Metoserpate Hydrochloride for the treatment of hysteria in replacement pullets.
Fifteen flocks of replacement pullets affected with hysteria were treated with metoserpate hydrochloride via the drinking water after water was withheld for an adequate period. The dose was 4 mg/kg body weight (BW) on day 1, and 2 mg/kg BW on days 5 and 9. Metoserpate hydrochloride proved effective and safe for treating clinical cases of hysteria in replacement pullets.


Gender differences in the healthy worker effect among synthetic vitreous fiber workers.
The aim of this study was to determine whether the healthy worker effect and its component parts operate similarly for women and men. A cohort of workers from 14 synthetic vitreous fiber factories in seven countries, employed for at least 1 year between 1933 and 1977 and followed up to the early 1990s, included 375 deaths and 53,608 person-years among females and 2,568 deaths and 210,073 person-years among males. Standardized mortality ratios for all-cause and circulatory diseases were adjusted for country, age, calendar time, and gender. In addition, internal comparisons were adjusted for time since hire and employment status. The analyses addressed the following: 1) the healthy hire effect, 2) the time since hire effect, and 3) the healthy worker survivor effect. In this cohort, an overall healthy worker effect was not present in either gender. The healthy hire effect, based on standardized mortality ratios for years 1-4 since hire, was observed in males (standardized mortality ratio (SMR) = 0.8; 95% confidence interval (CI): 0.7, 1.0) but was less in females (SMR = 0.9; 95% CI: 0.5, 1.6). The relative risks increased slightly with time since hire in males but not in females. Higher mortality ratios were seen among those leaving employment than among those who remained actively employed; however, this effect was substantially greater for women (relative risk (RR) = 3.4; 95% CI: 1.8, 6.3) than men (RR = 1.8; 95% CI: 1.5, 2.1). The gender difference for active versus inactive status was stronger up to age 60 (men: RR = 1.7; 95% CI: 1.4, 2.0; women: RR = 3.6; 95% CI: 1.8, 7.1) than above that age. In conclusion, it appears that there is a stronger selection of healthy men than women into the workforce, while health-related selection out of the workforce is stronger for women than men.


Morphological study of tooth development in podoplanin-deficient mice.
Podoplanin is a mucin-type highly O-glycosylated glycoprotein identified in several somatyic cells: podocytes, alveolar epithelial cells, lymphatic endothelial cells, lymph node stromal fibroblastic reticular cells, osteocytes, odontoblasts, mesothelial cells, glia cells, and others. It has been reported that podoplanin-RhoA interaction induces cytoskeleton relaxation and cell process stretching in fibroblastic cells and osteocytes, and that podoplanin plays a critical role in type I alveolar cell differentiation. It appears that podoplanin plays a number of different roles in contributing to cell functioning and growth by signaling. However, little is known about the functions of podoplanin in the somatic cells of the adult organism because an absence of podoplanin is lethal at birth by the respiratory failure. In this report, we investigated the tooth germ development in podoplanin-knockout mice, and the dentin formation in podoplanin-conditional knockout mice having neural crest-derived cells with deficiency in podoplanin by the Wnt1 promoter and enhancer-driven Cre recombinase: Wnt1-Cre;PdpnΔ/Δmice. In the Wnt1-Cre;PdpnΔ/Δmice, the tooth and alveolar bone showed no morphological abnormalities and grow normally, indicating that podoplanin is not critical in the development of the tooth and bone.


The TREATT Trial (TRial to EvaluAte Tranexamic acid therapy in Thrombocytopenia): safety and efficacy of tranexamic acid in patients with haematological malignancies with severe thrombocytopenia: study protocol for a double-blind randomised controlled trial.
Patients with haematological malignancies often develop thrombocytopenia as a consequence of either their disease or its treatment. Platelet transfusions are commonly given to raise a low platelet count and reduce the risk of clinical bleeding (prophylaxis) or stop active bleeding (therapy). Recent studies have shown that many patients continue to experience bleeding despite the use of prophylactic platelet transfusions. Tranexamic acid is an anti-fibrinolytic, which reduces the breakdown of clots formed in response to bleeding. Anti-fibrinolytics have been shown to prevent bleeding, decrease blood loss and use of red cell transfusions in elective and emergency surgery, and are used widely in these settings. The aim of this trial is to test whether giving tranexamic acid to patients receiving treatment for haematological malignancies reduces the risk of bleeding or death and the need for platelet transfusions. This is a multinational randomised, double-blind, placebo-controlled, parallel, superiority trial. Patients will be randomly assigned to receive tranexamic acid (given intravenously or orally) or a matching placebo in a 1:1 ratio, stratified by site. Patients with haematological malignancies receiving intensive chemotherapy or stem cell transplantation (or both) who are at least 18 years of age and expected to become severely thrombocytopenic for at least 5 days will be eligible for this trial. The primary outcome of the trial is the proportion of patients who died or had bleeding of World Health Organization grade 2 or above during the first 30 days of the trial. We will measure the rates of bleeding daily by using a short, structured assessment of bleeding, and we will record the number of transfusions given to patients. We will assess the risk of arterial and venous thrombosis for 120 days from the start of trial treatment. This trial will assess the safety and efficacy of using prophylactic tranexamic acid during a period of intensive chemotherapy and associated thrombocytopenia in people with haematological disorders. This study was prospectively registered on Current Controlled Trials on 25 March 2015 (ISRCTN73545489) and is also registered on ClinicalTrials.gov (NCT03136445).


