The influence of end-of-life education on attitudes of nursing students.
Palliative care is an important aspect of nursing when comfort and quality of life are the patient goals. The End-of-Life Nursing Education Consortium (ELNEC) developed a comprehensive program of teaching care of the dying to nurses and nursing students. This pretest-posttest study evaluated the influence of the integration of the ELNEC curriculum into a baccalaureate nursing program on students' attitudes toward care of the dying. The Frommelt Attitudes toward Care of the Dying Scale for nurses (FATCOD) was administered to traditional and accelerated baccalaureate students before and after exposure to a nursing curriculum that integrated essential ELNEC elements. Multiple regression analyses indicated that no previous experience with death and an age of 18-22 accounted for the most variance in attitude change. The findings suggest that integrating the ELNEC curriculum throughout a baccalaureate program positively affects the attitudes of nursing students toward the care of patients who are dying.


Mitochondria as the primary target of resveratrol-induced apoptosis in human retinoblastoma cells.
To determine the molecular mechanisms by which resveratrol induces retinoblastoma tumor cell death. After resveratrol treatment, Y79 tumor cell viability was measured using a fluorescence-based assay, and proapoptotic and antiproliferative effects were characterized by Hoechst stain and flow cytometry, respectively. Mitochondrial transmembrane potential (DeltaPsim) was measured as a function of drug treatment using 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-benzamidazolocarbocyanin iodide (JC-1), whereas the release of cytochrome c from mitochondria was assayed by immunoblotting and caspase activities were determined by monitoring the cleavage of fluorogenic peptide substrates. Resveratrol induced a dose- and time-dependent decrease in Y79 tumor cell viability and inhibited proliferation by inducing S-phase growth arrest and apoptotic cell death. Preceding cell death, resveratrol evoked a rapid dissipation of DeltaPsim. This was followed by the release of cytochrome c into the cytoplasm and a substantial increase in the activities of caspase-9 and caspase-3. Additionally, in a cell-free system, resveratrol directly induced the depolarization of isolated mitochondria. These results demonstrate that resveratrol, a nontoxic natural plant compound, inhibits Y79 cell proliferation and stimulates apoptosis through activation of the mitochondrial (intrinsic) apoptotic pathway and may warrant further exploration as an adjuvant to conventional anticancer therapies for retinoblastoma.


Cardiac T1 Mapping and Extracellular Volume (ECV) in clinical practice: a comprehensive review.
Cardiovascular Magnetic Resonance is increasingly used to differentiate the aetiology of cardiomyopathies. Late Gadolinium Enhancement (LGE) is the reference standard for non-invasive imaging of myocardial scar and focal fibrosis and is valuable in the differential diagnosis of ischaemic versus non-ischaemic cardiomyopathy. Diffuse fibrosis may go undetected on LGE imaging. Tissue characterisation with parametric mapping methods has the potential to detect and quantify both focal and diffuse alterations in myocardial structure not assessable by LGE. Native and post-contrast T1 mapping in particular has shown promise as a novel biomarker to support diagnostic, therapeutic and prognostic decision making in ischaemic and non-ischaemic cardiomyopathies as well as in patients with acute chest pain syndromes. Furthermore, changes in the myocardium over time may be assessed longitudinally with this non-invasive tissue characterisation method.


Electron-transfer induced repair of 6-4 photoproducts in DNA: a computational study.
The mechanism employed by DNA photolyase to repair 6-4 photoproducts in UV-damaged DNA is explored by means of quantum chemical calculations. Considering the repair of both oxetane and azetidine lesions, it is demonstrated that reduction as well as oxidation enables a reversion reaction by creating anionic or cationic radicals that readily fragment into monomeric pyrimidines. However, on the basis of calculated reaction energies indicating that electron transfer from the enzyme to the lesion is a much more favorable process than electron transfer in the opposite direction, it is suggested that the photoenzymic repair can only occur by way of an anionic mechanism. Furthermore, it is shown that reduction of the oxetane facilitates a mechanism involving cleavage of the C-O bond followed by cleavage of the C-C bond, whereas reductive fragmentation of the azetidine may proceed with either of the intermonomeric C-N and C-C bonds cleaved as the first step. From calculations on neutral azetidine radicals, a significant increase in the free-energy barrier for the initial fragmentation step upon protonation of the carbonylic oxygens is predicted. This effect can be attributed to protonation serving to stabilize reactant complexes more than transition structures.


A passive heat maintenance strategy implemented during a simulated half-time improves lower body power output and repeated sprint ability in professional Rugby Union players.
Reduced physical performance has been observed following the half-time period in team sports players, likely due to a decrease in muscle temperature during this period. We examined the effects of a passive heat maintenance strategy employed between successive exercise bouts on core temperature (Tcore) and subsequent exercise performance. Eighteen professional Rugby Union players completed this randomised and counter-balanced study. After a standardised warm-up (WU) and 15 min of rest, players completed a repeated sprint test (RSSA 1) and countermovement jumps (CMJ). Thereafter, in normal training attire (Control) or a survival jacket (Passive), players rested for a further 15 min (simulating a typical half-time) before performing a second RSSA (RSSA 2) and CMJ's. Measurements of Tcore were taken at baseline, post-WU, pre-RSSA 1, post-RSSA 1 and pre-RSSA 2. Peak power output (PPO) and repeated sprint ability was assessed before and after the simulated half-time. Similar Tcore responses were observed between conditions at baseline (Control: 37.06±0.05°C; Passive: 37.03±0.05°C) and for all other Tcore measurements taken before half-time. After the simulated half-time, the decline in Tcore was lower (-0.74±0.08% vs. -1.54±0.06%, p<0.001) and PPO was higher (5610±105 W vs. 5440±105 W, p<0.001) in the Passive versus Control condition. The decline in PPO over half-time was related to the decline in Tcore (r = 0.632, p = 0.005). In RSSA 2, best, mean and total sprint times were 1.39±0.17% (p<0.001), 0.55±0.06% (p<0.001) and 0.55±0.06% (p<0.001) faster for Passive versus Control. Passive heat maintenance reduced declines in Tcore that were observed during a simulated half-time period and improved subsequent PPO and repeated sprint ability in professional Rugby Union players.


Trends in the use of premium and discount cigarette brands: findings from the ITC US Surveys (2002-2011).
The purpose of this paper was to examine trends in the use of premium and discount cigarette brands and determine correlates of type of brand used and brand switching. Data from the International Tobacco Control (ITC) US adult smoker cohort survey were analysed. The total study sample included 6669 adult cigarette smokers recruited and followed from 2002 to 2011 over eight different survey waves. Each survey wave included an average of 1700 smokers per survey with replenishment of those lost to follow-up. Over the eight survey waves, a total of 260 different cigarette brands were reported by smokers, of which 17% were classified as premium and 83% as discount brands. Marlboro, Newport, and Camel were the most popular premium brands reported by smokers in our sample over all eight survey waves. The percentage of smokers using discount brands increased between 2002 and 2011, with a marked increase in brand switching from premium to discount cigarettes observed after 2009 corresponding to the $0.61 increase in the federal excise tax on cigarettes. Cigarette brand preferences varied by age group and income levels with younger, higher income smokers more likely to report smoking premium brand cigarettes, while older, middle and lower income, heavier smokers were more likely to report using discount brands. Our data suggest that demographic and smoking trends favour the continued growth of low priced cigarette brands. From a tobacco control perspective, the findings from this study suggest that governments should consider enacting stronger minimum pricing laws in order to keep the base price of cigarettes high, since aggressive price marketing will likely continue to be used by manufacturers to compete for the shrinking pool of remaining smokers in the population.


Protein concentration and mitochondrial content in the gastrocnemius predicts mortality rates in patients with peripheral arterial disease.
This study evaluated the hypothesis that protein concentration and mitochondrial content in gastrocnemius biopsies from patients with peripheral arterial disease (PAD) predict mortality rates. PAD patients experience advancing myopathy characterized by mitochondrial dysfunction, myofiber degradation, and fibrosis in their ischemic legs, along with increased mortality rates. Samples from the gastrocnemius of PAD patients were used for all analyses. Protein concentration was normalized to muscle wet weight, and citrate synthase activity (standard measure of mitochondrial content in cells) was normalized to muscle wet weight and protein concentration. Protein and citrate synthase data were grouped into tertiles and 5-year, all-cause mortality for each tertile was determined with Kaplan-Meier curves and compared by the modified Peto-Peto test. A Cox-regression model for each variable controlled for the effects of clinical characteristics. Of the 187 study participants, 46 died during a mean follow-up of 23.0 months. Five-year mortality rate was highest for patients in the lowest tertile of protein concentration. Mortality was lowest for patients in the middle tertile of citrate synthase activity when normalized to either muscle wet weight or protein concentration. The mortality hazard ratios (HRs) from the Cox analysis were statistically significant for protein concentration normalized to muscle wet weight (lowest vs middle tertile; HR = 2.93; P = 0.008) and citrate synthase normalized to protein concentration (lowest vs middle tertile; HR = 4.68; P = 0.003; and lowest vs highest tertile; HR = 2.36; P = 0.027). Survival analysis of a contemporaneous population of PAD patients identifies protein and mitochondrial content of their gastrocnemius as predictors of mortality rate.


Persistence of Salmonella Typhimurium LT2 in Soil Enhanced after Growth in Lettuce Medium.
The persistence of Salmonella in the environment is influenced by a multitude of biotic and abiotic factors. In addition, its persistence can be influenced by preadaptation before the introduction into the environment. In order to study how preadaptation changes the survival of Salmonella in soil and therefore its potential to colonize the phytosphere, we developed a new medium based on lettuce material [lettuce medium (LM)]. Salmonella enterica serovar Typhimurium strain LT2 was used as a model for Salmonella in this study. LT2 was inoculated into soil microcosms after pregrowth in Luria Bertani (LB) broth or in LM. Survival of LT2 in soil was monitored over 56 days by plate counts and quantification of the Typhimurium-specific gene STM4497 using qPCR in total community DNA for which primers and TaqMan probe were designed in this study. Significantly enhanced persistence was observed for LT2 pregrown in LM compared to LT2 pregrown in LB, indicating a preadaptation effect. Surprisingly, no improved survival could be observed for S. Typhimurium strain 14028s and S. enterica serovar Senftenberg after pregrowth on LM. This indicates a high strain specificity of preadaptation. Results from previous studies suggested that biofilm formation could enhance the survival of human pathogens in various environments and might contribute to enhanced survival on plants. In vitro biofilm assays with several Salmonella strains revealed a strain-specific effect of LM on the biofilm formation. While LM significantly improved the biofilm formation of S. Senftenberg, the biofilm formation of LT2 was better in LB. This indicates that the better survival of LM-pregrown LT2 in soil was not linked to an improved ability to form biofilms but was likely due to other factors. Most importantly, this study showed that the medium used to pregrow Salmonella can influence its survival in soil and its biofilm formation which might influence the fate of Salmonella in soil.


