NRG1 induces integrin-NRG1-ErbB3 ternary complex formation. In contrast, the 3KE mutant was much less effective in inducing ternary complex formation than WT NRG1, suggesting that this process depends on the ability of NRG1 to bind to integrins. These results suggest that direct NRG1-integrin interaction mediates integrin-ErbB cross-talk and that α6β4 plays a major role in NRG-ErbB signaling in these cancer cells.


A Multicenter Phase II Trial of Ipilimumab and Nivolumab in Unresectable or Metastatic Metaplastic Breast Cancer: Cohort 36 of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART, SWOG S1609).
Metaplastic breast cancer (MpBC) is a rare aggressive subtype that responds poorly to cytotoxics. Median survival is approximately 8 months for metastatic disease. We report results for advanced MpBC treated with ipilimumab + nivolumab, a cohort of S1609 for rare cancers (DART: NCT02834013). Prospective, open-label, multicenter phase II (two-stage) trial of ipilimumab (1 mg/kg i.v. every 6 weeks) plus nivolumab (240 mg i.v. every 2 weeks) for advanced MpBC. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. Overall, 17 evaluable patients enrolled. Median age was 60 years (26-85); median number of prior therapy lines was 2 (0-5). ORR was 18%; 3 of 17 patients achieved objective responses (1 complete, 2 partial responses; 2 spindle cell, 1 chondromyxoid histology), which are ongoing at 28+, 33+, and 34+ months, respectively. Median PFS and OS were 2 and 12 months, respectively. Altogether, 11 patients (65%) experienced adverse events (AE), including one grade 5 AE. Eight patients (47%) developed an immune-related AE (irAE), with adrenal insufficiency observed in all 3 responders. Responses occurred in tumors with low tumor mutational burden, low PD-L1, and absent tumor-infiltrating lymphocytes. The ipilimumab and nivolumab combination showed no new safety signals and met its primary endpoint with 18% ORR in advanced, chemotherapy-refractory MpBC. All responses are ongoing at >2 to almost 3 years later. The effect of ipilimumab and nivolumab was associated with exceptional responses in a subset of patients versus no activity. This combination warrants further investigation in MpBC, with special attention to understanding mechanism of action, and carefully designed to weigh against the significant risks of irAEs.


Hydrogel network formation revised: high-resolution magic angle spinning nuclear magnetic resonance as a powerful tool for measuring absolute hydrogel cross-link efficiencies.
In the present work, high-resolution magic angle spinning (hr-MAS) NMR spectroscopy is applied as a straightforward nondestructive technique to quantify unreacted methacrylamide functionalities in cross-linked gelatin hydrogels. By adjusting several cross-linking parameters including the ultraviolet (UV) irradiation time and the photo-initiator concentration, the cross-linking degree can be easily varied. Remarkably, under all experimental conditions typically applied for hydrogel development, no more than 40% of the methacrylamide moieties present have reacted. The hr-MAS based approach to determine the cross-linking efficiency is shown to provide an innovative and more convenient alternative to the well-established classical techniques. In addition, the results obtained are in good correlation with mechanical analysis data.


Spectral and spatial properties of polarized light reflections from the arms of squid (Loligo pealeii) and cuttlefish (Sepia officinalis L.).
On every arm of cuttlefish and squid there is a stripe of high-reflectance iridophores that reflects highly polarized light. Since cephalopods possess polarization vision, it has been hypothesized that these polarized stripes could serve an intraspecific communication function. We determined how polarization changes when these boneless arms move. By measuring the spectral and polarizing properties of the reflected light from samples at various angles of tilt and rotation, we found that the actual posture of the arm has little or no effect on partial polarization or the e-vector angle of the reflected light. However, when the illumination angle changed, the partial polarization of the reflected light also changed. The spectral reflections of the signals were also affected by the angle of illumination but not by the orientation of the sample. Electron microscope samples showed that these stripes are composed of several groups of multilayer platelets within the iridophores. The surface normal to each group is oriented at a different angle, which produces essentially constant reflection of polarized light over a range of viewing angles. These results demonstrate that cuttlefish and squid could send out reliable polarization signals to a receiver regardless of arm orientation.


Exploitation of the IDO Pathway in the Therapy of Rheumatoid Arthritis.
Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting step along the kynurenine pathway and is thought to play a key role in immune homeostasis through depletion of tryptophan and accumulation of kynurenines. In this review we summarize recent research into the possibility of harnessing the IDO pathway for the therapy of rheumatoid arthritis. Inhibition of IDO activity, or knockout of the gene encoding IDO, was shown to cause an increase in the severity of collagen-induced arthritis, an animal model of rheumatoid arthritis. The increased severity of disease was associated with elevated numbers of pathogenic Th1 and Th17 cells in the joints and draining lymph nodes. In another study, analysis of the kinetics of expression of downstream kynurenine pathway enzymes during the course of arthritis revealed a potential role for tryptophan metabolites in resolution of arthritis. Furthermore, the therapeutic administration of L-kynurenine or [3,4-dimethoxycinnamonyl]-anthranilic acid (a synthetic derivative of 3-hydroxy-anthranilic acid) significantly reduced both clinical and histological progression of experimental arthritis. These findings raise the possibility of exploiting the IDO pathway for the therapy of autoimmune disease.


Estimates of genetic parameters and genetic change for reproduction, weight, and wool characteristics of Columbia sheep.
Genetic parameters from both single-trait and bivariate analyses for prolificacy, weight and wool traits were estimated using REML with animal models for Columbia sheep from data collected from 1950 to 1998 at the U.S. Sheep Experiment Station (USSES), Dubois, ID. Breeding values from both single-trait and seven-trait analyses calculated using the parameters estimated from the single-trait and bivariate analyses were compared with respect to genetic trends. Number of observations were 31,401 for litter size at birth and litter size at weaning, 24,741 for birth weight, 23,903 for weaning weight, 29,572 for fleece weight and fleece grade, and 2,449 for staple length. Direct heritability estimates from single-trait analyses were 0.09 for litter size at birth, 0.06 for litter size at weaning, 0.27 for birth weight, 0.16 for weaning weight, 0.53 for fleece weight, 0.41 for fleece grade, and 0.55 for staple length. Estimate of direct genetic correlation between littersize at birth and weaning was 0.84 and between birth and weaning weights was 0.56. Estimate of genetic correlation between fleece weight and staple length was positive (0.55) but negative between fleece weight and fleece grade (-0.47) and between staple length and fleece grade (-0.70). Estimates of genetic correlations were positive but small between birth weight and litter size traits and moderate and positive between weaning weight and litter size traits. Fleece weight was lowly and negatively correlated with both litter size traits. Fleece grade was lowly and positively correlated with both litter size traits, while staple length was lowly and negatively correlated with the litter size traits. Estimates of correlations between weight traits and fleece weight were positive and low to moderate. Estimates of correlations between weight traits and fleece grade were negative and small. Estimates of correlations between staple length and birth weight (0.05) and weaning weight were small (-0.04). Estimated breeding values averaged by year of birth from both the single-trait and multiple-trait analyses for the prolificacy and weight traits increased over time, but were unchanged for the wool traits. Estimated changes in breeding values over time did not differ substantially for single-trait and multiple-trait analyses, except for traits highly correlated with another trait that was responding to selection.