Barriers to research utilisation among forensic mental health nurses.
This study used a cross-sectional, descriptive design to identify barriers to research utilisation among forensic mental health nurses. A postal questionnaire was sent to the total population of 88 registered nurses working in a forensic mental health hospital in the UK. Forty-seven responded representing a response rate of 53%. Results showed that the greatest barriers to research utilisation were those related to the characteristics of the setting in which nurses work or the personal characteristics of nurses themselves, which seems to be consistent with previous studies undertaken in the area. However, the nurses reported it especially difficult to trust what research shows because they feel that it is not always possible to apply those findings to their particular work environment. The main implications for policy are a need for an increase in support from management, programmes of advanced education to provide nurses with research skills, an improvement in accessibility and availability of research reports and an increase in time available to read and implement research. The main suggestions for future research are that qualitative studies should be carried out to attain a better understanding of mental health nurses' attitudes towards research utilisation.


Influence of probiotics on rat liver biotransformation enzymes.
The aim of the study was to find, whether probiotic Escherichia coli Nissle 1917 O6:K5:H1 (EcN) influence the amount and activity of cytochromes P450 (CYP) in rat liver. Live bacterial suspension of EcN was applied to the female Wistar rats in single dose or for 14 days consecutively. The bacterial lipopolysaccharide (LPS) isolated by phenol extraction from the EcN was given to the rats for 14 days as well. Control rats were treated with the saline solution daily for 14 days. Relative amount of CYP2C6, CYP2C9 (corresponding to rat CYP2C11), CYP3A1 and CYP1A2 protein expression in rat liver microsomes was determined by Western blotting. For the determination of six CYP activities (corresponding to human CYP1A2, CYP2A6, CYP2B6, CYP3A4, CYP2C9 and CYP2D6) fluorescence, luminescence or absorbance detection was used. The data presented show that the changes of the total content of the CYP enzymes in rat liver are not significant after administration of the probiotic for 1 or 14 days as well as of the LPS. Western blots revealed a slight increase in CYP2C6 protein expression; level of another rat CYP2C protein (readings with anti-human CYP2C9 antibody corresponding to the rat CYP2C11) as well as of CYP1A2 was elevated after administration of LPS; a small decrease was observed with CYP3A1 protein. Changes in activities of CYP forms are not significant, only the activity of rat CYP2C forms in liver microsomal samples of rats given free LPS appeared to exhibit a small, but significant tendency to increase. The results show that the p.o. administration of probiotics to rat does not markedly influence the rat hepatic CYP enzymes.


Will the Occupational Safety and Health Administration's Proposed Standards for Occupational Exposure to Respirable Crystalline Silica Reduce Workplace Risk?
The Occupational Safety and Health Administration (OSHA) is developing regulations to amend existing standards for occupational exposure to respirable crystalline silica by establishing a new permissible exposure limit as well as a series of ancillary provisions for controlling exposure. This article briefly reviews OSHA's proposed regulatory approach and the statutory authority on which it is based. It then evaluates OSHA's preliminary determination of significant risk and its analysis of the risk reduction achievable by its proposed controls. It recognizes that OSHA faces multiple challenges in devising a regulatory approach that reduces exposures and health risks and meets its statutory goal. However, the greatest challenge to reducing risks associated with silica exposure is not the lack of incentives (for either employers or employees) but rather lack of information, particularly information on the relative toxicity of different forms of silica. The article finds that OSHA's proposed rule would contribute little in the way of new information, particularly since it is largely based on information that is at least a decade old--a significant deficiency, given the rapidly changing conditions observed over the last 45 years. The article concludes with recommendations for alternative approaches that would be more likely to generate information needed to improve worker health outcomes.