Genome-wide insights into the patterns and determinants of fine-scale population structure in humans.
Studying genomic patterns of human population structure provides important insights into human evolutionary history and the relationship among populations, and it has significant practical implications for disease-gene mapping. Here we describe a principal component (PC)-based approach to studying intracontinental population structure in humans, identify the underlying markers mediating the observed patterns of fine-scale population structure, and infer the predominating evolutionary forces shaping local population structure. We applied this methodology to a data set of 650K SNPs genotyped in 944 unrelated individuals from 52 populations and demonstrate that, although typical PC analyses focus on the top axes of variation, substantial information about population structure is contained in lower-ranked PCs. We identified 18 significant PCs, some of which distinguish individual populations. In addition to visually representing sample clusters in PC biplots, we estimated the set of all SNPs significantly correlated with each of the most informative axes of variation. These polymorphisms, unlike ancestry-informative markers (AIMs), constitute a much larger set of loci that drive genomic signatures of population structure. The genome-wide distribution of these significantly correlated markers can largely be accounted for by the stochastic effects of genetic drift, although significant clustering does occur in genomic regions that have been previously implicated as targets of recent adaptive evolution.


Interplanetary transfer of photosynthesis: an experimental demonstration of a selective dispersal filter in planetary island biogeography.
We launched a cryptoendolithic habitat, made of a gneissic impactite inoculated with Chroococcidiopsis sp., into Earth orbit. After orbiting the Earth for 16 days, the rock entered the Earth's atmosphere and was recovered in Kazakhstan. The heat of entry ablated and heated the rock to a temperature well above the upper temperature limit for life to below the depth at which light levels are insufficient for photosynthetic organisms ( approximately 5 mm), thus killing all of its photosynthetic inhabitants. This experiment shows that atmospheric transit acts as a strong biogeographical dispersal filter to the interplanetary transfer of photosynthesis. Following atmospheric entry we found that a transparent, glassy fusion crust had formed on the outside of the rock. Re-inoculated Chroococcidiopsis grew preferentially under the fusion crust in the relatively unaltered gneiss beneath. Organisms under the fusion grew approximately twice as fast as the organisms on the control rock. Thus, the biologically destructive effects of atmospheric transit can generate entirely novel and improved endolithic habitats for organisms on the destination planetary body that survive the dispersal filter. The experiment advances our understanding of how island biogeography works on the interplanetary scale.


Free radical production in peripheral vascular disease. A risk for critical ischaemia?
Malondialdehyde (MDA) plasma concentrations (marker of lipid free radical peroxidation) and the unfractionated leucocyte and erythrocyte filterability rates (through 5 micron Nuclepore filters in a positive pressure filtration system) were determined during a partial ischaemia induced by two consecutive treadmill tests in 64 stage II peripheral vascular disease (PVD) patients and in 32 matched controls. Transcutaneous oxygen pressure (tcPO2) was monitored constantly throughout the walking tests and recovery periods. In the PVD patients impairments in the flow properties of leucocytes and erythrocytes were associated with increases in MDA plasma concentrations which correlated significantly with a lengthening of the tcPO2 half recovery times--index of the worsening of ischaemia. Patients could be divided into two sub-groups on the basis of these impairments and their half recovery times, suggesting this experimental model may provide a means to identify those stage II PVD patients most likely to develop critical limb ischaemia.


Effect of two assisted oocyte activation protocols used to overcome fertilization failure on the activation potential and calcium releasing pattern.
To assess the effect of two assisted oocyte activation (AOA) protocols with the use of two calcium (Ca(2+)) ionophores, ionomycin and A23187 (calcimycin), on the intracellular Ca(2+) level in mouse and human oocytes and the fertilization rates. Comparison of two Ca(2+) ionophores, ionomycin and A23187, regarding their capacity to increase the intracellular Ca(2+) level and to support subsequent oocyte activation and development. University hospital research laboratory. Patients undergoing intracytoplasmic sperm injection (ICSI) treatment and B6D2F1 mice. Assisted oocyte activation and microinjection of mouse and human oocytes with sperm. Measurement of the fertilizing and Ca(2+)-releasing ability of human sperm. Ionomycin was more potent than A23187 in provoking Ca(2+) increases in both mouse and human oocytes with significantly higher amplitude and area under the receiver operating characteristic curve. The oocyte activation rate was significantly higher when mouse oocytes were activated with the use of the ionomycin- rather than the A23187-based AOA protocol. Furthermore, oocyte activation rate was higher when human in vitro matured oocytes were activated with the ionomycin-based AOA protocol, but the difference did not reach statistical significance. In both mouse and human oocytes, the AOA protocol that used ionomycin was more efficient than the one that used A23187. Bearing in mind that mammalian fertilization is successful when the total dose of Ca(2+) released reaches a minimal threshold, the use of ionomycin for human AOA might be justified instead of the use of A23187.


Changes in Photosystem II fluorescence in Chlamydomonas reinhardtii exposed to increasing levels of irradiance in relationship to the photosynthetic response to light.
The effects of a 60 min exposure to photosynthetic photon flux densities ranging from 300 to 2200 μmol m(-2)s(-1) on the photosynthetic light response curve and on PS II heterogeneity as reflected in chlorophyll a fluorescence were investigated using the unicellular green alga Chlamydomonas reinhardtii. It was established that exposure to high light acts at three different regulatory or inhibitory levels; 1) regulation occurs from 300 to 780 μmol m(-2)s(-1) where total amount of PS II centers and the shape of the light response curve is not significantly changed, 2) a first photoinhibitory range above 780 up to 1600 μmol m(-2)s(-1) where a progressive inhibition of the quantum yield and the rate of bending (convexity) of the light response curve can be related to the loss of QB-reducing centers and 3) a second photoinhibitory range above 1600 μmol m(-2)s(-1) where the rate of light saturated photosynthesis also decreases and convexity reaches zero. This was related to a particularly large decrease in PS IIα centers and a large increase in spill-over in energy to PS I.


Reviewing outcomes of psychological interventions with torture survivors: Conceptual, methodological and ethical Issues.
Torture survivors face multiple problems, including psychological difficulties, whether they are refugees or remain in the country where they were tortured. Provision of rehabilitation varies not only with the needs of survivors and resources available, but also with service models, service provider preferences and the local and country context. Despite increasing efforts in research on effectiveness of psychological interventions with torture survivors, results are inconclusive. We undertook a Cochrane systematic review of psychological, social and welfare provision, with meta-analysis to best estimate efficacy. The process raised conceptual, methodological and ethical issues of relevance to the wider field. We searched very widely, but rejected hundreds of papers which recommended treatment without providing evidence. We found nine randomised controlled trials, from developed and under-resourced settings. All conceptualised survivors' problems in psychiatric terms, using outcomes of post-traumatic stress symptoms, distress, and quality of life, by self-report, with or without translation or unstandardised interpretation, and with little mention of cultural or language issues. None used social or welfare interventions. Four related studies used narrative exposure therapy (NET) in a brief form, and without ensuring a safe setting as recommended. Five used mixed methods, including exposure, cognitive behavioural therapy, and eye movement desensitisation. Combined, the studies showed no immediate improvement in PTSD, distress, or quality of life; at six months follow-up, a minority showed some improvement in PTSD and distress, although participants remained severely affected. While applauding researchers' commitment in running these trials, we raise ethical issues about exposure in particular, and about the effects of shortcomings in methodology, particularly around assessment using unfamiliar cultural frameworks and language, and the lack of concern about dropout which may indicate harm. The issues addressed aid interpretation of existing research, and guide clinical practice as well as future studies evaluating its effectiveness.


Aortic relative pressure components derived from four-dimensional flow cardiovascular magnetic resonance.
To describe the assessment of the spatiotemporal distribution of relative aortic pressure quantifying the magnitude of its three major components. Nine healthy volunteers and three patients with aortic disease (bicuspid aortic valve, dissection, and Marfan syndrome) underwent 4D-flow CMR. Spatiotemporal pressure maps were computed from the CMR flow fields solving the pressure Poisson equation. The individual components of pressure were separated into time-varying inertial ("transient"), spatially varying inertial ("convective"), and viscous components. Relative aortic pressure is primarily caused by transient effects followed by the convective and small viscous contributions (64.5, 13.6, and 0.3 mmHg/m, respectively, in healthy subjects), although regional analysis revealed prevalent convective effects in specific contexts, e.g., Sinus of Valsalva and aortic arch at instants of peak velocity. Patients showed differences in peak transient values and duration, and localized abrupt convective changes explained by abnormalities in aortic geometry, including the presence of an aneurysm, a pseudo-coarctation, the inlet of a dissection, or by complex flow patterns. The evaluation of the three components of relative pressure enables the quantification of mechanistic information for understanding and stratifying aortic disease, with potential future implications for guiding therapy.


A CD4(+) T-cell immune response to a conserved epitope in the circumsporozoite protein correlates with protection from natural Plasmodium falciparum infection and disease.
Many human T-cell responses specific for epitopes in Plasmodium falciparum have been described, but none has yet been shown to be predictive of protection against natural malaria infection. Here we report a peptide-specific T-cell assay that is strongly associated with protection of humans in The Gambia, West Africa, from both malaria infection and disease. The assay detects interferon-gamma-secreting CD4(+) T cells specific for a conserved sequence from the circumsporozoite protein, which binds to many human leukocyte antigen (HLA)-DR types. The correlation was observed using a cultured, rather than an ex vivo, ELISPOT assay that measures central memory-'type T cells rather than activated effector T cells. These findings provide direct evidence for a protective role for CD4(+) T cells in humans, and a precise target for the design of improved vaccines against P. falciparum.