Direct identification of stylet secreted proteins from root-knot nematodes by a proteomic approach.
The stylet secretions produced by plant parasitic root-knot nematodes are thought to be pathogenicity factors involved in the invasion of the root tissue and in the induction and maintenance of feeding cells. A new procedure was established that allowed the direct qualitative analysis of proteins secreted by Meloidogyne incognita infective juveniles. Purified proteins whose isoelectric point (pI) ranged from 5.0 to 7.5 were separated by two-dimensional (2D) electrophoresis and the seven most abundant proteins were identified by micro-sequencing. A calreticulin (CRT) was isolated and transcription of its gene in infective juveniles and adults was demonstrated. Moreover, evidence for expression of the CRT in the subventral oesophageal glands of infective juveniles was obtained. The potential roles of this secreted protein in pathogenesis and the advantages of developing this strategy to obtain new insights into plant-nematode interactions are discussed.


'Painting' nanostructured metals-playing with liquid metal.
Materials scientists always dream to 'paint' nanostructured metal on a metallic foil, just as artists paint a painting on a canvas. Herein, we have, for the first time, realized this dream using liquid gallium (Ga) as the paint. Through a liquid Ga stimulated painting-alloying-dealloying strategy, seven kinds of nanostructured metallic films including Au, Ag, Pd, Pt, Cu, Co, and Ni were generally fabricated and supported on the corresponding metallic foils. Owing to the painting-like operation, nanostructured films with complicated patterns and large sizes (up to meters) were successfully produced without any shape/size limitations. The nanostructured metallic films possess advantages like their unique nanoporous structures, self-supporting nature, good continuity, flexibility and high specific surface areas, and could serve as robust electrodes in devices like batteries, fuel cells, water splitting electrolyzers, etc. Moreover, the proposed strategy shows great potential in the fabrication of other self-supporting, flexible, advanced nanomaterials.


Self-assembled nanoparticles based on chondroitin sulfate-deoxycholic acid conjugates for docetaxel delivery: Effect of degree of substitution of deoxycholic acid.
Hydrophobically-modified polymers based on chondroitin sulfate with different degree of substitution (DS) of deoxycholic acid (DOCA) were developed for docetaxel delivery. Chondroitin sulfate-deoxycholic acid (CSAD) bioconjugates were synthesized via the linker of adipic dihydrazide by amide bond. They were characterized with spherical shape, mean diameter of around 165.2nm and negative zeta potential (-14.87 to -20.53mV). An increase of DOCA DS reduced size of nanoparticles, while increasing drug loading efficiency. Drug release in vitro showed a triphasic sustained pattern and higher accumulative drug release percentage was observed with increased DS of DOCA on polymer. Self-assemblies with higher DS also had enhanced internalization of nanoparticles and stronger cytotoxicity at the cellular level. The self-assemble nanoparticles demonstrate to be excellent targeting drug delivery systems and the desired therapeutics can be achieved via the alteration of DS.


Origin and timing of New Zealand's earliest domestic chickens: Polynesian commensals or European introductions?
Human settlers transported chickens (Gallus gallus domesticus) to most East Polynesian archipelagos between AD 1000 and 1300; however, it has long been assumed that New Zealand was an exception. Despite the fact that chicken bones have been recovered from localities of early archaeological middens in New Zealand, their age and genetic relationships have never been critically assessed. Here, we test the assumption that chickens were not introduced to New Zealand during prehistory through ancient DNA and radiocarbon analyses of chicken bones from sites of Māori middens containing prehistoric material. The chickens belong to the widespread mitochondrial control region haplogroup E. Radiocarbon dating reveals that the bones are not prehistoric, but are still the earliest chicken remains known from New Zealand. Two of the bones pre-date permanent European settlement (ca 1803s onwards) but overlap with the arrival of James Cook's second voyage (1773-1774), and, therefore, they are likely to be chickens, or progeny thereof, liberated during that voyage. Our results support the idea that chickens were first introduced to New Zealand by Europeans, and provide new insights into Māori uptake and integration of resources introduced during the early post-European period.


A comparative study of cervical cancer screening methods in a rural community setting of North India.
Pap smear testing as a conventional cervical screening approach has limitations for implementation and aided visual cervical testing has varying results in different regions. The aim of this study is to demonstrate the performance of aided visual cervical screening tests as against conventional Pap smear testing in a rural community setting of North India. This was a rural community based cross-sectional study. All 7603 ever married women of age 30-59 years surveyed in a pocket of Dadri Tehsil, Uttar Pradesh, India were targeted for screening by Pap, visual inspection of cervix using acetic acid (VIA) and visual inspection of cervix using Lugol's iodine (VILI) methods. Screen positives were referred to colposcopy and confirmation by histology. Detection of histological cervical intraepithelial neoplasia (CIN) II + and CIN III + assessed separately by sensitivity, specificity and likelihood ratio's and predictive values. Analysis of data was performed by using IBM SPSS statstics software version 16.0. A total of 65.6%(4988/7604) eligible women of 30-59 years age group in the target population were screened. Out of 4988, further analysis was performed on 4148 after excluding those who did not complete all screenings, who lost to follow-up and had missing histology results. Screen positivity rates by Pap (ASCUS and above), VIA and VILI were 2.6%, 9.7% and 13.5% respectively. Sensitivity and specificity of detecting the CIN III+ lesions were 87.5 and 98.8% for Pap, 50.0% and 96.7% for VIA and 50.0% and 95.7% for VILI respectively. VIA screening demonstrated as a feasible primary screening test for detecting high grade CIN and as to perform better when the Pap test is not feasible.


Impaired formation of beta-adrenergic receptor-nucleotide regulatory protein complexes in pseudohypoparathyroidism.
Decreased activity of the guanine nucleotide regulatory protein (N) of the adenylate cyclase system is present in cell membranes of some patients with pseudohypoparathyrodism (PHP-Ia) whereas others have normal activity of N (PHP-Ib). Low N activity in PHP-Ia results in a decrease in hormone (H)-stimulatable adenylate cyclase in various tissues, which might be due to decreased ability to form an agonist-specific high affinity complex composed of H, receptor (R), and N. To test this hypothesis, we compared beta-adrenergic agonist-specific binding properties in erythrocyte membranes from five patients with PHP-Ia (N = 45% of control), five patients with PHP-Ib (N = 97%), and five control subjects. Competition curves that were generated by increasing concentrations of the beta-agonist isoproterenol competing with [125I]pindolol were shallow (slope factors less than 1) and were computer fit to a two-state model with corresponding high and low affinity for the agonist. The agonist competition curves from the PHP-Ia patients were shifted significantly (P less than 0.02) to the right as a result of a significant (P less than 0.01) decrease in the percent of beta-adrenergic receptors in the high affinity state from 64 +/- 22% in PHP-Ib and 56 +/- 5% in controls to 10 +/- 8% in PHP-Ia. The agonist competition curves were computer fit to a "ternary complex" model for the two-step reaction: H + R + N in equilibrium HR + N in equilibrium HRN. The modeling was consistent with a 60% decrease in the functional concentration of N, and was in good agreement with the biochemically determined decrease in erythrocyte N protein activity. These in vitro findings in erythrocytes taken together with the recent observations that in vivo isoproterenol-stimulated adenylate cyclase activity is decreased in patients with PHP (Carlson, H. E., and A. S. Brickman, 1983, J. Clin. Endocrinol. Metab. 56:1323-1326) are consistent with the notion that N is a bifunctional protein interacting with both R and the adenylate cyclase. It may be that in patients with PHP-Ia a single molecular and genetic defect accounts for both decreased HRN formation and decreased adenylate cyclase activity, whereas in PHP-Ib the biochemical lesion(s) appear not to affect HRN complex formation.