Teamwork evaluation during emergency medicine residents' high-fidelity simulation.
Teamwork training has been included in several emergency medicine (EM) curricula; the aim of this study was to compare different scales' performance in teamwork evaluation during simulation for EM residents. In the period October 2013-June 2014, we performed bimonthly high-fidelity simulation sessions, with novice (I-III year, group 1 (G1)) and senior (IV-V year, group 2 (G2)) EM residents; scenarios were designed to simulate management of critical patients. Videos were assessed by three independent raters with the following scales: Emergency Team Dynamics (ETD), Clinical Teamwork Scale (CTS) and Team Emergency Assessment Measure (TEAM). In the period March-June, after each scenario, participants completed the CTS and ETD. The analysis based on 18 sessions showed good internal consistency and good to fair inter-rater reliability for the three scales (TEAM, CTS, ETD: Cronbach's α 0.954, 0.954, 0.921; Intraclass Correlation Coefficients (ICC), 0.921, 0.917, 0.608). Single CTS items achieved highly significant ICC results, with 12 of the total 13 comparisons achieving ICC results ≥0.70; a similar result was confirmed for 4 of the total 11 TEAM items and 1 of the 8 total ETD items. Spearman's r was 0.585 between ETD and CTS, 0.694 between ETD and TEAM, and 0.634 between TEAM and CTS (scales converted to percentages, all p<0.0001). Participants gave themselves a better evaluation compared with external raters (CTS: 101±9 vs 90±9; ETD: 25±3 vs 20±5, all p<0.0001). All examined scales demonstrated good internal consistency, with a slightly better inter-rater reliability for CTS compared with the other tools.


Minimum sample size for developing a multivariable prediction model: Part I - Continuous outcomes.
In the medical literature, hundreds of prediction models are being developed to predict health outcomes in individuals. For continuous outcomes, typically a linear regression model is developed to predict an individual's outcome value conditional on values of multiple predictors (covariates). To improve model development and reduce the potential for overfitting, a suitable sample size is required in terms of the number of subjects (n) relative to the number of predictor parameters (p) for potential inclusion. We propose that the minimum value of n should meet the following four key criteria: (i) small optimism in predictor effect estimates as defined by a global shrinkage factor of ≥0.9; (ii) small absolute difference of ≤ 0.05 in the apparent and adjusted R2 ; (iii) precise estimation (a margin of error ≤ 10% of the true value) of the model's residual standard deviation; and similarly, (iv) precise estimation of the mean predicted outcome value (model intercept). The criteria require prespecification of the user's chosen p and the model's anticipated R2 as informed by previous studies. The value of n that meets all four criteria provides the minimum sample size required for model development. In an applied example, a new model to predict lung function in African-American women using 25 predictor parameters requires at least 918 subjects to meet all criteria, corresponding to at least 36.7 subjects per predictor parameter. Even larger sample sizes may be needed to additionally ensure precise estimates of key predictor effects, especially when important categorical predictors have low prevalence in certain categories.


Efficacy of web-based personalized normative feedback: a two-year randomized controlled trial.
Web-based brief alcohol interventions have the potential to reach a large number of individuals at low cost; however, few controlled evaluations have been conducted to date. The present study was designed to evaluate the efficacy of gender-specific versus gender-nonspecific personalized normative feedback (PNF) with single versus biannual administration in a 2-year randomized controlled trial targeting a large sample of heavy-drinking college students. Participants included 818 freshmen (57.6% women; 42% non-Caucasian) who reported 1 or more heavy-drinking episodes in the previous month at baseline. Participants were randomly assigned in a 2 (gender-specific vs. gender-nonspecific PNF) × 2 (single vs. biannual administration of PNF) + 1 (attention control) design. Assessments occurred every 6 months for a 2-year period. Results from hierarchical generalized linear models provided modest effects on weekly drinking and alcohol-related problems but not on heavy episodic drinking. Relative to control, gender-specific biannual PNF was associated with reductions over time in weekly drinking (d = -0.16, 95% CI [-0.02, -0.31]), and this effect was partially mediated by changes in perceived norms. For women, but not men, gender-specific biannual PNF was associated with reductions over time in alcohol-related problems relative to control (d = -0.29, 95% CI [-0.15, -0.58]). Few other effects were evident. The present research provides modest support for the use of biannually administered web-based gender-specific PNF as an alternative to more costly indicated prevention strategies.