β-arrestin1 is an E3 ubiquitin ligase adaptor for substrate linear polyubiquitination.
G protein-coupled receptor (GPCR) signaling and trafficking are regulated by multiple mechanisms, including posttranslational modifications such as ubiquitination by E3 ubiquitin ligases. E3 ligases have been linked to agonist-stimulated ubiquitination of GPCRs via simultaneous binding to βarrestins. In addition, βarrestins have been suggested to assist E3 ligases for ubiquitination of key effector molecules, yet mechanistic insight is lacking. Here, we developed an in vitro reconstituted system and show that βarrestin1 (βarr1) serves as an adaptor between the effector protein signal-transducing adaptor molecule 1 (STAM1) and the E3 ligase atrophin-interacting protein 4. Via mass spectrometry, we identified seven lysine residues within STAM1 that are ubiquitinated and several types of ubiquitin linkages. We provide evidence that βarr1 facilitates the formation of linear polyubiquitin chains at lysine residue 136 on STAM1. This lysine residue is important for stabilizing the βarr1:STAM1 interaction in cells following GPCR activation. Our study identifies atrophin-interacting protein 4 as only the second E3 ligase known to conjugate linear polyubiquitin chains and a possible role for linear ubiquitin chains in GPCR signaling and trafficking.


Vigor of movements and the cost of time in decision making.
If we assume that the purpose of a movement is to acquire a rewarding state, the duration of the movement carries a cost because it delays acquisition of reward. For some people, passage of time carries a greater cost, as evidenced by how long they are willing to wait for a rewarding outcome. These steep discounters are considered impulsive. Is there a relationship between cost of time in decision making and cost of time in control of movements? Our theory predicts that people who are more impulsive should in general move faster than subjects who are less impulsive. To test our idea, we considered elementary voluntary movements: saccades of the eye. We found that in humans, saccadic vigor, assessed using velocity as a function of amplitude, was as much as 50% greater in one subject than another; that is, some people consistently moved their eyes with high vigor. We measured the cost of time in a decision-making task in which the same subjects were given a choice between smaller odds of success immediately and better odds if they waited. We measured how long they were willing to wait to obtain the better odds and how much they increased their wait period after they failed. We found that people that exhibited greater vigor in their movements tended to have a steep temporal discount function, as evidenced by their waiting patterns in the decision-making task. The cost of time may be shared between decision making and motor control.


Study of camelpox virus pathogenesis in athymic nude mice.
Camelpox virus (CMLV) is the closest known orthopoxvirus genetically related to variola virus. So far, CMLV was restricted to camelids but, recently, three human cases of camelpox have been described in India, highlighting the need to pursue research on its pathogenesis, which has been hampered by the lack of small animal models. Here, we confirm that NMRI immunocompetent mice are resistant to intranasal (i.n.) CMLV infection. However, we demonstrate that CMLV induced a severe disease following i.n. challenge of athymic nude mice, which was accompanied with a failure in gaining weight, leading to euthanasia of the animals. On the other hand, intracutaneous (i.c.) infection resulted in disease development without impacting the body weight evolution. CMLV replication in tissues and body fluids was confirmed in the two models. We further analyzed innate immune and B cell responses induced in the spleen and draining lymph nodes after exposure to CMLV. In both models, strong increases in CD11b(+)F4/80(+) macrophages were seen in the spleen, while neutrophils, NK and B cell responses varied between the routes of infection. In the lymph nodes, the magnitude of CD11c(+)CD8α(+) lymphoid and CD11c(+)CD11b(+) myeloid dendritic cell responses increased in i.n. challenged animals. Analysis of cytokine profiles revealed significant increases of interleukin (IL)-6 and IL-18 in the sera of infected animals, while those of other cytokines were similar to uninfected controls. The efficacy of two antivirals (cidofovir or HPMPC, and its 2, 6-diaminopurine analog) was evaluated in both models. HPMPC was the most effective molecule affording 100% protection from morbidity. It appeared that both treatments did not affect immune cell responses or cytokine expression. In conclusion, we demonstrated that immunodeficient mice are permissive for CMLV propagation. These results provide a basis for studying the pathogenesis of CMLV, as well as for evaluating potential antiviral therapies in an immunodeficiency context.


Bioabsorbable radiopaque water-responsive shape memory embolization plug for temporary vascular occlusion.
We describe the preparation, characterization and evaluation of a biodegradable radiopaque water-triggered shape memory embolization plug for temporary vascular occlusion. The shape memory occluding device consists of a composite of a radio-opaque filler and a poly (dl-lactide-co-glycolide) (PLGA) blend, which was coated with a crosslinked poly (ethylene glycol) diacrylate (PEGDA) hydrogel. The mechanical properties, the degradation timeframe, the effect of programming conditions on the shape memory behaviour and the extent of radio-opacity for imaging were evaluated. Based on the tests, the mechanism responsible for the water-induced shape memory effect in such an embolization plug was elucidated. Suitable materials were optimized to fabricate an embolic plug prototype and its in vitro performance was evaluated as an occlusion rate (using a custom-built set up) and its biocompatibility. Finally, a feasibility study was conducted in vivo in a rabbit model to investigate the ease of device deployment, device migration and extent of vessel occlusion. The in vivo results demonstrated that the prototypes were visible under fluoroscopy and complete vascular occlusion occurred within 2 min of deployment of the prototypes in vivo. In conclusion, the developed embolization plug enables controlled and temporary vascular embolization, and is ready for safety studies.


Development and validation of a novel protein extraction methodology for quantitation of protein expression in formalin-fixed paraffin-embedded tissues using western blotting.
The development of efficient formaldehyde cross-link reversal strategies will make the vast diagnostic tissue archives of pathology departments amenable to prospective and retrospective translational research, particularly in biomarker-driven proteomic investigations. Heat-induced antigen retrieval strategies (HIARs) have achieved varying degrees of cross-link reversal, potentially enabling archival tissue usage for proteomic applications outside its current remit of immunohistochemistry (IHC). While most successes achieved so far have been based on retrieving tryptic peptide fragments using shot-gun proteomic approaches, attempts at extracting full-length, non-degraded, immunoreactive proteins from archival tissue have proved challenging. We have developed a novel heat-induced antigen retrieval strategy using SDS-containing Laemmli buffer for efficient intact protein recovery from formalin-fixed tissues for subsequent analysis by western blotting. Protocol optimization and comparison of extraction efficacies with frozen tissues and current leader methodology is presented. Quantitative validation of methodology was carried out in a cohort of matched tumour/normal, frozen/FFPE renal tissue samples from 10 patients, probed by western blotting for a selected panel of seven proteins known to be differentially expressed in renal cancer. Our data show that the protocol enables efficient extraction of non-degraded, full-length, immunoreactive protein, with tumour versus normal differential expression profiles for a majority of the panel of proteins tested being comparable to matched frozen tissue controls (rank correlation, r = 0.7292, p < 1.825e-09). However, the variability observed in extraction efficacies for some membrane proteins emphasizes the need for cautious interpretation of quantitative data from this subset of proteins. The method provides a viable, cost-effective quantitative option for the validation of potential biomarker panels through a range of clinical samples from existing diagnostic archives, provided that validation of the method is first carried out for the specific proteins under study.


Role of secreted frizzled-related protein 3 in human renal cell carcinoma.
The secreted frizzled-related protein (sFRP) family plays an important role in the inhibition of the Wnt signaling pathway in various cancers. The functional significance of Wnt antagonist sFRP3 has not been investigated in renal cancer. We performed tissue microarray and found that the level of sFRP3 protein was high in normal kidney, low in primary renal cancer tissues, and high in metastatic renal cancer tissues. Therefore, we hypothesized that sFRP3 may play an important role in metastatic renal cancer. To test this hypothesis, we performed a series of experiments to determine the role of sFRP3 using primary and metastatic renal cancer cell lines. Functional analysis showed increased numbers of viable and invaded cells and tube formation and decreased numbers of apoptotic cells in the sFRP3-transfected renal cancer cell line A498. Promotion of tumor growth was also observed in nude mice injected with sFRP3-transfected A498 cells. In contrast, the number of viable cells and invasive cells was decreased in sFRP3 mRNA knockdown metastatic cells (ACHN and Hs891.T). To investigate the mechanism of sFRP3 function, we performed microarray analysis to see which genes were upregulated or downregulated by sFRP3 expression. Among these genes, MMP-3 and ANGPT1 were significantly upregulated in sFRP3-transfected cells. In conclusion, this is the first report to show that sFRP3 expression promotes cell growth, invasion, and inhibition of apoptosis in renal cancer cells.


Translating preclinical MRI methods to clinical oncology.
The complexity of modern in vivo magnetic resonance imaging (MRI) methods in oncology has dramatically changed in the last 10 years. The field has long since moved passed its (unparalleled) ability to form images with exquisite soft-tissue contrast and morphology, allowing for the enhanced identification of primary tumors and metastatic disease. Currently, it is not uncommon to acquire images related to blood flow, cellularity, and macromolecular content in the clinical setting. The acquisition of images related to metabolism, hypoxia, pH, and tissue stiffness are also becoming common. All of these techniques have had some component of their invention, development, refinement, validation, and initial applications in the preclinical setting using in vivo animal models of cancer. In this review, we discuss the genesis of quantitative MRI methods that have been successfully translated from preclinical research and developed into clinical applications. These include methods that interrogate perfusion, diffusion, pH, hypoxia, macromolecular content, and tissue mechanical properties for improving detection, staging, and response monitoring of cancer. For each of these techniques, we summarize the 1) underlying biological mechanism(s); 2) preclinical applications; 3) available repeatability and reproducibility data; 4) clinical applications; and 5) limitations of the technique. We conclude with a discussion of lessons learned from translating MRI methods from the preclinical to clinical setting, and a presentation of four fundamental problems in cancer imaging that, if solved, would result in a profound improvement in the lives of oncology patients. Level of Evidence: 5 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;50:1377-1392.


Concurrent infection of Bluetongue and Peste-des-petits-ruminants virus in small ruminants in Haryana State of India.
Bluetongue (BT) and peste-des-petits-ruminants (PPR) are major transboundary diseases of small ruminant, which are endemic in India. Testing of bluetongue virus (BTV) and peste-des-petits-ruminants virus (PPRV) from recent outbreaks (2015-2016) in different regions of Haryana State of India revealed that 27.5% of the samples showed the presence of dual infection of BTV and PPRV. Analysis of Seg-2 of BTV (the serotype-determining protein) showed the presence of BTV-12w in several isolates. However, analysis of N gene fragment amplicons showed that viruses belong to lineage IV were most closely related to a pathogenic strain of PPRV from Delhi. This is the first report of co-circulation of PPRV lineage IV and bluetongue virus serotype 12 in the state.