Grasping the changes seen in older adults when reaching for objects of varied texture.
Old age is associated with reduced mobility of the hand. To investigate age related decline when reaching-to-lift an object we used sophisticated kinematic apparatus to record reaches carried out by healthy older and younger participants. Three objects of different widths were placed at three different distances, with objects having either a high or low friction surface (i.e. rough or slippery). Older participants showed quantitative differences to their younger counterparts - movements were slower and peak speed did not scale with object distance. There were also qualitative differences with older adults showing a greater propensity to stop the hand and adjust finger position before lifting objects. The older participants particularly struggled to lift wide slippery objects, apparently due to an inability to manipulate their grasp to provide the level of precision necessary to functionally enclose the object. These data shed light on the nature of age related changes in reaching-to-grasp movements and establish a powerful technique for exploring how different product designs will impact on prehensile behavior.


Prospective intermediate follow-up of carcinoma in situ involving the distal ureter at cystectomy: is there a role for ureteroscopy?
The presence of urothelial carcinoma in situ (CIS) at the distal ureteral margin has been identified as a risk factor for upper tract recurrence after radical cystectomy. Management of this finding is controversial. The objective of this study was to determine if follow-up with ureteroscopy could aid in early detection of recurrences in these patients. We collected prospective clinical-pathologic data for all patients who underwent radical cystectomy between 1999 and 2004. Patients with CIS at the distal ureteral margin were followed with endoscopy of the urinary diversion and bilateral ureteroscopy in addition to standard imaging and cytologic evaluation every 6 months. Recurrence was defined as detection of any malignant urothelial cells. In 250 consecutive cystectomies, eight patients were identified with CIS that involved a ureteral margin of 12 renal units. Ureteroscopy was successful in all cases, and there were no complications. Imaging was diagnostic in one patient, all cytologic examinations from the diversion were nondiagnostic, and ureteroscopy was positive in all recurrences. Six patients had recurrences at a median follow-up of 52.7 months; five needed laparoscopic nephroureterectomy, and one had disease controlled with percutaneous mitomycin C. Five patients were disease free at last follow-up, and one patient died with brain metastasis at 30 months. Patients with CIS that involves the ureteral margin are at increased risk for upper tract recurrence and progression. Aggressive follow-up with scheduled ureteroscopy may identify recurrences at an earlier stage. Development of additional markers for risk stratification and protocols for adjuvant treatment are needed.


Willingness of Certified Health Education Specialists to Conduct Rapid HIV Testing: Results From the Promoting Research on Methods in Screening Expertise Study.
Approximately 16% of people living with HIV are not aware of their infection. Health education specialists, with their training in health program design, implementation, evaluation, and work with vulnerable communities, may have the necessary expertise to conduct rapid HIV testing (RHT). A national, cross-sectional, online survey of Certified Health Education Specialists (CHES) and Master CHES (MCHES) was conducted from April to October 2013, with participants recruited through the National Commission on Health Education Credentialing. We surveyed CHES/MCHES on HIV knowledge and attitudes as well as willingness to conduct RHT. A total of 1,421 CHES/MCHES completed the survey, with a median age of 32 years and median level of 7 years of experience. The majority were White (70.3%), female (91.7%), and heterosexual (93.1%). The majority of respondents had high knowledge of HIV (69.7%), thought that CHES/MCHES should offer RHT (75.2%), and was willing to get trained/certified to conduct RHT (80.3%). Those willing to get trained/certified were more likely to feel comfortable educating clients about HIV prevention methods (p < .001) and planning health promotion programs for people living with HIV (p < .001). Perceived barriers to conducting RHT were related to lack of knowledge of RHT counseling (34.8%) and procedures (25%). CHES/MCHES have the potential to play a significant role in increasing the availability of HIV testing, and the majority of respondents expressed a willingness to become involved. However, training and implementation barriers were identified. Piloting such an approach should be considered to further evaluate the optimum ways in which expanding HIV testing can be achieved.


The effects of black tea and other beverages on aspects of cognition and psychomotor performance.
Nineteen healthy volunteers ingested 400 ml black tea, coffee, caffeinated water, decaffeinated tea or plain water on three occasions through the day (0900, 1400 and 1900 hours). A 2 x 2 factorial design with caffeine (0, 100 mg) and beverage type (water, tea) was employed, with coffee (100 mg caffeine) as a positive internal control, based on a five-way crossover. A psychometric test battery comprising critical flicker fusion (CFF), choice reaction time (CRT), short-term memory (STM) and subjective sedation (LARS) was performed at regular intervals throughout the day, and intensively so immediately following each beverage. Consumption of tea compared to water was associated with transient improvements in performance (CFF) within 10 min of ingestion and was not affected by the time of day. Caffeine ingestion was associated with a rapid (10 min) and persistent reduction in subjective sedation values (LARS), again independent of time of day, but did not acutely alter CFF threshold. Over the whole day, consumption of tea rather than water, and of caffeinated compared to decaffeinated beverages, largely prevented the steady decline in alertness (LARS) and cognitive capacity observed with water ingestion. The effects of tea and coffee were similar on all measures, except that tea consumption was associated with less variation in CFF over the whole day. No significant treatment effects were apparent in the data for the STM. Tea ingestion is associated with rapid increases in alertness and information processing capacity and tea drinking throughout the day largely prevents the diurnal pattern of performance decrements found with the placebo (no caffeine) condition. It appears that the effects of tea and coffee were not entirely due to caffeine per se; other factors either intrinsic to the beverage (e.g. sensory attributes or the presence of other biologically active substances) or of a psychological nature (e.g. expectancy) are likely to play a significant role in mediating the responses observed in this study.


Polarity protein Par3/Bazooka follows myosin-dependent junction repositioning.
The polarity protein Par3/Bazooka (Baz) has been established as a central component of the apical basal polarity system that determines the position of cell-cell junctions in epithelial cells. Consistent with that view, we show that shortly before gastrulation in Drosophila, Baz protein in the mesoderm is down-regulated from junctional sites in response to Snail (Sna) expression. This down-regulation leads to a specific decrease in adherens junctions without affecting other E-Cadherin pools. However, we further show that, interactions between Baz and junctions are not unidirectional. During apical constriction and the internalization of the mesoderm, down-regulation of Baz is transiently blocked as adherens junctions shift apically and are strengthened in response to tension generated by contractile actomyosin. When such junction remodeling is prevented by down-regulating myosin, Baz is lost prematurely in mesodermal epithelium. During such apical shifts, Baz is initially left behind as the junction shifts position, but then re-accumulates at the new location of the junctions. On the dorsal side of the embryo, a similar pattern of myosin activity appears to limit the basal shift in junctions normally driven by Baz that controls epithelium folding. Our results suggest a model where the sensitivity of Baz to Sna expression leads to the Sna-dependent junction disassembly required for a complete epithelium-mesenchymal transition. Meanwhile this loss of Baz-dependent junction maintenance is countered by the myosin-based mechanism which promotes an apical shift and strengthening of junctions accompanied by a transient re-positioning and maintenance of Baz proteins.