Receptor binding specificity of recent human H3N2 influenza viruses.
Human influenza viruses are known to bind to sialic acid linked alpha2-6 to galactose, but the binding specificity beyond that linkage has not been systematically examined. H3N2 human influenza isolates lost binding to chicken red cells in the 1990s but viruses isolated since 2003 have re-acquired the ability to agglutinate chicken erythrocytes. We have investigated specificity of binding, changes in hemagglutinin sequence of the recent viruses and the role of sialic acid in productive infection. Viruses that agglutinate, or do not agglutinate, chicken red cells show identical binding to a Glycan Array of 264 oligosaccharides, binding exclusively to a subset of alpha2-6-sialylsaccharides. We identified an amino acid change in hemagglutinin that seemed to correlate with chicken red cell binding but when tested by mutagenesis there was no effect. Recombinant hemagglutinins expressed on Sf-9 cells bound chicken red cells but the released recombinant baculoviruses agglutinated only human red cells. Similarly, an isolate that does not agglutinate chicken red cells show hemadsorption of chicken red cells to infected MDCK cells. We suggest that binding of chicken red cells to cell surface hemagglutinin but not to virions is due to a more favorable hemagglutinin density on the cell surface. We investigated whether a virus specific for alpha2-6 sialyloligosaccharides shows differential entry into cells that have varying proportions of alpha2-6 and alpha2-3 sialic acids, including human A549 and HeLa cells with high levels of alpha2-6 sialic acid, and CHO cells that have only alpha2-3 sialic acid. We found that the virus enters all cell types tested and synthesizes viral nucleoprotein, localized in the nucleus, and hemagglutinin, transported to the cell surface, but infectious progeny viruses were released only from MDCK cells. Agglutination of chicken red cells does not correlate with altered binding to any oligosaccharide on the Glycan Array, and may result from increased avidity due to density of hemagglutinin and not increased affinity. Absence of alpha2-6 sialic acid does not protect a cell from influenza infection and the presence of high levels of alpha2-6-sialic acids on a cell surface does not guarantee productive replication of a virus with alpha2-6 receptor specificity.


Anal squamous cell carcinoma with metastasis to duodenum causing duodenal stricture and gastric outlet obstruction.
Squamous cell carcinoma (SCC) of the anal canal is a rare entity encompassing only 2-4 percent of all colon, rectal, and anal cancers. SCC of the anal canal tends to be loco-regional, and in the event of distant metastasis, a most common site of spread is to liver and lung. We report an unusual case of SCC of the anal canal with duodenal metastases in a 49-year-old female who had presented with symptoms of abdominal pain, nausea, and vomiting eight months after the primary diagnosis of SCC of the anal canal. Esophagogastroduodenoscopy (EGD) revealed duodenal stricture with subsequent biopsy revealing duodenal mucosa with scattered malignant cell clusters within lymphatic spaces, consistent with metastatic carcinoma. Immunohistological staining demonstrated malignant cells positive for CK7, p16, p63 favoring a metastatic SCC.


Effect of CYP2C19 polymorphisms on antidepressant prescription patterns and treatment emergent mania in bipolar disorder.
Antidepressant medication is used extensively to treat bipolar depression despite uncertain efficacy. The cytochrome P450 (CYP) 2C19 enzyme metabolize several antidepressants, and polymorphisms in the corresponding gene CYP2C19 influence plasma concentration and hence treatment outcomes in major depressive disorder. Here, we investigate if CYP2C19 polymorphisms are associated with antidepressant treatment patterns and the risk of mania when antidepressants are used in bipolar disorder. Two single nucleotide polymorphisms (rs4244285 and rs12248560) were used to classify 5019 bipolar disorder patients into CYP2C19 metabolic phenotypes ranging from poor to ultra-rapid metabolizers. We used Swedish national registry data 2005-2017 on dispensed medications and inpatient care to estimate risks for early-treatment persistence, treatment discontinuation, switching to a new antidepressant medication, and mania within 3 months of treatment initiation in patients treated with citalopram, escitalopram, sertraline, amitriptyline, and clomipramine. Metabolic phenotypes of CYP2C19 were not robustly associated with the investigated treatment outcomes based on dispense patterns. Slower metabolism was associated with an increased risk of treatment emergent mania for sertraline (hazard ratio [HR] = 1.3, 95% CI = 1.04-1.62, p = 0.02) and the tricyclic antidepressants amitriptyline and clomipramine (HR = 1.46, 95% CI = 1.05-2.02, p = 0.024). In a large study of the impact of CYP2C19 metabolic phenotypes on antidepressant treatment of bipolar depression, we found an association between slower CYP2C19 metabolism and higher risk of treatment emergent mania, which is a step towards personalized risk assessments. There were, however, no clear associations with early treatment persistence, treatment discontinuation, and switching to a new antidepressant.