Restenosis and stent fracture following sirolimus-eluting stent (SES) implantation.
Restenosis still occurs, even with the sirolimus-eluting stent (SES), and the precise mechanisms and the impact of stent fracture on restensosis have not yet been elucidated. Intravascular ultrasound (IVUS)-guided SES implantation was performed in 184 lesions in 151 patients with stable and unstable angina. Serial (pre-, post- and follow-up) quantitative coronary angiography analysis was obtained in 169 lesions in 138 patients (angiographic follow-up rate: 91%) and 12-month clinical follow-up was done in all patients. Restenosis occurred in 13 (7.7%) of 169 lesions. Stent fracture occurred in 4 (2.4%) of 169 lesions at follow-up. Of the 13 restenotic lesions, 8 had intimal hyperplasia, 4 had stent fracture, and 1 had late stent thrombosis at 7 months. Although multivariate logistic regression analysis revealed that minimal lumen area (min-LA) post (p=0.027), total stent length (p=0.003) and diabetes (p=0.032) were significant independent predictors of restenosis, univariate analysis showed that stent fracture was more common in the restenosis than in the non-restenosis groups (p=0.001). Although min-LA post by IVUS, total stent length by QCA and diabetes are independent predictors for angiographic restenosis, stent fracture occurred in 4 lesions (2.4%) and all of them resulted in restenosis (31% of the restenosis). The impact of stent fracture and its potential role in the development of restenosis deserves further study.


Electron kinetic energies from vibrationally promoted surface exoemission: evidence for a vibrational autodetachment mechanism.
We report kinetic energy distributions of exoelectrons produced by collisions of highly vibrationally excited NO molecules with a low work function Cs dosed Au(111) surface. These measurements show that energy dissipation pathways involving nonadiabatic conversion of vibrational energy to electronic energy can result in electronic excitation of more than 3 eV, consistent with the available vibrational energy. We measured the dependence of the electron energy distributions on the translational and vibrational energy of the incident NO and find a clear positive correlation between final electron kinetic energy and initial vibrational excitation and a weak but observable inverse dependence of electron kinetic energy on initial translational energy. These observations are consistent with a vibrational autodetachment mechanism, where an electron is transferred to NO near its outer vibrational turning point and ejected near its inner vibrational turning point. Within the context of this model, we estimate the NO-to-surface distance for electron transfer.


Laparoscopically Assisted Anorectal Pull-Through versus Posterior Sagittal Anorectoplasty for High and Intermediate Anorectal Malformations: A Systematic Review and Meta-Analysis.
Anorectal malformations (ARMs) are one of the commonest anomalies in neonates. Both laparoscopically assisted anorectal pull-through (LAARP) and posterior sagittal anorectoplasty (PSARP) can be used for the treatment of ARMs. The aim of this systematic review and meta-analysis is to compare these two approaches in terms of intraoperative and postoperative outcomes. MEDLINE, Embase, Web of Science and the Cochrane Library were searched from 2000 to August 2016. Both randomized and non-randomized studies, assessing LAARP and PSARP in pediatric patients with high/intermediate ARMs, were included. The primary outcome measures were operative time, length of hospital stay and total postoperative complications. The second outcome measures were rectal prolapse, anal stenosis, wound infection/dehiscence, anorectal manometry, Kelly's clinical score, and Krickenbeck classification. The quality of the randomized and non-randomized studies was assessed using the Cochrane Collaboration's Risk of Bias tool and Newcastle-Ottawa scale (NOS) respectively. The quality of evidence was assessed by GRADEpro. From 332 retrieved articles, 1, 1, and 8 of randomized control, prospective and retrospective studies, respectively, met the inclusion criteria. The randomized clinical trial was judged to be of low risk of bias, and the nine cohort studies were of moderate to high quality. 191 and 169 pediatric participants had undergone LAARP and PSARP, respectively. Shorter hospital stays, less wound infection/dehiscence, higher anal canal resting pressure, and a lower incidence of grade 2 or 3 constipation were obtained after LAARP compared with PSARP group values. Besides, the LAARP group had marginally less total postoperative complications. However, the result of operative time was inconclusive; meanwhile, there was no significant difference in rectal prolapse, anal stenosis, anorectal manometry, Kelly's clinical score and Krickenbeck classification. For pediatric patients with high/intermediate anorectal malformations, LAARP is a better option compared with PSARP. However, the quality of evidence was very low to moderate.


Healthy Life-Years Lost and Excess Bed-Days Due to 6 Patient Safety Incidents: Empirical Evidence From English Hospitals.
There is little satisfactory evidence on the harm of safety incidents to patients, in terms of lost potential health and life-years. To estimate the healthy life-years (HLYs) lost due to 6 incidents in English hospitals between the years 2005/2006 and 2009/2010, to compare burden across incidents, and estimate excess bed-days. The study used cross-sectional analysis of the medical records of all inpatients treated in 273 English hospitals. Patients with 6 types of preventable incidents were identified. Total attributable loss of HLYs was estimated through propensity score matching by considering the hypothetical remaining length and quality of life had the incident not occurred. The 6 incidents resulted in an annual loss of 68 HLYs and 934 excess bed-days per 100,000 population. Preventable pressure ulcers caused the loss of 26 HLYs and 555 excess bed-days annually. Deaths in low-mortality procedures resulted in 25 lost life-years and 42 bed-days. Deep-vein thrombosis/pulmonary embolisms cost 12 HLYs, and 240 bed-days. Postoperative sepsis, hip fractures, and central-line infections cost <6 HLYs and 100 bed-days each. The burden caused by the 6 incidents is roughly comparable with the UK burden of Multiple Sclerosis (80 DALYs per 100,000), HIV/AIDS and Tuberculosis (63 DALYs), and Cervical Cancer (58 DALYs). There were marked differences in the harm caused by the incidents, despite the public attention all of them receive. Decision makers can use the results to prioritize resources into further research and effective interventions.


Electronic Health Records in the Cloud: Improving Primary Health Care Delivery in South Africa.
In South Africa, the recording of health data is done manually in a paper-based file, while attempts to digitize healthcare records have had limited success. In many countries, Electronic Health Records (EHRs) has developed in silos, with little or no integration between different operational systems. Literature has provided evidence that the cloud can be used to 'leapfrog' some of these implementation issues, but the adoption of this technology in the public health care sector has been very limited. This paper aims to identify the major reasons why the cloud has not been used to implement EHRs for the South African public health care system, and to provide recommendations of how to overcome these challenges. From the literature, it is clear that there are technology, environmental and organisational challenges affecting the implementation of EHRs in the cloud. Four recommendations are provided that can be used by the National Department of Health to implement EHRs making use of the cloud.


Hormone receptor loss in endometrial carcinoma curettage predicts lymph node metastasis and poor outcome in prospective multicentre trial.
Preoperative histologic examination of tumour tissue is essential when deciding if endometrial cancer surgery should include lymph node sampling. We wanted to investigate if biomarkers could improve prediction of lymph node metastasis and outcome. Curettage specimens from 832 endometrial carcinoma patients prospectively recruited from 10 centres in the MoMaTEC trial (Molecular Markers in Treatment of Endometrial Cancer) were investigated for hormone receptor and p53 status. Eighteen per cent of tumours were double negative for oestrogen- and progesterone receptors (ER/PR loss), 24% overexpressed p53. Pathologic expression of all markers correlated with nodal metastases, high FIGO (Federation International of Gynecology and Obstetrics) stage, non-endometrioid histology, high grade and poor prognosis (all P<0.001). ER/PR loss independently predicted lymph node metastasis (odds ratios (OR) 2.0, 95% confidence interval (CI) 1.1-3.7) adjusted for preoperative curettage histology and predicted poor disease-specific survival adjusted for age, FIGO stage, histologic type, grade and myometrial infiltration (hazard ratio (HR) 2.3, 95% CI 1.4-3.9). For lymph node negative endometrioid tumours, ER/PR loss influenced survival independent of grade. Double negative hormone receptor status in endometrial cancer curettage independently predicts lymph node metastasis and poor prognosis in a prospective multicentre setting. Implementing hormone receptor status to improve risk-stratification for selecting patients unlikely to benefit from lymphadenectomy seems justified.


Results of a randomized trial comparing high-dose chemotherapy plus Auto-SCT and R-FC in CLL at diagnosis.
The importance of early therapy intensification in B-cell CLL (B-CLL) patients remains to be defined. Even though several studies have been published, no randomized trials comparing directly autologous stem cell transplant (ASCT) and the accepted conventional therapy (that is, rituximab, fludarabine and CY; R-FC) have been reported so far. To assess the benefit of a first-line aggressive therapy, we designed a multicenter, randomized, phase 3 trial comparing R-FC and high-dose chemotherapy supported by ASCT in patients under 65 years of age, with stage B(II) or C B-CLL. Primary end point was CR: 96 patients were enrolled (48 in each arm). On an intent-to-treat basis, the CR rates in the ASCT and R-FC arms were 62.5% and 58%, respectively. After 5 years of follow-up, PFS was 60.4% in the ASCT arm and 65.1% in the R-FC arm, time to progression 65.8 and 70.5%, and overall survival 88% vs 88.1%, respectively. Our trial demonstrates, for the first time in a randomized manner, that frontline ASCT does not translate into a survival advantage when compared with benchmark chemoimmunotherapy in B-CLL patients; the possibility of its clinical benefit in certain subgroups remains uncertain.