Modeling optical properties of liquid-crystal devices by numerical solution of time-harmonic Maxwell equations.
We consider numerical modeling of the optical properties of devices typical of beam-steering devices based on liquid-crystal materials: two-dimensional, anisotropic and inhomogeneous dielectric properties, periodic in one dimension. A mathematical formulation of the system of second-order partial differential equations for the components of the time-harmonic electric field is discretized by using a finite-element method based on curl-conforming edge elements. The discrete equations are also interpreted as equivalent finite-difference equations. It is shown how the resulting large sparse complex system of linear algebraic equations can be solved by an iterative method with convergence accelerated by a preconditioner based on fast Fourier transforms. Benchmarking results and the application to a realistic problem are reported. The practical limitations of the approach and its advantages and disadvantages compared with other approaches are discussed.


Association of Strawberries and Anthocyanidin Intake with Alzheimer's Dementia Risk.
Strawberries have been identified to have antioxidant and anti-inflammatory properties that improve neuronal function and cognition, mostly in animal studies. It is unknown if the consumption of strawberries or related bioactives may reduce the risk of Alzheimer's dementia risk. The study was conducted in 925 participants, aged 58-98 years of the Rush Memory and Aging Project. Participants were dementia-free at baseline, completed a food frequency questionnaire, and had at least two annual neurological evaluations. The diagnosis of Alzheimer's dementia was based on structured clinical neurological examination and standardized diagnostic criteria. The association of strawberry intake and incident Alzheimer's dementia was analyzed using proportional hazard models adjusted for age, sex, education, physical activity, participation in cognitive activities, APOE-ɛ4 genotype, dietary intake of other fruits, and total calorie intake. A total of 245 participants developed Alzheimer's dementia over the mean follow-up of 6.7 (±3.6) years. Higher strawberry intake was associated with reduced risk of Alzheimer's dementia (HR = 0.76, 95% CI: 0.60-0.96). In separate adjusted models, highest vs. lowest quartile intakes of Vitamin C (HR = 0.64, 95% CI: 0.45, 0.92), Pelargonidin (0.63, 95% CI: 0.43, 0.92), total anthocyanidins (0.69, 95% CI: 0.48, 0.99), and total flavonoids (0.67, 95% CI: 0.46, 0.98) were each associated with lower Alzheimer's dementia risk. These associations remained after further adjustment for cardiovascular conditions. Consumption of strawberries and foods rich in vitamin C, pelargonidin, anthocyanidins, and total flavonoids may reduce the risk of Alzheimer's dementia.


Detection of an explosive simulant via electrical impedance spectroscopy utilizing the UiO-66-NH2 metal-organic framework.
Electrical impedance spectroscopy, in conjunction with the metal-organic framework (MOF) UiO-66-NH2, is used to detect trace levels of the explosive simulant 2,6-dinitrotoluene. The combination of porosity and functionality of the MOF provides an effective dielectric structure, resulting in changes of impedance magnitude and phase angle. The promising data indicate that MOFs may be used in low-cost, robust explosive detection devices.


Streptolysin S induces mitochondrial damage and macrophage death through inhibiting degradation of glycogen synthase kinase-3β in Streptococcus pyogenes infection.
Group A Streptococcus (GAS) infection is associated with a variety of human diseases. Previous studies indicate GAS infection leads to RAW264.7 cell death, but the mechanism is unclear. Here, analyzing the timing of reactive oxygen species (ROS) production and using mitochondrial ROS scavenger, we found the wild type GAS-induced RAW264.7 cell death was associated with mitochondrial ROS. The wild type GAS infection could activate glycogen synthase kinase-3β (GSK-3β). Inhibition of GSK-3β activity by lithium chloride or decreasing GSK-3β expression by lentivirus-mediated short hairpin RNA for GSK-3β could not only decrease the wild type GAS-induced mitochondrial ROS generation, mitochondria damage and cell death, but also reduced GAS intracellular replication. Streptolysin S (SLS), a GAS toxin, played the important role on GAS-induced macrophage death. Compared to the wild type GAS with its isogenic sagB mutant (SLS mutant)-infected macrophages, we found sagB mutant infection caused less mitochondrial ROS generation and cell death than those of the wild type GAS-infected ones. Furthermore, the sagB mutant, but not the wild type or the sagB-complementary mutant, could induce GSK-3β degradation via a proteasome-dependent pathway. These results suggest that a new mechanism of SLS-induced macrophage death was through inhibiting GSK-3β degradation and further enhancing mitochondrial damage.


Unaffected contractility of diaphragm muscle fibers in humans on mechanical ventilation.
Several studies have indicated that diaphragm dysfunction develops in patients on mechanical ventilation (MV). Here, we tested the hypothesis that the contractility of sarcomeres, i.e., the smallest contractile unit in muscle, is affected in humans on MV. To this end, we compared diaphragm muscle fibers of nine brain-dead organ donors (cases) that had been on MV for 26 ± 5 h with diaphragm muscle fibers from nine patients (controls) undergoing surgery for lung cancer that had been on MV for less than 2 h. In each diaphragm specimen we determined 1) muscle fiber cross-sectional area in cryosections by immunohistochemical methods and 2) the contractile performance of permeabilized single muscle fibers by means of maximum specific force, kinetics of cross-bridge cycling by rate of tension redevelopment, myosin heavy chain content and concentration, and calcium sensitivity of force of slow-twitch and fast-twitch muscle fibers. In case subjects, we noted no statistically significant decrease in outcomes compared with controls in slow-twitch or fast-twitch muscle fibers. These observations indicate that 26 h of MV of humans is not invariably associated with changes in the contractile performance of sarcomeres in the diaphragm.


A Step toward Standardization: Results of two National Surveys of Best Practices in Donation after Circulatory Death Liver Recovery and Recommendations from The American Society of Transplant Surgeons and Association of Organ Procurement Organizations.
Donation after circulatory death (DCD) liver allografts remain underutilized. Inconsistent processes for DCD procurement may contribute to allograft discard. Optimal surgical and organ procurement organization (OPO) practices for DCD liver recovery should be developed and adopted. DCD practice surveys were distributed to transplant surgeons and OPO leadership. DCD liver recovery best practices were assembled based on survey data, literature review, and subject-matter expert consensus opinion. Data were obtained from transplant surgeons (n = 188) and OPO leadership (n = 48 OPOs). Surgeons preferred attending physician presence at recovery (72.4%); while only 27.7% of OPOs require this. Pre-withdrawal communication huddle (Surgeons: 88.7%; OPOs: 93.8%) and administration of pre-withdrawal heparin (Surgeons: 90.6%; OPOs: 84.8%) are widely accepted. Surgical preference for withdrawal of support is in the operating room (89.3%); OPO practice varies dependent upon hospital and family requirements. Functional donor warm ischemic time (fDWIT) start time is variable, while fDWIT end time is agreed upon as initiation of aortic flush by surgeons (81%) and OPOs (81%). DCD liver recovery practices including mandatory communication huddle, pre-withdrawal heparin administration, and clearly defined start and end of fDWIT should be implemented nationally. Creating a set of best practices for DCD recovery guidelines is necessary for improving DCD liver utilization.