Development of fearfulness in birds: genetic factors modulate non-genetic maternal influences.
The development of fearfulness and the capacity of animals to cope with stressful events are particularly sensitive to early experience with mothers in a wide range of species. However, intrinsic characteristics of young animals can modulate maternal influence. This study evaluated the effect of intrinsic fearfulness on non-genetic maternal influence. Quail chicks, divergently selected for either higher (LTI) or lower fearfulness (STI) and from a control line (C), were cross-fostered by LTI or STI mothers. Behavioural tests estimated the chicks' emotional profiles after separation from the mother. Whatever their genotype, the fearfulness of chicks adopted by LTI mothers was higher than that of chicks adopted by STI mothers. However, genetic background affected the strength of maternal effects: the least emotional chicks (STI) were the least affected by early experience with mothers. We demonstrated that young animal's intrinsic fearfulness affects strongly their sensitivity to non-genetic maternal influences. A young animal's behavioural characteristics play a fundamental role in its own behavioural development processes.


Auricular composite graft for skin defect of the philtrum dimple.
Our method of performing an auricular composite graft for a skin defect of the philtrum dimple in a patient whose lip is not damaged and has retained its original softness and elasticity is presented. After resecting the lesion, an auricular composite graft is harvested from the conchal region. The size of the graft is almost the same as the size of the resected lesion, although the cartilage is harvested in an elliptical shape, and its size is approximately 60% in area of the overriding skin of the graft. The graft is harvested from the site, which has a similar curvature to the defect. The cartilage is sutured tightly to the graft bed at a minimum of four points with 6-0 absorbable suture. The transversal axis of the harvested cartilage is sutured as vertically as possible so as to fit the direction of the wrinkle line of the upper lip. The skin is sutured to the defect margin using 5-0 nylon suture. The graft donor site is closed primarily. This method has been used for the closure of six comparatively large skin defects after resecting a skin lesion (pigmented nevus in three cases and hypertrophic scar in three cases) in the philtrum dimple in six patients. In all cases, the upper lip was not damaged and retained its original softness and elasticity. The "take" of the graft was complete in all patients, and the donor site healed without any problem. In all cases, postoperative shrinkage of the graft was not significant during the follow-up period, and the graft had a smooth surface. In addition, no patients suffered from a feeling of discomfort in moving the mouth, and an acceptable shape of the philtrum dimple was achieved in all cases. There were no deformational changes in the graft donor site. In conclusion, our method is valid in the patient whose lip is not damaged and has retained its original softness and elasticity and in whom a full-thickness skin graft is selected as the covering method for a skin defect of the philtrum dimple.


Dynamics of breakthrough pain vs. pharmacokinetics of oral morphine: implications for management.
Dynamics of breakthrough pain vs. pharmacokinetics of oral morphine: implications for managementBreakthrough pain is a transient exacerbation of pain that occurs either spontaneously, or in relation to a specific predictable or unpredictable trigger, despite relatively stable and adequately controlled background pain. The onset of breakthrough pain is typically fast and the duration is usually relatively short, but despite the self-limiting nature of each breakthrough pain, the repeated episodes can have a significant impact on patients' quality of life. Effective management is therefore imperative and often involves the use of supplemental doses of medication known as 'rescue medication'. The ideal rescue medication should be efficacious, have a rapid onset of action, a relatively short duration of effect and minimal adverse effects. Normal-release oral opioids have been the mainstay approach for patients who are receiving around the clock opioid regimen, but the onset and duration of action of oral opioids such as morphine may not be suitable for treating many breakthrough pains.


The Long-Term Effectiveness of Trigger Point Dry Needling and Exercise for Individuals With Shoulder Pain: A Critically Appraised Topic.
Clinical Scenario: Shoulder pain is a very common symptom encountered in outpatient physical therapy practice. In addition to therapeutic exercise and manual therapy interventions, trigger point dry needling (TDN) has emerged as a possible treatment option for reducing shoulder pain and improving function. Dry needling consists of inserting a thin stainless-steel filament into a myofascial trigger point with the intention of eliciting a local twitch response of the muscle. It is theorized that this twitch response results in reduced muscle tension and can aid in reduced pain and disability. To this point, multiple studies have found TDN to be effective at reducing pain and improving function in the short-term, but the long-term outcomes remain unknown. Clinical Question: Does the addition of TDN to an exercise program result in better long-term pain intensity and disability reduction in patients with shoulder pain? Summary of Findings: Improvement in long-term pain and function can be expected regardless of the addition of TDN to an evidence-based exercise program for patients with shoulder pain. Clinical Bottom Line: Either TDN or an evidence-based therapeutic exercise program elicits improved long-term pain and disability reduction in patients with shoulder pain, which suggests that clinicians can confidently use either approach with their patients. Strength of Recommendation: Strong evidence (level 2 evidence with PEDro scores >8/10) suggesting that TDN does not outperform therapeutic exercise regarding long-term pain reduction.