Patterns of Staphylococcus aureus colonization, toxin production, immunity and illness in burned children.
Toxic shock syndrome toxin-one (TSST-1) produced from some but not all strains of Staphylococcus aureus is considered to be responsible for the development of the serious illness, toxic shock syndrome (TSS). The aim of this study was to establish the importance of S. aureus in the aetiology of suspected cases of TSS in acutely burned children. The pattern of colonization of S. aureus, and in particular toxic shock syndrome toxin-one (TSST-1) producing isolates, was studied in 53 burned children admitted as consecutive cases. S. aureus was not normally present on admission. Although it was the most common wound pathogen, it was acquired during the first few days after admission. Antibody status to TSST-1 on admission and at discharge was determined. Only half (49 per cent) of the children had antibodies to TSST-1. When it was possible to obtain paired admission and discharge samples in patients who had been given blood products, an assessment of seroconversion could be made. Two of the four patients given blood products during the resuscitation and postoperative period were antibody negative on admission (the other two were TSST-1 antibody positive). By discharge they had antibodies to TSST-1. Whilst the majority of donated blood products had antibodies to TSST-1 (76 per cent), some (24 per cent) did not. Seven of 53 children (13 per cent) developed a toxic shock-like illness which caused clinical concern.(ABSTRACT TRUNCATED AT 250 WORDS)


Hippocampal volume deficits in alcoholic Korsakoff's syndrome.
To examine whether the amnesic syndrome of alcoholic Korsakoff's syndrome (KS) originates from pathology of the hippocampus and not solely the diencephalon. The authors studied 5 patients with KS and two comparison groups: 20 patients with Alzheimer's disease (AD) with known bilateral hippocampal volume loss and 36 healthy control subjects. The authors used quantitative MRI to characterize the hippocampus and comparison brain structures (temporal cortex, lateral ventricles, temporal horns, and third ventricle). Relative to healthy control subjects, the KS and AD groups had comparable, significant bilateral hippocampal volume deficits. Although both patient groups also had extensive volume abnormalities in temporal lobe cortical gray matter, temporal horns, and lateral and third ventricles, declarative memory test performance was selectively related to hippocampal volumes in KS and not to any of the comparison volumes. The characteristic memory deficit of Korsakoff's syndrome involves hippocampal and diencephalic pathology.


Association of delay of urgent or emergency surgery with mortality and use of health care resources: a propensity score-matched observational cohort study.
Delay of surgery for hip fracture is associated with increased risk of morbidity and mortality, but the effects of surgical delays on mortality and resource use in the context of other emergency surgeries is poorly described. Our objective was to measure the independent association between delay of emergency surgery and in-hospital mortality, length of stay and costs. We identified all adult patients who underwent emergency noncardiac surgery between January 2012 and October 2014 at a single tertiary care centre. Delay of surgery was defined as the time from surgical booking to operating room entry exceeding institutionally defined acceptable wait times, based on a standardized 5-level priority system that accounted for surgery type and indication. Patients with delayed surgery were matched to those without delay using propensity scores derived from variables that accounted for details of admission and the hospital stay, patient characteristics, physiologic instability, and surgical urgency and risk. Of 15 160 patients, 2820 (18.6%) experienced a delay. The mortality rates were 4.9% (138/2820) for those with delay and 3.2% (391/12 340) for those without delay (odds ratio [OR] 1.59, 95% confidence interval [CI] 1.30-1.93). Within the propensity-matched cohort, delay was significantly associated with mortality (OR 1.56, 95% CI 1.18-2.06), increased length of stay (incident rate ratio 1.07, 95% CI 1.01-1.11) and higher total costs (incident rate ratio 1.06, 95% CI 1.01-1.11). Delayed operating room access for emergency surgery was associated with increased risk of inhospital mortality, longer length of stay and higher costs. System issues appeared to underlie most delays and must be addressed to improve the outcomes of emergency surgery.


Relationship of somatosensory evoked potentials and cerebral oxygen consumption during hypoxic hypoxia in dogs.
The effects of hypoxic hypoxia on cerebral hemodynamics and somatosensory evoked potential (SEP) were studied in 10 pentobarbital anestheteized dogs. Cerebral blood flow (CBF) was measured using the venous outflow technique and cerebral oxygen consumption (CMRO2) was calculated from the arterio-cerebro-venous oxygen difference times CBF. SEP was evaluated by percutaneous stimulation of an upper extremity nerve and was recorded over the contralateral somatosensory cortex. The latencies of the initial negative wave (N1), second positive wave (P2) and the amplitude of the primary complex (P1N1) were measured. Animals were breathed sequentially with oxygen concentrations of 21, 10, 6, 5, and 4.5% for five minutes each. Animals were returned to room air breathing when the amplitude of the SEP decreased to less than 20% of control and were observed for 30 minutes following reoxygenation. Severe hypoxia (4.5% O2) increased CBF to 200% of control, decreased CMRO2 to 45% of control, decreased amplitude and increased latency of SEP. Following reoxygenation, as CMRO2 increased toward control, latency of SEP decreased and amplitude increased and CBF returned to baseline within 30 min. During hypoxia and reoxygenation, the latencies of N1 and P2 and the amplitude of P1N1 were correlated with CMRO2 in individual animals. We conclude that changes in SEP amplitude and latency reflect changes in CMRO2 despite high CBF during rapidly progressive hypoxic hypoxia and following reoxygenation.


EARNINGS MANAGEMENT IN U.S. HOSPITALS.
This paper examines the hospital management practices of manipulating financial earnings within the bounds of generally accepted accounting principles (GAAP). We conduct regression analyses that relate earnings management to hospital characteristics to assess the economic determinants of hospital earnings management behavior. From the CMS Cost Reports we collected hospital financial data of all U.S. hospitals that request reimbursement from the federal government for treating Medicare patients, and regress discretionary accruals on hospital size, profitability, asset liquidity, operating efficiency, labor cost, and ownership. Hospitals with higher profit margin, current ratio, working capital, days of patient receivables outstanding and total wage are associated with more earnings management, whereas those with larger size and higher debt level, asset turnover, days cash on hand, fixed asset age are associated with lower level of earnings manipulation. Additionally, managers of non-profit hospitals are more likely to undertake some form of window-dressing by manipulating accounting accruals without changing business models or pricing strategies than their public hospital counterparts. We provide direct evidence of the use of discretionary accruals to manage financial earnings among U.S. hospitals and the finding has profound policy implications in terms of assessing the pervasiveness of accounting manipulation and the overall integrity of financial reporting in this very special public and quasi-public service sector.


Psoriasis today: experiences of healthcare and impact on quality of life in a major UK cohort.
To establish how people with psoriasis in the United Kingdom today experience living with their condition including diagnosis, treatment, healthcare provision and impact on daily life. Psoriasis is a debilitating long-term inflammatory skin disease which can result in severe itching, discomfort and soreness, and may be associated with problems beyond the specific symptoms related to the skin. For many it is accompanied by difficult-to-manage treatment regimes, emotional distress and a negative impact on their quality of life and psychosocial functioning. To date there is little published information about the health experiences of people in the United Kingdom with psoriasis. A postal self-administered questionnaire was completed by members of the Psoriasis Association and the responses analysed (n = 1564). The findings suggest some similarities to surveys in other nations, but specifically highlighted that patients feel under-informed and are dissatisfied with current treatment regimes. Responses provided an insight into aspects of the condition that treatments should be targeting. Specific areas of negative impact on psychosocial functioning were identified, including the lack of available support for those experiencing emotional distress. The research provides important information about how the care of patients with psoriasis can be improved, especially at primary care level. This includes: improved training in psoriasis knowledge and awareness at general practitioner level and greater use of dermatology specialist nurses in primary care settings; more effective and manageable treatment regimes that target visible areas and general well-being; greater support for emotional distress and psychosocial functioning.


School-based health services.
Children, particularly adolescents, have unique health care needs and experience frequent barriers to receiving needed medical care. The expansion of school-based health services since the early 1970s is one recent development in the area of health services delivery that is a specific response to facilitate meeting the medical needs of youth. Limited resources, shrinking budgets, demographic and behavioral changes among our nation's youth, and recent trends toward managed care all demand innovative strategies by school-based health services if they are to ensure their viability in providing adequate health care to children and adolescents. This article reviews the recently published literature regarding the role of school-based health centers as sites providing primary care services to children and adolescents. In addition, it addresses recent efforts to develop strategies that school-based health centers may need to consider in order to adapt and survive within the environment of health care reform and managed care.


Impact of three biological decontamination methods on filtering facepiece respirator fit, odor, comfort, and donning ease.
The objective of this study was to determine if ultraviolet germicidal irradiation (UVGI), moist heat incubation (MHI), or microwave-generated steam (MGS) decontamination affects the fitting characteristics, odor, comfort, or donning ease of six N95 filtering facepiece respirator (FFR) models. For each model, 10 experienced test subjects qualified for the study by passing a standard OSHA quantitative fit test. Once qualified, each subject performed a series of fit tests to assess respirator fit and completed surveys to evaluate odor, comfort, and donning ease with FFRs that were not decontaminated (controls) and with FFRs of the same model that had been decontaminated. Respirator fit was quantitatively measured using a multidonning protocol with the TSI PORTACOUNT Plus and the N95 Companion accessory (designed to count only particles resulting from face to face-seal leakage). Participants' subjective appraisals of the respirator's odor, comfort, and donning ease were captured using a visual analog scale survey. Wilcoxon signed rank tests compared median values for fit, odor, comfort, and donning ease for each FFR and decontamination method against their respective controls for a given model. Two of the six FFRs demonstrated a statistically significant reduction (p < 0.05) in fit after MHI decontamination. However, for these two FFR models, post-decontamination mean fit factors were still ≥ 100. One of the other FFRs demonstrated a relatively small though statistically significant increase (p < 0.05) in median odor response after MHI decontamination. These data suggest that FFR users with characteristics similar to those in this study population would be unlikely to experience a clinically meaningful reduction in fit, increase in odor, increase in discomfort, or increased difficulty in donning with the six FFRs included in this study after UVGI, MHI, or MGS decontamination. Further research is needed before decontamination of N95 FFRs for purposes of reuse can be recommended.


Socioeconomic status impacts cognitive and socioemotional processes in healthy ageing.
Socioeconomic status (SES) negatively impacts cognitive and executive functioning in older adults, yet its effects on socioemotional abilities have not been studied in this population. Also, evidence on neurocognitive processes associated with ageing primarily comes from Western, educated, industrialized, rich, and democratic (WEIRD) populations, hindering the generalization of findings to persons from upper-middle- and low-middle-income countries, such as those of Latin America. Here, we compared the performance of low- and high-SES older adults from Argentina in cognitive state, executive functions, social cognition (emotion recognition and theory of mind), and counter-empathic social emotions (envy and Schadenfreude; displeasure at others' fortune and pleasure at others' misfortune, respectively). Subsequently, we developed a path analysis to test the relationship among those variables in a theoretically plausible model and tested the main paths via multiple regression analyses. Relative to the high-SES group, low-SES older adults showed poorer performance on all assessed domains. Convergent evidence from covariance analysis, path analysis, and linear regressions suggested that low-SES impact on socioemotional processes was not primary but mediated by cognitive and executive impairment. These findings offer the first characterization of SES impacts on cognitive and socioemotional processes in a non-WEIRD population and have relevant equity-related implications for brain health.