Identifying Communication-Impaired Pediatric Patients Using Detailed Hospital Administrative Data.
Pediatric inpatients with communication impairment may experience inadequate pain and symptom management. Research regarding potential variation in care among patients with and without communication impairment is hampered because existing pediatric databases do not include information about patient communication ability per se, even though these data sets do contain information about diagnoses and medical interventions that are probably correlated with the probability of communication impairment. Our objective was to develop and evaluate a classification model to identify patients in a large administrative database likely to be communication impaired. Our sample included 236 hospitalized patients aged ≥12 months whose ability to communicate about pain had been assessed. We randomly split this sample into development (n = 118) and validation (n = 118) sets. A priori, we developed a set of specific diagnoses, technology dependencies, procedures, and medications recorded in the Pediatric Health Information System likely to be strongly associated with communication impairment. We used logistic regression modeling to calculate the probability of communication impairment for each patient in the development set, assessed the model performance, and evaluated the performance of the 11-variable model in the validation set. In the validation sample, the classification model showed excellent classification accuracy (area under the receiver operating characteristic curve 0.92; sensitivity 82.6%; 95% confidence interval, 74%-100%; specificity 86.3%; 95% confidence interval, 80%-97%). For the complete sample, the predicted probability of communication impairment demonstrated excellent calibration with the observed communication impairment status. Hospitalized pediatric patients with communication impairment can be accurately identified in a large hospital administrative database.


Improved derivation efficiency and pluripotency of stem cells from the refractory inbred C57BL/6 mouse strain by small molecules.
The ability of small molecules to maintain self-renewal and to inhibit differentiation of pluripotent stem cells has been well-demonstrated. Two widely used molecules are PD 98059 (PD), an inhibitor of extracellular-signal-regulated kinase 1 (ERK), and SC1 (Pluripotin), which inhibits the RasGAP and ERK pathways. However, no studies have been conducted to compare their effects on the pluripotency and derivation of embryonic stem (ES) cells from inbred mice C57BL/6, an important mouse strain frequently used to model behavior, cognitive functions, immune system, and metabolic disorders in humans and also the first mouse strain chosen to be sequenced for its entire genome. We found significantly increased derivation efficiency of ES cells from in vivo fertilized embryos (fES) of C57BL/6 with the use of PD (71.4% over the control of 35.3%). Because fES and ES from cloned embryos (ntES) are not distinguishable in transcription or translation profiles, we used ntES cells to compare the effect of small molecules on their in vitro characteristics, in vitro differentiation ability, and the ability to generate full-term ntES-4N pups by tetraploid complementation. NtES cells exhibited typical ES characteristics and up-regulated Sox2 expression in media with either small-molecule. Higher rates of full term ntES-4N pup were generated by the supplementation of PD or SC1. We obtained the highest efficiency of ntES-4N pup generation ever reported from this strain by supplementing ES medium with SC1. Lastly, we compared the pluripotency of fES, ntES and induced pluripotent stem (iPS) cells of C57BL/6 background using the tetraploid complementation assay. A significant increase in implantation sites and the number of full-term pups were obtained when fES, ntES, and iPS cells were cultured with SC1 compared to the control ES medium. In conclusion, supplementing ES cell culture medium with PD and SC1 increases the derivation efficiency and pluripotency, respectively, of stem cells derived from the refractory inbred C57BL/6 strain.


Development and Evaluation of a Lung Cancer Screening Decision Aid.
Lung cancer is the second most common cancer; however, it often is not diagnosed until the advanced stages. Early-stage lung cancer is curable, but screening tools are not usually implemented in practice because of a lack of provider awareness. A lung cancer screening decision aid may increase screening use and, ultimately, reduce lung cancer deaths.


Postprandial plasma bile acid responses in normal weight and obese subjects.
Bile acids can act as signalling molecules via various receptors including the nuclear farnesoid X receptor (FXR) and pregnane X receptor (PXR), and the cell surface G-protein-coupled receptor TGR5. The signalling has been implicated in the release of peptide YY (PYY) and glucagon-like peptide 1 (GLP-1), which improves glycaemic control and energy expenditure. We investigated whether morbidly obese subjects have altered postprandial bile acid responses in comparison to normal weight subjects. Blood samples were taken every 30 min from 0 to 180 min following a 400 kcal test meal. Samples were taken from 12 normal weight subjects with a body mass index (BMI) of 23.2 (2.8) kg/m(2) (median [interquartile range (IQR)]) and seven obese patients with a BMI of 47.2 (7.2) kg/m(2). Fractionated bile acids were measured on these samples using high-performance liquid chromatography tandem mass spectrometry. The obese subjects showed a lower postprandial response in total bile acids compared with the normal weight subjects. An increase of 6.4 (5.0) and 2.6 (3.3) micromol/L (median [IQR]) in normal weight and obese subjects was observed, respectively (P = 0.02). The difference was predominantly due to the glycine-conjugated fraction (P = 0.03). There was no difference in the increase of the unconjugated or taurine-conjugated fractions. The decreased postprandial bile acid response in obese subjects compared with normal weight subjects may partly explain the suboptimal GLP-1 and PYY responses and could affect appetite, glycaemic control and energy expenditure.


Can automated alerts within computerized physician order entry improve compliance with laboratory practice guidelines for ordering Pap tests?
The electronic health record (EHR) provides opportunity to improve health and enhance appropriate test utilization through decision support. Electronic alerts in the order entry system can guide test use. Few published reports have assessed the impact of automated alerts on compliance of Pap ordering with published screening guidelines. Programming rules for Pap test ordering were developed within the EHR (Epic, Madison, WI) of the University of California, Davis Health System using American College of Obstetrics and Gynecology's 2009 guidelines and implemented in primary care clinics in 2010. Alerts discouraged Pap orders in women <21 and >71 years and displayed when an order was initiated. Providers were not prevented from placing an order. Results were measured during four calendar periods: (1) pre-alert (baseline) (July 2010 to June 2011), (2) post alert (alerts on) (July 2011 to December 2011), (3) inadvertent alert turn-off ("glitch") (January 2012 to December 2012), (5) post-glitch (alerts re-instated) (1/2013-7/2013). Metrics used to measure alert impact were between time and period seasonally adjusted relative frequency ratios. Alerts were most effective in the <21 year old age group. During the baseline period 2.7 Pap tests were order in patients less than age 21 for every 100 Paps in those 21-71 years of age. This relative frequency decreased to 1.7 in the post-alert period and 1.4 during the glitch, with an even greater decline to 0.8 post-glitch when alerts were reinstated. Less impact was observed in the >70 year old group where the baseline relative frequency was 2.4 and declined to 2.1 post-alert, remained stable at 2.0 during the glitch period, and declined again to 1.7 post-glitch when alerts were reinstated. This likely reflects inclusion of women with a history of abnormal Pap tests for whom continued Pap testing is indicated, as well as reluctance by providers and patients to accept discontinuation of Pap testing for women with a history of normal Pap results. In both age groups, decreases in ordering were greatest when the alerts were functioning, indicating that the alerts had an effect beyond the influences of the environment. Discouraging alerts can impact ordering of Pap tests and improve compliance with established guidelines, thus avoiding unnecessary follow-up tests that can create potential patient harm and unnecessary expense. Alerts represent a potential model to address utilization of other lab tests. Longer study intervals are necessary to determine if provider compliance is maintained.