Transition metal complexes with thiosemicarbazide-based ligands. LIII. [4-(2-Diphenylphosphino-alpha-ethoxybenzyl-kappaP)-S-methyl-1-(4-oxidopent-3-en-4-ylidene-kappaO)thiosemicarbazido-kappa(2)N(1),N(4)]nickel(II).
The title compound, [Ni(C(28)H(30)N(3)O(2)PS)], crystallizes with two independent molecules in the asymmetric unit. The Ni(II) atoms are in significantly deformed square-planar environments formed by an ONNP donor set from a thiosemicarbazide-based tetradentate ligand. The Ni(II) atom and the ONN donor atoms are nearly coplanar, while the P atom deviates from their mean planes by 0.278 (4) and 0.202 (4) Angstrom for the two independent molecules. The P-containing chelate rings are remarkably non-planar, adopting a boat conformation, which is unusual for chelate rings in transition metal complexes with thiosemicarbazide-based tetradentate ligands. The orientation of the ethoxy group bonded to this chelate ring is caused by an intramolecular C-H...pi interaction with the opposing phenyl ring. There are no hydrogen bonds; instead, numerous intermolecular C-H...pi interactions dominate in the crystal packing.


Vibrio aestuarianus zinc metalloprotease causes lethality in the Pacific oyster Crassostrea gigas and impairs the host cellular immune defenses.
Extracellular products (ECPs) of the pathogenic Vibrio aestuarianus 01/32 were previously reported to display lethality in Crassostrea gigas oysters and to cause morphological changes and immunosuppression in oyster hemocytes. To identify the source of this toxicity, biochemical and genetic approaches were developed. ECP protease activity and lethality were shown to be significantly reduced following incubation with metal chelators, suggesting the involvement of a zinc metalloprotease. An open reading frame of 1836 bp encoding a 611-aa metalloprotease (designated Vam) was identified. The deduced protein sequence showed high homology to other Vibrio metalloproteases reported to be involved in pathogenicity. To further confirm the role of this enzyme in ECP toxicity, a plasmid carrying the vam gene under the control of an araC-P(BAD) expression cassette was transferred to a Vibrio splendidus related strain, LMG20012(T), previously characterized as non-pathogenic to oysters. Expression of Vam conferred a toxic phenotype to LMG20012(T) ECPs in vivo and cytotoxicity to oyster hemocytes in vitro. Collectively, these data suggest that the Vam metalloprotease is a major contributor to the toxicity induced by V. aestuarianus ECPs and is involved in the impairment of oyster hemocyte functions.


Down syndrome and GATA1 mutations in transient abnormal myeloproliferative disorder: mutation classes correlate with progression to myeloid leukemia.
Twenty percent to 30% of transient abnormal myelopoiesis (TAM) observed in newborns with Down syndrome (DS) develop myeloid leukemia of DS (ML-DS). Most cases of TAM carry somatic GATA1 mutations resulting in the exclusive expression of a truncated protein (GATA1s). However, there are no reports on the expression levels of GATA1s in TAM blasts, and the risk factors for the progression to ML-DS are unidentified. To test whether the spectrum of transcripts derived from the mutant GATA1 genes affects the expression levels, we classified the mutations according to the types of transcripts, and investigated the modalities of expression by in vitro transfection experiments using GATA1 expression constructs harboring mutations. We show here that the mutations affected the amount of mutant protein. Based on our estimates of GATA1s protein expression, the mutations were classified into GATA1s high and low groups. Phenotypic analyses of 66 TAM patients with GATA1 mutations revealed that GATA1s low mutations were significantly associated with a risk of progression to ML-DS (P < .001) and lower white blood cell counts (P = .004). Our study indicates that quantitative differences in mutant protein levels have significant effects on the phenotype of TAM and warrants further investigation in a prospective study.