Non-parametric estimation of posterior error probabilities associated with peptides identified by tandem mass spectrometry.
A mass spectrum produced via tandem mass spectrometry can be tentatively matched to a peptide sequence via database search. Here, we address the problem of assigning a posterior error probability (PEP) to a given peptide-spectrum match (PSM). This problem is considerably more dif.cult than the related problem of estimating the error rate associated with a large collection of PSMs. Existing methods for estimating PEPs rely on a parametric or semiparametric model of the underlying score distribution. We demonstrate how to apply non-parametric logistic regression to this problem. The method makes no explicit assumptions about the form of the underlying score distribution; instead, the method relies upon decoy PSMs, produced by searching the spectra against a decoy sequence database, to provide a model of the null score distribution. We show that our non-parametric logistic regression method produces accurate PEP estimates for six different commonly used PSM score functions. In particular, the estimates produced by our method are comparable in accuracy to those of PeptideProphet, which uses a parametric or semiparametric model designed speci.cally to work with SEQUEST. The advantage of the non-parametric approach is applicability and robustness to new score functions and new types of data. C++ code implementing the method as well as supplementary information is available at http://noble.gs. washington.edu/proj/qvality


Black Scab of Jojoba (Simmondsia chinensis) in Australia Caused by a Putative New Pathotype of Elsinoë australis.
A new disease of jojoba in Australia is described. We have demonstrated that this disease is caused by Elsinoë australis, a pathogen which is normally associated with citrus. This pathogen has not been found previously in Australia on citrus or any other crop. The fungus causes a scab on leaves and stems of jojoba and is widely distributed in eastern Australia. Although molecular analysis of the pathogen indicates that it is closely related to the natsudaidai and the sweet orange pathotypes of E. australis, glasshouse and laboratory experiments demonstrate that it is not pathogenic to a range of citrus cultivars grown in Australia. The data indicate that the isolates from jojoba represent a new pathotype of E. australis.


Coexistence of occult vascular malformations and developmental venous anomalies in the central nervous system: MR evaluation.
We sought to determine the prevalence of coexistent occult vascular malformations (OVMs) and developmental venous anomalies (DVAs) and to investigate the relationship between them. One hundred two patients with OVMs were examined with precontrast and postcontrast T1-weighted MR imaging and with noncontrast T2-weighted MR imaging. Seventy-two patients had surgery, with subsequent pathologic confirmation of the final diagnosis. Coexistent DVAs and OVMs were present in 23 (23%) of 102 patients. Seventy-nine patients had OVMs without DVAs, and in this population, multiple OVMs (from two to 10 or more) were seen in 13 patients (16%). In contrast, multiple OVMs were seen in 10 (43%) of 23 patients with coexisting OVMs and DVAs. Twenty-five (83%) of 30 OVMs coexisting with DVAs were infratentorial. In 72 patients with surgically resected OVMs, 49 (68%) had pathologically confirmed cavernous malformations. Among the patients with coexistent DVAs, seven (46%) had cavernous malformations, four (27%) had thrombosed arteriovenous malformations, and four (27%) had vascular malformations that were not classifiable. Our study revealed a high prevalence of OVMs with coexistent DVAs, and a high percentage of these were in the posterior fossa. Contrast-enhanced MR imaging may increase the probability of finding these lesions, and therefore should be considered part of the preoperative evaluation, since the finding of unexpected coexistent lesions may affect surgical management.


Systemic safety of bevacizumab versus ranibizumab for neovascular age-related macular degeneration.
Neovascular age-related macular degeneration (AMD) is the leading cause of legal blindness in elderly populations of industrialised countries. Bevacizumab (Avastin®) and ranibizumab (Lucentis®) are targeted biological drugs (a monoclonal antibody) that inhibit vascular endothelial growth factor, an angiogenic cytokine that promotes vascular leakage and growth, thereby preventing its pathological angiogenesis. Ranibizumab is approved for intravitreal use to treat neovascular AMD, while bevacizumab is approved for intravenous use as a cancer therapy. However, due to the biological similarity of the two drugs, bevacizumab is widely used off-label to treat neovascular AMD. To assess the systemic safety of intravitreal bevacizumab (brand name Avastin®; Genentech/Roche) compared with intravitreal ranibizumab (brand name Lucentis®; Novartis/Genentech) in people with neovascular AMD. Primary outcomes were death and All serious systemic adverse events (All SSAEs), the latter as a composite outcome in accordance with the International Conference on Harmonisation Good Clinical Practice. Secondary outcomes examined specific SSAEs: fatal and non-fatal myocardial infarctions, strokes, arteriothrombotic events, serious infections, and events grouped in some Medical Dictionary for Regulatory Activities System Organ Classes (MedDRA SOC). We assessed the safety at the longest available follow-up to a maximum of two years. We searched CENTRAL, MEDLINE, EMBASE and other online databases up to 27 March 2014. We also searched abstracts and clinical study presentations at meetings, trial registries, and contacted authors of included studies when we had questions. Randomised controlled trials (RCTs) directly comparing intravitreal bevacizumab (1.25 mg) and ranibizumab (0.5 mg) in people with neovascular AMD, regardless of publication status, drug dose, treatment regimen, or follow-up length, and whether the SSAEs of interest were reported in the trial report. Two authors independently selected studies and assessed the risk of bias for each study. Three authors independently extracted data.We conducted random-effects meta-analyses for the primary and secondary outcomes. We planned a pre-specified analysis to explore deaths and All SSAEs at the one-year follow-up. We included data from nine studies (3665 participants), including six published (2745 participants) and three unpublished (920 participants) RCTs, none supported by industry. Three studies excluded participants at high cardiovascular risk, increasing clinical heterogeneity among studies. The studies were well designed, and we did not downgrade the quality of the evidence for any of the outcomes due to risk of bias. Although the estimated effects of bevacizumab and ranibizumab on our outcomes were similar, we downgraded the quality of the evidence due to imprecision.At the maximum follow-up (one or two years), the estimated risk ratio (RR) of death with bevacizumab compared with ranibizumab was 1.10 (95% confidence interval (CI) 0.78 to 1.57, P value = 0.59; eight studies, 3338 participants; moderate quality evidence). Based on the event rates in the studies, this gives a risk of death with ranibizumab of 3.4% and with bevacizumab of 3.7% (95% CI 2.7% to 5.3%).For All SSAEs, the estimated RR was 1.08 (95% CI 0.90 to 1.31, P value = 0.41; nine studies, 3665 participants; low quality evidence). Based on the event rates in the studies, this gives a risk of SSAEs of 22.2% with ranibizumab and with bevacizumab of 24% (95% CI 20% to 29.1%).For the secondary outcomes, we could not detect any difference between bevacizumab and ranibizumab, with the exception of gastrointestinal disorders MedDRA SOC where there was a higher risk with bevacizumab (RR 1.82; 95% CI 1.04 to 3.19, P value = 0.04; six studies, 3190 participants).Pre-specified analyses of deaths and All SSAEs at one-year follow-up did not substantially alter the findings of our review.Fixed-effect analysis for deaths did not substantially alter the findings of our review, but fixed-effect analysis of All SSAEs showed an increased risk for bevacizumab (RR 1.12; 95% CI 1.00 to 1.26, P value = 0.04; nine studies, 3665 participants): the meta-analysis was dominated by a single study (weight = 46.9%).The available evidence was sensitive to the exclusion of CATT or unpublished results. For All SSAEs, the exclusion of CATT moved the overall estimate towards no difference (RR 1.01; 95% CI 0.82 to 1.25, P value = 0.92), while the exclusion of LUCAS yielded a larger RR, with more SSAEs in the bevacizumab group, largely driven by CATT (RR 1.19; 95% CI 1.06 to 1.34, P value = 0.004). The exclusion of all unpublished studies produced a RR of 1.12 for death (95% CI 0.78 to 1.62, P value = 0.53) and a RR of 1.21 for SSAEs (95% CI 1.06 to 1.37, P value = 0.004), indicating a higher risk of SSAEs in those assigned to bevacizumab than ranibizumab. This systematic review of non-industry sponsored RCTs could not determine a difference between intravitreal bevacizumab and ranibizumab for deaths, All SSAEs, or specific subsets of SSAEs in the first two years of treatment, with the exception of gastrointestinal disorders. The current evidence is imprecise and might vary across levels of patient risks, but overall suggests that if a difference exists, it is likely to be small. Health policies for the utilisation of ranibizumab instead of bevacizumab as a routine intervention for neovascular AMD for reasons of systemic safety are not sustained by evidence. The main results and quality of evidence should be verified once all trials are fully published.


Correlation of serum interleukin-31 with pruritus and blood eosinophil markers in children with atopic dermatitis.
Background: Atopic dermatitis (AD) is chronic pruritic inflammatory skin disease in children. Interleukin (IL) 31 is a recently discovered cytokine associated with chronic skin inflammation and pruritus. Objectives: The aims of this study were to determine whether serum IL-31 levels are increased in children with AD and to examine the relationship between IL-31 and other clinical biomarkers in AD. Methods: Serum cytokine levels, including IL-31, IL-4, and IL-12, were measured in 38 patients with AD and 10 healthy children. Peripheral blood eosinophils, serum immunoglobulin E levels, eosinophil cationic protein, and thymic stromal lymphopoietin (TSLP) were measured. We also estimated the clinical severity of AD by using the Scoring Atopic Dermatitis (SCORAD) index by a single clinician. Results: The serum IL-31 levels were significantly higher in the patients with AD than in the healthy children. IL-31 correlated well with the SCORAD index and blood eosinophilic inflammatory markers. The serum level of TSLP was also higher in patients with AD than in the healthy children; however, levels of IL-4 and IL-12 were not different between AD and healthy children. There was no significant difference in serum IL-31 levels between patients with atopic AD and nonatopic AD. Conclusion: This study showed that serum IL-31 levels were significantly elevated in patients with AD than in the healthy children and correlated well with disease severity. IL-31 seemed to be one of the cytokines that induce pruritus and eosinophilic inflammation in AD. Serum IL-31 correlated with pruritic symptoms and disease course of AD.