Learning Spatial-Spectral-Temporal EEG Features With Recurrent 3D Convolutional Neural Networks for Cross-Task Mental Workload Assessment.
Mental workload assessment is essential for maintaining human health and preventing accidents. Most research on this issue is limited to a single task. However, cross-task assessment is indispensable for extending a pre-trained model to new workload conditions. Because brain dynamics are complex across different tasks, it is difficult to propose efficient human-designed features based on prior knowledge. Therefore, this paper proposes a concatenated structure of deep recurrent and 3D convolutional neural networks (R3DCNNs) to learn EEG features across different tasks without prior knowledge. First, this paper adds frequency and time dimensions to EEG topographic maps based on a Morlet wavelet transformation. Then, R3DCNN is proposed to simultaneously learn EEG features from the spatial, spectral, and temporal dimensions. The proposed model is validated based on the EEG signals collected from 20 subjects. This paper employs a binary classification of low and high mental workload across spatial n-back and arithmetic tasks. The results show that the R3DCNN achieves an average accuracy of 88.9%, which is a significant increase compared with that of the state-of-the-art methods. In addition, the visualization of the convolutional layers demonstrates that the deep neural network can extract detailed features. These results indicate that R3DCNN is capable of identifying the mental workload levels for cross-task conditions.


[Evaluation of three methods for in vitro detection of antifungal susceptibility of Candida species].
Reference methods E.Def 7.1 and M27-A3 detect in vitro resistance; however, they are expensive and very laborious. Thus, their actual use in hospital laboratories is limited. There are commercial techniques available, having easier accessibility and development, which would yield results comparable to those of the reference methods. The objectives of this study were: a) to compare the results of minimal inhibitory concentration of 82 Candida spp. clinic isolates according to reference method E.Def 7.1 and ATB® Fungus 3; b) to compare the results of fluconazole susceptibility testing by disk diffusion in agar with Neo-SensitabsTM tablets and Malbrán disks with those of the reference methods. Minimal inhibitory concentration for amphotericin B, 5-flucytosine, fluconazole and itraconazole was performed according to the E.Def 7.1 and the ATB Fungus 3 methods and diffusion was carried out with fluconazole disks and tablets. General concordance between the reference method and ATB Fungus 3 was 90.2 % and 96.3 and 92.7% for diffusion with disks and tablets. The ATB Fungus 3 method was effective to determine susceptibility against amphotericin B and 5-flucytosine; however, discrepancies were observed with azole drugs. Disk diffusion methods are useful to determine susceptibility to fluconazole; however, 3 very major, 1 major and 2 minor errors were observed with the tablets, whereas only 3 minor errors were observed with the disks.


Direct and indirect measures of Level-2 perspective-taking in children and adults.
Studies with infants show divergence between performance on theory of mind tasks depending on whether direct or indirect measures are used. It has been suggested that direct measures assess a flexible but cognitively demanding ability to reason about the minds of others, whereas indirect measures assess distinct processes which afford more efficient but less flexible theory of mind abilities (Apperly & Butterfill, 2009). This leads to the prediction that performance on indirect measures should be subject to signature limits. The current study tested whether the Level-1/Level-2 distinction might constitute one such limit. The study adapted a task that has shown evidence of Level-1 perspective-taking on both direct and indirect measures (Samson, Apperly, Braithwaite, Andrews, & Bodley-Scott, 2010). The aim was to test Level-2 perspective-taking in a sample of 6- to 11-year-olds (N = 80) and adults (N = 20). Participants were able to make Level-2 judgements on the direct measure. In contrast with the findings from Level-1 perspective-taking, there was no evidence of automatic processing of Level-2 perspectives on the indirect measure. This finding is consistent with the view that theory of mind abilities assessed by indirect measures are subject to signature limits. The Level-1/Level-2 distinction, suitably refined, marks one way in which efficient but inflexible theory of mind abilities are limited.


Synthesis, characterization, and evaluation of a novel 99mTc(CO)3 pyrazolyl conjugate of a peptide nucleic acid sequence.
The 16-mer peptide nucleic acid sequence H-A GAT CAT GCC CGG CAT-Lys-NH2 (1), which is complementary to the translation start region of the N-myc oncogene messenger RNA, was synthesized and conjugated to a pyrazolyl diamine bifunctional chelator (pz). The novel conjugate pz-A GAT CAT GCC CGG CAT-Lys-NH2 (2) was labeled with technetium tricarbonyl, yielding quantitatively the complex fac-[99mTc(CO)3(kappa3-pz-A GAT CAT GCC CGG CAT-Lys-NH2)]2+ (4). Complex 4 was obtained with high radiochemical purity and high specific activity, revealing high stability in human serum and in cell culture medium. The identity of 4 was confirmed by comparing its reversed-phase high performance liquid chromatography profile with that of the rhenium analog fac-[Re(CO)3(kappa3-pz-A GAT CAT GCC CGG CAT-Lys-NH2)]2+ (3), prepared by conjugation of fac-[Re(CO)3(3,5-Me2pz(CH2)2N((CH2)3COOH)(CH2)2NH2)]+ to 1, using solid-phase techniques. UV melting experiments of 1 and 3 with the complementary DNA sequence led to the formation of stable duplexes, indicating that the conjugation of 1 to the pyrazolyl chelator and to the metal fragment fac-[M(CO)3]+ did not affect the recognition of the complementary sequence as well as the duplex stability. For a first screening, SH-SY5Y human neuroblastoma cells, which express N-myc, were treated with 4. The results show that 4 internalizes (7% of the activity goes into the cells, after 4 h at 37 degrees C), presenting also a relatively high cellular retention (only 40% of internalized activity is released from the cells after 5 h).


Real-time acquisition of complex optical fields by binary amplitude modulation.
We describe, through simulations and experiments, a real-time wavefront acquisition technique using random binary amplitude masks and an iterative phase retrieval algorithm based on the Fresnel propagator. By using a digital micromirror device, it is possible to recover an unknown complex object by illuminating with this set of masks and simultaneously recording the resulting intensity patterns with a high-speed camera, making this technique suitable for dynamic applications.