Early Endotracheal Tube Insertion with the GlideScope: A Randomized Controlled Trial.
The GlideScope videolaryngoscope is an intubating device routinely used by anesthesiologists for tracheal intubation. It is occasionally difficult to advance the endotracheal tube (ETT) into the trachea, despite a good view of the glottis. One technique that may be used when difficulty is encountered is to remove the GlideScope from the pharynx and introduce the ETT into the pharynx first, leaving it in place posteriorly while the GlideScope is inserted. Frequently, when the GlideScope is subsequently inserted, the ETT tip will then be in good view, resting near the glottis, and will easily advance into the trachea. In this randomized, single-blinded trial, we assessed whether orotracheal intubation with the GlideScope is faster and/or easier with the ETT-first technique as a primary technique in elective patients. One hundred sixty patients with normal-appearing airways who required elective orotracheal intubation were allocated randomly to intubation with insertion of the ETT or GlideScope into the oropharynx first. The primary outcome was time to intubation. The secondary outcomes were subjective ease of intubation (100-mm visual analog scale, 0 = easy; 100 = difficult), number of attempts/failures, incidence of oropharyngeal bleeding, and postoperative sore throat and/or vocal changes. Baseline demographics were similar between the 2 groups. Mean time to intubation was 48.2 ± 17.1 seconds with the ETT-first technique and 51.5 ± 21.8 seconds with the GlideScope-first technique (P = 0.30). The mean difference was 3.3 seconds in favor of the ETT-first technique (95% confidence interval, -2.9 to 9.6). The median ease of intubation using the visual analog scale was 13.3 mm (interquartile range, 5.3 to 21) with the ETT-first technique and 13.5 mm (interquartile range, 5.6 to 29.5) with the GlideScope-first technique (P = 0.30). The difference between the medians was -2.0 mm in favor of the ETT-first group (95% confidence interval, -1.5 to 6.0). There was no difference between groups for number of intubation attempts, incidence of oropharyngeal bleeding, laryngoscopic grade, sore throat, or vocal changes. In this study of GlideScope laryngoscopy, no statistically significant difference was observed in the time to intubate or the subjective ease of intubation whether the ETT or GlideScope was inserted into the oropharynx first.


Growth of BiFeO3 thin films by chemical solution deposition: the role of electrodes.
BiFeO3 (BFO) thin films were grown by chemical solution deposition on a range of electrodes to determine their role in controlling the phase formation and microstructure of the films. The crystallization on oxide electrodes followed the sequence: amorphous → Bi2O2(CO3) → perovskite, while those on Pt crystallized directly from the amorphous phase. IrO2 electrodes promoted perovskite phase formation at the lowest temperature and LaNiO3 additionally induced local epitaxial growth. All compositions exhibited fully coherent Fe-rich precipitates within the grain interior of the perovskite matrix, whereas the incoherent Bi2Fe4O9 second phase was also observed at the grain boundaries of BFO grown on Pt electrodes. The latter could be observed by X-ray diffraction as well as transmission electron microscopy (TEM) but coherent precipitates were only observed by TEM, principally evidenced by their Z contrast in annular dark field images. These data have pronounced consequences for the extended use of BFO films under an applied field for actuator, sensor and memory applications.


In vivo genome-wide profiling of RNA secondary structure reveals novel regulatory features.
RNA structure has critical roles in processes ranging from ligand sensing to the regulation of translation, polyadenylation and splicing. However, a lack of genome-wide in vivo RNA structural data has limited our understanding of how RNA structure regulates gene expression in living cells. Here we present a high-throughput, genome-wide in vivo RNA structure probing method, structure-seq, in which dimethyl sulphate methylation of unprotected adenines and cytosines is identified by next-generation sequencing. Application of this method to Arabidopsis thaliana seedlings yielded the first in vivo genome-wide RNA structure map at nucleotide resolution for any organism, with quantitative structural information across more than 10,000 transcripts. Our analysis reveals a three-nucleotide periodic repeat pattern in the structure of coding regions, as well as a less-structured region immediately upstream of the start codon, and shows that these features are strongly correlated with translation efficiency. We also find patterns of strong and weak secondary structure at sites of alternative polyadenylation, as well as strong secondary structure at 5' splice sites that correlates with unspliced events. Notably, in vivo structures of messenger RNAs annotated for stress responses are poorly predicted in silico, whereas mRNA structures of genes related to cell function maintenance are well predicted. Global comparison of several structural features between these two categories shows that the mRNAs associated with stress responses tend to have more single-strandedness, longer maximal loop length and higher free energy per nucleotide, features that may allow these RNAs to undergo conformational changes in response to environmental conditions. Structure-seq allows the RNA structurome and its biological roles to be interrogated on a genome-wide scale and should be applicable to any organism.