Neurophysiology of timing in the hundreds of milliseconds: multiple layers of neuronal clocks in the medial premotor areas.
The precise quantification of time in the subsecond scale is critical for many complex behaviors including music and dance appreciation/execution, speech comprehension/articulation, and the performance of many sports. Nevertheless, its neural underpinnings are largely unknown. Recent neurophysiological experiments from our laboratory have shown that the cell activity in the medial premotor areas (MPC) of macaques can represent different aspects of temporal processing during a synchronization-continuation tapping task (SCT). In this task the rhythmic behavior of monkeys was synchronized to a metronome of isochronous stimuli in the hundreds of milliseconds range (synchronization phase), followed by a period where animals internally temporalized their movements (continuation phase). Overall, we found that the time-keeping mechanism in MPC is governed by different layers of neural clocks. Close to the temporal control of movements are two separate populations of ramping cells that code for elapsed or remaining time for a tapping movement during the SCT. Thus, the sensorimotor loops engaged during the task may depend on the cyclic interplay between two neuronal chronometers that quantify in their instantaneous discharge rate the time passed and the remaining time for an action. In addition, we found MPC neurons that are tuned to the duration of produced intervals during the rhythmic task, showing an orderly variation in the average discharge rate as a function of duration. All the tested durations in the subsecond scale were represented in the preferred intervals of the cell population. Most of the interval-tuned cells were also tuned to the ordinal structure of the six intervals produced sequentially in the SCT. Hence, this next level of temporal processing may work as the notes of a musical score, providing information to the timing network about what duration and ordinal element of the sequence are being executed. Finally, we describe how the timing circuit can use a dynamic neural representation of the passage of time and the context in which the intervals are executed by integrating the time-varying activity of populations of cells. These neural population clocks can be defined as distinct trajectories in the multidimensional cell response-space. We provide a hypothesis of how these different levels of neural clocks can interact to constitute a coherent timing machine that controls the rhythmic behavior during the SCT.


Efficacy and Safety of a Modified Vaccinia Ankara-NP+M1 Vaccine Combined with QIV in People Aged 65 and Older: A Randomised Controlled Clinical Trial (INVICTUS).
Pre-existing T cell responses to influenza have been correlated with improved clinical outcomes in natural history and human challenge studies. We aimed to determine the efficacy, safety and immunogenicity of a T-cell directed vaccine in older people. This was a multicentre, participant- and safety assessor-blinded, randomised, placebo-controlled trial of the co-administration of Modified Vaccinia Ankara encoding nucleoprotein and matrix protein 1 (MVA-NP+M1) and annual influenza vaccine in participants ≥ 65. The primary outcome was the number of days with moderate or severe influenza-like symptoms (ILS) during the influenza season. 846 of a planned 2030 participants were recruited in the UK prior to, and throughout, the 2017/18 flu season. There was no evidence of a difference in the reported rates of days of moderate or severe ILS during influenza-like illness episodes (unadjusted OR = 0.95, 95% CI: 0.54-1.69; adjusted OR = 0.91, 95% CI: 0.51-1.65). The trial was stopped after one season due to a change in the recommended annual flu vaccine, for which safety of the new combination had not been established. More participants in the MVA-NP+M1 group had transient moderate or severe pain, redness, and systemic responses in the first seven days. The MVA-NP+M1 vaccine is well tolerated in those aged 65 years and over. Larger trials would be needed to determine potential efficacy.


The effect of dietary protein on reproduction in the mare. VII. Embryonic development, early embryonic death, foetal losses and their relationship with serum progestagen.
Sixty-four Thoroughbred and Anglo-Arab mares aged 6-12 years were randomly allocated to 4 dietary groups and fed diets that differed in the total protein content and quality (essential amino-acids). Forty mares were non-lactating and 24 lactating. Eight mares were withdrawn from the investigation owing to injuries or gynaecological pathology. An overall conception rate of 94.6% and a foaling rate of 80% was achieved. Five of 14 (35.7%) mares (Group 1) fed a low-quality protein diet suffered from early embryonic loss before 90 days of pregnancy compared to 3 of 41 (7.3%) mares in the remaining groups that received the higher-quality protein in their diets. Serum progestagen concentrations of mares in Group 1 that suffered foetal loss were indicative of luteal function insufficiency during the 1st 40 days post-ovulation. Non-lactating mares in all 4 groups gained on average approximately 30 kg in mass during the 90 days before the breeding period. Lactating mares in Group 1 (low-quality protein) lost on average 25 kg in mass during lactation, with no weight loss observed among the lactating mares in the other 3 groups. No difference in the diameter of the embryonic vesicle was found between dietary groups until Day 35 of pregnancy.


Optical spectral surveillance of breast tissue landscapes for detection of residual disease in breast tumor margins.
We demonstrate a strategy to "sense" the micro-morphology of a breast tumor margin over a wide field of view by creating quantitative hyperspectral maps of the tissue optical properties (absorption and scattering), where each voxel can be deconstructed to provide information on the underlying histology. Information about the underlying tissue histology is encoded in the quantitative spectral information (in the visible wavelength range), and residual carcinoma is detected as a shift in the histological landscape to one with less fat and higher glandular content. To demonstrate this strategy, fully intact, fresh lumpectomy specimens (n = 88) from 70 patients were imaged intra-operatively. The ability of spectral imaging to sense changes in histology over large imaging areas was determined using inter-patient mammographic breast density (MBD) variation in cancer-free tissues as a model system. We discovered that increased MBD was associated with higher baseline β-carotene concentrations (p = 0.066) and higher scattering coefficients (p = 0.007) as measured by spectral imaging, and a trend toward decreased adipocyte size and increased adipocyte density as measured by histological examination in BMI-matched patients. The ability of spectral imaging to detect cancer intra-operatively was demonstrated when MBD-specific breast characteristics were considered. Specifically, the ratio of β-carotene concentration to the light scattering coefficient can report on the relative amount of fat to glandular density at the tissue surface to determine positive margin status, when baseline differences in these parameters between patients with low and high MBD are taken into account by the appropriate selection of threshold values. When MBD was included as a variable a priori, the device was estimated to have a sensitivity of 74% and a specificity of 86% in detecting close or positive margins, regardless of tumor type. Superior performance was demonstrated in high MBD tissue, a population that typically has a higher percentage of involved margins.


Systematic distortions of perceived planar surface motion in active vision.
Recent studies suggest that the active observer combines optic flow information with extra-retinal signals resulting from head motion. Such a combination allows, in principle, a correct discrimination of the presence or absence of surface rotation. In Experiments 1 and 2, observers were asked to perform such discrimination task while performing a lateral head shift. In Experiment 3, observers were shown the optic flow generated by their own movement with respect to a stationary planar slanted surface and were asked to classify perceived surface rotation as being small or large. We found that the perception of surface motion was systematically biased. We found that, in active, as well as in passive vision, perceived surface rotation was affected by the deformation component of the first-order optic flow, regardless of the actual surface rotation. We also found that the addition of a null disparity field increased the likelihood of perceiving surface rotation in active, but not in passive vision. Both these results suggest that vestibular information, provided by active vision, is not sufficient for veridical 3D shape and motion recovery from the optic flow.


The impact of conjugate vaccine on carriage of Haemophilus influenzae type b.
Conjugate vaccines against Haemophilus influenzae type b (Hib) may modify Hib pharyngeal colonization. Hib colonization was compared in 371 infants and their families. In Oxfordshire, infants received PRP-T (polyribosylribitol phosphate conjugated to tetanus toxoid) and in Buckinghamshire they did not (controls). Infants were followed at 6, 9, and 12 months of age. Also, 6 unvaccinated Hib carriers were vaccinated and followed for 6 weeks. Hib acquisition was lower in vaccinees than controls (P < .01). During surveillance, 1.5% of vaccinees and 6.3% of controls carried Hib (P = .04). Among those with family Hib exposure, the carriage rates were 8.7% and 38.5% (P = .07), respectively. Hiv carriage rates were lower among vaccinees' unvaccinated siblings. Giving conjugate vaccine to a child carrying Hib did not rapidly terminate carriage. Thus, a primary means by which herd immunity to Hib is induced in a vaccinated population may be through reduction or delay in the initial acquisition of Hib.


Effects of D- and L-isomers of timolol on retinal and choroidal blood flow in ocular hypertensive rabbit eyes.
An ocular hypertensive rabbit eye model was used to study the effect of L- and D-timolol on retinal and choroidal blood flow. Ocular hypertension was induced artificially by raising the intraocular pressure to 40 mmHg which reduced the ocular blood flow to 1/3 that of the normal blood flow. The effects of L- and D-isomers of timolol on the ocular blood flow of ocular hypertensive eyes were then determined using the colored microspheres technique over a range of 0-180 min after eyedrop instillation. It was found that L-timolol produced biphasic action on the blood flow in the iris, ciliary body and choroid by significantly reducing it initially at 30 min, then markedly increasing it later at 90 min and thereafter. Although L-timolol produced a tendency to reduce the blood flow in the retina, it was not statistically significant. At 90 min and thereafter, the blood flow in all ocular tissues was markedly increased by L-timolol. D-timolol did not reduce the blood flow of ocular tissues initially. There was a tendency to increase the blood flow in all ocular tissues from the very beginning by D-timolol. The increase of blood flow became significant at 90 min and thereafter, up to 3 hrs. D-timolol was less potent than L-timolol in increasing the blood flow in ocular tissues.