[Comparison of Antiviral Effect of Olive Leaf Extract and Propolis with Acyclovir on Herpes Simplex Virus Type 1].
While acyclovir, a nucleoside analogue, is widely used for herpes simplex virus type 1 (HSV-1), emergence of drug-resistant viruses due to frequent usage of this class of medicines, and their toxic side effects require exploring novel active molecules. Despite the studies on developing synthetic molecules in medical sciences and pharmacology, herbs as a natural source of biologically-active compounds remain popular. In this in vitro study, olive leaf extract (OLE) and propolis alone or in combination with acyclovir were investigated for their antiviral efficacy in HSV-1.Toxic doses of OLE, propolis, and dimethyl sulfoxide, propolis diluent, for Hep-2 (ATCC, CCL-23) cells were determined by conventional cell culture. Using "endpoint" method, the viral dose infecting half of the cell culture (TCID50) was calculated, and viral quantity was determined with Spearman-Karber method. Antiviral effects of OLE and propolis on HSV-1 were investigated by conventional cell culture and real-time cell analysis (RTCA). Combinations of the two extracts with one another and with acyclovir were evaluated by RTCA. Active substances prepared at three different dilutions were added to tubes with HSV-1 of logTCID50: 11.5 in descending order starting from the highest non-toxic concentration, and they were left at room temperature for two different durations (one hour and three hours). The aliquots taken from the tubes were cultured in plates containing Hep-2 cells and evaluated after 72 hours. Combinations of extracts and acyclovir at concentrations at least four times lower than the lowest concentration showing antiviral efficacy against HSV-1 were cultured with Hep-2 cells in the e-plates of the xCELLigence RTCA device, measurements were obtained at 30 minute intervals, and data were recorded in real time. In the test with two different durations and at different concentrations of OLE and propolis, antiviral efficacy was observed both with one-hour and three-hour incubation at a concentration of 10 μg/ ml for propolis and 1.2 mg/ml for OLE with RTCA. The duration and concentration of the greatest decrease in viral quantity were in the first one hour and 10 μg/ml for propolis, and in the first one hour and 1.2 mg/ ml for OLE. Combination of propolis and OLE with acyclovir caused no cytopathic effects, and the combination of extracts led to delayed cytopathic effect. According to these results, propolis and OLE, alone and in combinations with acyclovir, have antiviral efficacy against HSV-1. These agents may reduce the dose and side effects of acyclovir in case of co-administration since they exert their effects through a different mechanism than acyclovir,possibly through direct virucidal activity, inhibition of virus internalization or viral inhibition in early stages of replication (inhibition of adsorption/binding of viral particles to the cell). These extracts that do not require conversion to active form have the potential to reduce infectivity in oral lesions, prevent spread, and be used in the topical treatment of acyclovir-resistant HSV infections, particularly in immunocompromised patients. However, in vivo studies should be conducted to determine their medicinal properties and potential toxicities. These results should be supported by further comprehensive studies and the efficacy against other viruses should also be investigated.


Social circumstances of initiation of injection drug use and early shooting gallery attendance: implications for HIV intervention among adolescent and young adult injection drug users.
To determine correlates of early shooting gallery (SG) attendance and HIV prevalence and incidence among new injection drug users (IDUs), baseline data from a prospective cohort study of street-recruited IDUs aged 15 to 30 years and injecting < or =5 years were used to identify early high-risk practices and salient social circumstances associated with early SG attendance to help in the design of innovative intervention strategies. Of 226 IDUs, 10.6% were HIV-seropositive, and HIV incidence was 6.6 per 100 person-years (95% CI: 2.2-13.3). Median age was 25 years, and most participants were African American (64%) and female (61%). Using multiple logistic regression, early SG attendees were three times as likely to be HIV-seropositive and twice as likely to be initiated by an older IDU. Early SG attendees were also five times more likely to share injection equipment and over three times more likely to report a high-risk injecting network soon after initiating injection. These data suggest that young new IDUs who attend SGs early tend to be initiated by older high-risk IDUs and to share and inject within a high-risk social setting early on as well. Hence, older IDUs may serve as a bridge group to SGs, transmitting HIV from older to younger IDUs.


Association of polo-like kinase with alpha-, beta- and gamma-tubulins in a stable complex.
The polo-like kinase (Plk) family has been shown to have an important role in the regulation of the cell-division cycle, especially in organization of the spindle structure, in species from fungi to humans. Recent reports have demonstrated that in mammalian cells Plk is associated with components of the anaphase-promoting complex and a peptidyl-prolyl isomerase, Pin1. To characterize a putative Plk-containing complex, we fractionated mitotic cell lysates on a gel-filtration column. The Plk complex was eluted from the column at molecular sizes ranging from 669 to 2500 kDa in the presence of detergent and high concentrations of salt. Specific associations of Plk with alpha-, beta- and gamma-tubulins in both interphase and mitotic cells were shown by reciprocal immunoprecipitations and immunoblottings and were independent of the microtubule polymerization state, whereas binding assays in vitro indicated that Plk interacts with alpha- and beta-tubulins directly. In addition, mitotic Plk was able to phosphorylate associated tubulins in vitro. Finally, we show that the kinase domain of the Plk molecule is both required and sufficient for its binding to tubulins in vivo. The specific interaction between Plk and tubulins might provide a molecular basis for the physiological functions of Plk in regulating the cell cycle, particularly in establishing the normal bipolar spindle.


Variational Bayesian identification and prediction of stochastic nonlinear dynamic causal models.
In this paper, we describe a general variational Bayesian approach for approximate inference on nonlinear stochastic dynamic models. This scheme extends established approximate inference on hidden-states to cover: (i) nonlinear evolution and observation functions, (ii) unknown parameters and (precision) hyperparameters and (iii) model comparison and prediction under uncertainty. Model identification or inversion entails the estimation of the marginal likelihood or evidence of a model. This difficult integration problem can be finessed by optimising a free-energy bound on the evidence using results from variational calculus. This yields a deterministic update scheme that optimises an approximation to the posterior density on the unknown model variables. We derive such a variational Bayesian scheme in the context of nonlinear stochastic dynamic hierarchical models, for both model identification and time-series prediction. The computational complexity of the scheme is comparable to that of an extended Kalman filter, which is critical when inverting high dimensional models or long time-series. Using Monte-Carlo simulations, we assess the estimation efficiency of this variational Bayesian approach using three stochastic variants of chaotic dynamic systems. We also demonstrate the model comparison capabilities of the method, its self-consistency and its predictive power.


Causes of death in people with coeliac disease in England compared with the general population: a competing risk analysis.
Quantifying excess cause-specific mortality among people with coeliac disease (CD) compared with the general population accounting for competing risks will allow accurate information to be given on risk of death from specific causes. We identified from the Clinical Practice Research Datalink all patients with CD linked to Office for National Statistics between 1998 and 2012. We selected controls by frequency matching from the registered general practice population within 10-year age bands. We calculated the adjusted cumulative incidence (including adjustment for competing risks) and excess cumulative incidence for different causes of death up to 10 years from diagnosis. Of the 10 825 patients with CD, 773 died within the study period. The overall mortality rate among patients with CD was 128/10 000 person years compared with 153/10 000 in controls (HR=0.94 95% CI 0.84 to 1.01). We found no overall difference in the cumulative incidence of respiratory disease, digestive disease or cancer related death among cases and controls. The adjusted cumulative incidence of death from cardiovascular deaths was slightly lower compared with those without CD diagnosis (CD 0.32% vs controls 0.41%) with a corresponding excess cumulative incidence of -0.08% (95% CI -0.13 to -0.04). However, patients with CD had 0.15% excess risk (95% CI 0.03 to 0.27) of deaths from non-Hodgkin's lymphoma from the general population baseline risk. Overall, people with CD have no major excess risk of cancer, digestive disease or respiratory disease related or cardiovascular mortality compared with the general population. These findings should be reassuring to patients with CD and clinicians managing their care.