A Cross-Cultural Exploratory Study of Health Behaviors and Wellbeing During COVID-19.
This study explored the influence of the COVID-19 pandemic on perceived health behaviors; physical activity, sleep, and diet behaviors, alongside associations with wellbeing. Participants were 1,140 individuals residing in the United Kingdom (n = 230), South Korea (n = 204), Finland (n = 171), Philippines (n = 132), Latin America (n = 124), Spain (n = 112), North America (n = 87), and Italy (n = 80). They completed an online survey reporting possible changes in the targeted behaviors as well as perceived changes in their physical and mental health. Multivariate analyses of covariance (MANCOVA) on the final sample (n = 1,131) revealed significant mean differences regarding perceived physical and mental health "over the last week," as well as changes in health behaviors during the pandemic by levels of physical activity and country of residence. Follow up analyses indicated that individuals with highest decrease in physical activity reported significantly lower physical and mental health, while those with highest increase in physical activity reported significantly higher increase in sleep and lower weight gain. United Kingdom participants reported lowest levels of physical health and highest increase in weight while Latin American participants reported being most affected by emotional problems. Finnish participants reported significantly higher ratings for physical health. The physical activity by country interaction was significant for wellbeing. MANCOVA also revealed significant differences across physical activity levels and four established age categories. Participants in the oldest category reported being significantly least affected by personal and emotional problems; youngest participants reported significantly more sleep. The age by physical activity interaction was significant for eating. Discussed in light of Hobfoll (1998) conservation of resources theory, findings endorse the policy of advocating physical activity as a means of generating and maintaining resources combative of stress and protective of health.


Plasmonic ridge waveguides with deep-subwavelength outside-field confinements.
Subwavelength plasmonic waveguides are the most promising candidates for developing planar photonic circuitry platforms. In this study a subwavelength metallic ridge waveguide is numerically and experimentally investigated. Differing from previous plasmonic waveguides, the metallic strip of the subwavelength ridge waveguide is placed on a thick metal film. It is found that the surface-plasmon-polariton (SPP) waveguide modes result from the coupling of the corner modes in the two ridge corners. The bottom metal film has a great influence on the SPP modes, and nearly all the evanescent fields of the SPP modes are tightly confined outside the ridge waveguide. Simulations show that 50% of the total power flow in the SPP mode can be confined outside the ridge waveguide with an area of only about λ (2)/20. The propagation length is still about 10 times the plasmon wavelength. Through comparison with a metallic strip placed directly on the dielectric substrate, the proposed ridge waveguide exhibits a much higher sensing performance. This plasmonic ridge waveguide with deep-subwavelength outside-field confinements is of significance in a range of nano-optics applications, especially in nanosensing.


Nontuberculous mycobacteria pulmonary infection in medical intensive care unit: the incidence, patient characteristics, and clinical significance.
The clinical significance of nontuberculous mycobacteria (NTM) pulmonary infection in medical intensive care unit (ICU) is still unclear. We conducted a retrospective study in the medical ICUs of a medical center in Taiwan from January 1999 to June 2007. Patients with NTM isolated from respiratory specimens within 1 month before or during the ICU course were identified. Those who fulfilled the diagnostic criteria of NTM pulmonary infection were identified and compared with patients with NTM colonization and control subjects who were culture-negative for mycobacteria. Among the 5,378 patients admitted to medical ICUs, 2,866 (53.3%) had received mycobacterial culture for respiratory specimens. NTM were isolated from 169 (5.8%) patients. Of them, 47 (27.8%) were considered NTM pulmonary infection. M. avium complex and M. abscessus were the most common pathogens. Within 100 days after ICU admission, significantly more patients with NTM infection died than those with NTM colonization and control subjects (47 vs. 8 vs. 14%, P < 0.001). Twenty-one (49%) patients with NTM pulmonary infection received anti-NTM treatment, with four experiencing adverse effects. Although statistically insignificant, anti-NTM treatment was associated with prolonged survival for those who died in the ICU and shorter ICU stay for those who survived the ICU course. Our findings suggest that NTM pulmonary infection seems to associate with higher mortality in medical ICUs. Anti-NTM treatment is probably associated with a better outcome. Therefore, keeping a high suspicion when NTM is isolated and using careful consideration when starting anti-NTM treatment should be emphasized.


The emerging picture of autism spectrum disorder: genetics and pathology.
Autism spectrum disorder (ASD) is defined by impaired social interaction and communication accompanied by stereotyped behaviors and restricted interests. Although ASD is common, its genetic and clinical features are highly heterogeneous. A number of recent breakthroughs have dramatically advanced our understanding of ASD from the standpoint of human genetics and neuropathology. These studies highlight the period of fetal development and the processes of chromatin structure, synaptic function, and neuron-glial signaling. The initial efforts to systematically integrate findings of multiple levels of genomic data and studies of mouse models have yielded new clues regarding ASD pathophysiology. This early work points to an emerging convergence of disease mechanisms in this complex and etiologically heterogeneous disorder.


Effects of subclinical hypothyroidism treatment on psychiatric symptoms, muscular complaints, and quality of life.
To evaluate the impact of subclinical hypothyroidism (sHT) treatment on health-related quality of life (QoL), psychiatric symptoms, clinical score, and muscle function. In this randomized double-blind study, patients were assigned either to treatment (n = 35) or placebo (n = 36). Clinical and psychiatric symptoms were assessed by the Zulewski, Hamilton and Beck scales. QoL was assessed by the SF-36 questionnaire. Assessments of quadriceps (QS) and inspiratory muscle (IS) strength were performed by a chair dynamometer and a manuvacuometer. Treatment improved IS (+11.5 ± 17.2; p = 0.041), as did QoL domains "Pain" and "Role Physical" (+19.7 ± 15.2, 0.039 and +22.1 ± 47.5, p = 0.054; respectively). Clinical and psychiatric symptoms showed similar responses to both interventions. sHT treatment improved IS and physical aspects of QoL, despite no impact in other muscle parameters. Clinical score, psychiatric symptoms, and SF-36 domains, based on mental dimensions of QoL may be more susceptible to "placebo effect" in patients with sHT.


Impact of outdoor air pollution on survival after stroke: population-based cohort study.
The impact of air pollution on survival after stroke is unknown. We examined the impact of outdoor air pollution on stroke survival by studying a population-based cohort. All patients who experienced their first-ever stroke between 1995 and 2005 in a geographically defined part of London, where road traffic contributes to spatial variation in air pollution, were followed up to mid-2006. Outdoor concentrations of nitrogen dioxide and particulate matter <10 microm in diameter modeled at a 20-m grid point resolution for 2002 were linked to residential postal codes. Hazard ratios were adjusted for age, sex, social class, ethnicity, smoking, alcohol consumption, prestroke functional ability, pre-existing medical conditions, stroke subtype and severity, hospital admission, and neighborhood socioeconomic deprivation. There were 1856 deaths among 3320 patients. Median survival was 3.7 years (interquartile range, 0.1 to 10.8). Mean exposure levels were 41 microg/m(3) (SD, 3.3; range, 32.2 to 103.2) for nitrogen dioxide and 25 microg/m(3) (SD, 1.3; range, 22.7 to 52) for particulate matter <10 microm in diameter. A 10-microg/m(3) increase in nitrogen dioxide was associated with a 28% (95% CI, 11% to 48%) increase in risk of death. A 10-microg/m(3) increase in particulate matter <10 mum in diameter was associated with a 52% (6% to 118%) increase in risk of death. Reduced survival was apparent throughout the follow-up period, ruling out short-term mortality displacement. Survival after stroke was lower among patients living in areas with higher levels of outdoor air pollution. If causal, a 10-microg/m(3) reduction in nitrogen dioxide exposure might be associated with a reduction in mortality comparable to that for stroke units. Improvements in outdoor air quality might contribute to better survival after stroke.


Rete mirabile associated with pial arteriovenous fistula: imaging features with literature review.
A rete mirabile is a vascular network of intercommunicating small arteries or arterioles that replace the definitive adult artery supplying the brain. It supplies the brain in lower mammals but is not seen in normal human embryological development. A 26-year-old man presented with worsening tinnitus that was interfering with his sleep. On CT and digital subtraction angiography he was found to have a temporal lobe pial arteriovenous fistula with bilateral carotid and vertebral rete mirabile. The patient was offered open surgical and endovascular treatment options for pial arteriovenous fistula but he refused both and opted for conservative medical management. At 6-month follow-up he continued to have pulsatile tinnitus but was otherwise neurologically normal. We present the first described association of rete mirabile with pial arteriovenous fistula and discuss its clinical presentation and imaging features, with a review of the literature for bilateral carotid and vertebral rete mirabile.


DNA polymerases and DNA topoisomerases solubilized from nuclear matrices of regenerating rat livers.
DNA topoisomerase activity together with the activities of DNA polymerase were detected in a form tightly associated with rat liver nuclear matrices. DNA polymerase activities were solubilized from the nuclear matrices of regenerating rat livers by sonic treatment followed by extraction of these activities with detergent and salt. The predominant activity was mainly alpha-polymerase as judged from the size determined by sucrose density gradient centrifugation. However, only beta-polymerase activity was detected in the matrix of normal rat livers. DNA topoisomerase activity, detected in both regenerating and normal liver nuclear matrices, showed a molecular size of about 4 S in sucrose gradient, and was active in the presence of EDTA. These results suggest that this enzyme belongs to type I topoisomerase.


Quantitation of membrane glycoprotein IIIa on intact human platelets using the monoclonal antibody, AP-3.
A murine monoclonal antibody specific for glycoprotein (GP)IIIa was prepared by immunization with a GPIIb- and GPIIIa-enriched Triton X-114 extract of platelet membranes. This antibody, designated AP-3, was shown by indirect immunoprecipitation to react solely with GPIIIa derived from either P1A1-positive or -negative individuals. The epitope on GPIIIa recognized by AP-3 is expressed on dissociated GPIIIa as well as on Ca+2-dependent complexes of GPIIb and GPIIIa, as shown by crossed immunoelectrophoresis in the presence or absence of EDTA. A previously described monoclonal antibody specific for the GPIIb/IIIa complex (AP-2) inhibited platelet aggregation induced by ADP, thrombin, collagen, or arachidonic acid (Pidard et al, J Biol Chem 258:12582-12586, 1983). In contrast, AP-3 had no effect on aggregation induced by any of these reagents, a finding similar to that previously reported for the GPIIb-specific monoclonal antibody, Tab (McEver et al, J Clin Invest 66:1311-1318, 1980). At saturation, 40,200 AP-3 molecules were bound per platelet, a value similar to that obtained for AP-2 or Tab. Thus, data derived using AP-3 indicate that significant amounts of free GPIIIa are not present, thereby supporting the hypothesis that GPIIb and GPIIIa exist complexed in a 1:1 stoichiometry in the plasma membrane of intact, nonactivated platelets.