A Central Component of the N1 Event-Related Brain Potential Could Index the Early and Automatic Inhibition of the Actions Systematically Activated by Objects.
Stimuli of the environment, like objects, systematically activate the actions they are associated to. These activations occur extremely fast. Nevertheless, behavioral data reveal that, in most cases, these activations are then automatically inhibited, around 100 ms after the occurrence of the stimulus. We thus tested whether this early inhibition could be indexed by a central component of the N1 event-related brain potential (ERP). To achieve that goal, we looked at whether this ERP component is larger in tasks that could increase the inhibition and in trials where reaction times (RTs) happen to be long. The illumination of a real space bar of a keyboard out of the dark was used as a stimulus. To maximize the modulation of the inhibition, the task participants had to perform was manipulated across blocks. A look-only task and a count task were used to increase inhibition and an immediate press task was used to decrease it. ERPs of the two block-conditions where presses had to be prevented and where the largest central N1s were predicted were compared to those elicited in the press task, differentiating the ERPs to the third of the trials where presses were the slowest from the ERPs to the third of the trials with the fastest presses. Despite larger negativities due to lateralized readiness potentials (LRPs) and despite greater attention likely in immediate press-trials, central N1s were found to be minimal for the fastest presses, intermediate for the slowest ones and maximal for the two no-press conditions. These results thus provide a strong support for the idea that the central N1 indexes an early and short lasting automatic inhibition of the actions systematically activated by objects. They also confirm that the strength of this automatic inhibition spontaneously fluctuates across trials and tasks. On the other hand, just before N1s, parietal P1s were found larger for fastest presses. They might thus index the initial activation of these actions. Finally, consistent with the idea that N300s index late inhibition processes, that occur preferentially when the task requires them, these ERPs were quasi absent for fast presses trials and much larger in the three other conditions.


Unmet needs at the end of life: perceptions of hospice social workers.
Among persons at the end of life, it is important to understand whether the needs of patients are being adequately addressed. In particular, in hospice settings where the emphasis is on comfort care and quality of life, we know little about the presence of unmet needs. The purpose of this study was to examine the experiences of hospice social workers in working with hospice patients who had unmet needs at the end of life. Surveys were mailed to hospice social workers (N = 212) in two Southeastern states with a response rate of 36%. Results revealed that hospice social workers perceived patients to experience a wide variety of unmet needs-more commonly at the time of admission than during subsequent patient interactions. The most common unmet need reported at both times was a decreased ability to participate in activities that make life enjoyable. In situations where unmet needs exist, social workers reported that the most common perceived reasons were patient- related psychosocial issues and family conflict/issues. Additionally, a variety of interventions were used to address unmet needs, but a large number of barriers appear to impact outcomes in the cases. Results suggest that hospice patients experience a number of unmet needs, many of which are potentially treatable problems and concerns. Hospice professionals must continue to seek ways to assess and intervene effectively with patients who have unmet needs.


Impact of maternal obesity on inhaled corticosteroid use in childhood: a registry based analysis of first born children and a sibling pair analysis.
It has been proposed that maternal obesity during pregnancy may increase the risk that the child develops allergic disease and asthma, although the mechanisms underpinning this relationship are currently unclear. We sought to assess if this association may be due to confounding by genetic or environmental risk factors that are common to maternal obesity and childhood asthma, using a sibling pair analysis. The study population comprised a Swedish national cohort of term children born between 1992 and 2008 to native Swedish parents. Maternal body mass index (BMI) was measured at 8-10 weeks gestation. Unconditional logistic regression models were used to determine if maternal obesity was associated with increased risk of inhaled corticosteroid (ICS) in 431,718 first-born children, while adjusting for potential confounders. An age-matched discordant sib-pair analysis was performed, taking into account shared genetic and environmental risk factors. Maternal over-weight and obesity were associated with increased risk that the child would require ICS (for BMI≥35 kg/m(2), aOR = 1.30, 95%CI = 1.10-1.52 compared with normal weight mothers) in children aged 6-12 years. Similar effects were seen in younger children, but in children aged 13-16 years, maternal obesity (BMI≥30) was related to increased risk of ICS use in girls (aOR = 1.28, 95%CI = 1.07-1.53) but not boys (OR = 1.05, 95%CI = 0.87-1.26). The sib-pair analysis, which included 2,034 sib-pairs older than six years who were discordant for both ICS use and maternal BMI category, failed to find any evidence that increasing maternal weight was related to increased risk of ICS use. Maternal obesity is associated with increased risk of childhood ICS use up to approximately 12 years of age, but only in girls after this age. These effects could not be confirmed in a sib pair analysis, suggesting either limited statistical power, or the effects of maternal BMI may be due to shared genetic or environmental risk factors.


Laser Acupuncture for Neonatal Abstinence Syndrome: A Randomized Controlled Trial.
Neonatal abstinence syndrome (NAS) is usually treated with opiate derivatives and supported with nonpharmacological treatment. This prospective, randomized, controlled, blinded, single-center study was carried out between March 2009 and November 2014. Newborn infants diagnosed with NAS after maternal opioid substitution therapy were eligible for inclusion. Infants were randomly allocated to the acupuncture group (combining laser acupuncture and pharmacological therapy of morphine and phenobarbital) or control group (pharmacological therapy alone). Laser acupuncture was performed with a LABpen MED 10 (675 nm/10 mW) at 5 ear and 4 body acupuncture points, bilaterally, and sessions were repeated every day. The primary outcome measure was duration of oral morphine therapy for NAS. Secondary outcomes included highest single Finnegan score, time to highest single Finnegan score, maximum amount of oral morphine solution (in milliliters per kilogram and milligrams per kilogram), time to maximum amount of oral morphine solution, and length of hospital stay. Twenty-eight newborns (14 in each group) were eligible for analysis. Duration of oral morphine therapy was significantly reduced in the acupuncture group compared with the control group (28 vs 39 days, respectively, P = .019). In addition, we observed a significantly reduced length of hospital stay in the acupuncture group compared with the control group (35 days [interquartile range 25 to 47] vs 50 days [36 to 66], P = .048). Adjunctive laser acupuncture significantly reduced the duration of morphine therapy in newborns with NAS.


A fluorescence LIDAR sensor for hyper-spectral time-resolved remote sensing and mapping.
In this work we present a LIDAR sensor devised for the acquisition of time resolved laser induced fluorescence spectra. The gating time for the acquisition of the fluorescence spectra can be sequentially delayed in order to achieve fluorescence data that are resolved both in the spectral and temporal domains. The sensor can provide sub-nanometric spectral resolution and nanosecond time resolution. The sensor has also imaging capabilities by means of a computer-controlled motorized steering mirror featuring a biaxial angular scanning with 200 μradiant angular resolution. The measurement can be repeated for each point of a geometric grid in order to collect a hyper-spectral time-resolved map of an extended target.