Characterization of daptomycin oligomerization with perylene excimer fluorescence: stoichiometric binding of phosphatidylglycerol triggers oligomer formation.
Daptomycin is a lipopeptide antibiotic that binds to and depolarizes bacterial cell membranes. Its antibacterial activity requires calcium and correlates with the content of phosphatidylglycerol in the target membrane. Daptomycin has been shown to form oligomers on liposome membranes. We here use perylene excimer fluorescence to further characterize the membrane-associated oligomer. To this end, the N-terminal fatty acyl chain was replaced with perylene-butanoic acid. The perylene derivative retains one third of the antibacterial activity of native daptomycin. On liposomes containing phosphatidylcholine and phosphatidylglycerol, as well as on Bacillus subtilis cells, the perylene-labeled daptomycin forms excimers, which shows that the N-terminal acyl chains of neighboring oligomer subunits are in immediate contact with one another. In a lipid bicelle system, oligomer formation can be titrated with stoichiometric amounts of phosphatidylglycerol. Therefore, the interaction of daptomycin with a single molecule of phosphatidylglycerol is sufficient to trigger daptomycin oligomerization.


Three-year-old children can access their own memory to guide responses on a visual matching task.
Many models of learning rely on accessing internal knowledge states. Yet, although infants and young children are recognized to be proficient learners, the ability to act on metacognitive information is not thought to develop until early school years. In the experiments reported here, 3.5-year-olds demonstrated memory-monitoring skills by responding on a non-verbal task originally developed for non-human animals, in which they had to access their knowledge states. Children learned a set of paired associates, and were given the option to skip uncertain trials on a recognition memory test. Accuracy for accepted items was significantly higher than for skipped on a subsequent memory task that included all items. Additionally, children whose memory-monitoring assessments more closely matched actual memory performance showed superior overall learning, suggesting a correlation between memory-monitoring and memory itself. The results suggest that children may have implicit access to internal knowledge states at very young ages, providing an explanation for how they are able to guide learning, even as infants.


Phase I clinical study of the recombinant oncotoxin TP40 in superficial bladder cancer.
Transforming growth factor alpha-Pseudomonas exotoxin-40 (TP40) is a hybrid fusion protein that selectively binds to cancer cells that express the epidermal growth factor receptor. TP40 is then internalized and kills these cells by virtue of its Pseudomonas exotoxin-derived domains. We studied the safety and short-term antitumor activity of intravesical TP40 in 43 patients with refractory superficial bladder cancer. These patients had resected Ta/T1 disease (n = 19), visible Ta or T1 lesions (n = 11), or carcinoma in situ (n = 13). Patients were treated with increasing dose levels of TP40 at 0.15, 0.3, 0.6, 1.2, 2.4, 4.8, or 9.6 mg/week for 6 weeks and evaluated by comparing pretreatment and posttreatment cystoscopic examinations, cytology, and histopathology. All TP40 doses were well tolerated. No evidence of antitumor activity was seen in any of the patients with Ta or T1 lesions. However, 8 of 9 patients with evaluable carcinoma in situ were judged by histopathology of multiple biopsy specimens to exhibit clinical improvement following TP40 therapy. In most of these responsive patients, cystoscopic examination supported the histopathological findings, although cytology of urine and bladder washings persistently demonstrated malignant cells. Therefore, TP40 appears to be a well-tolerated biological agent that may prove to have utility in treating carcinoma in situ of the bladder.


Gait changes as the result of deformity reconstruction surgery in a group of adults with lumbar scoliosis.
This was a prospective analysis of adult spinal deformity patients having fusions from the thoracic spine down to L5 or the sacrum. Gait analysis was performed before surgery and 1 and 2 years postoperatively, as was questionnaire analysis. To compare the preoperative and postoperative gait of revision and primary patients having long fusions to the distal lumbar spine or sacrum with that of a group of able-bodied adults. The experimental hypothesis was that both patient groups would have significantly compromised preoperative gait and gait endurance compared to the able-bodied group and that significant changes would be noted in both groups at 1 and 2 years postoperation. Spinal reconstructive surgery is often performed on adults with progressive lumbar spinal deformities. These patients can be divided into two major groups. The first are those patients who have degenerative changes superimposed on idiopathic scoliosis (primary patients) without previous operative treatment; the second are those patients who have already had a long fusion to L4, L5, or the sacrum (revision patients). Twenty-nine women participated in the investigation (8 primary, 12 revision, 9 able-bodied controls). A gait analysis was performed before surgery and 1 and 2 years postoperation. Walking endurance (time) was estimated from a submaximal graded treadmill exercise test. Motion variables describing the gait of the subjects, as well as gait speed, were determined. The SRS, Oswestry questionnaires, and an analog pain scale were also administered. The primary group showed no adverse changes in lower extremity kinematics after surgery, and their gait speed improved such that it was not significantly different from the able-bodied group at 2 years postoperation. The revision group displayed lower extremity gait kinematics that were significantly different from the able-bodied group before surgery, but were no longer different from the able-bodied 2 years after surgery. They also had a significant increase in gait endurance. Questionnaire data indicated significant improvements for both groups after surgery. Objective gait data quantifying the efficacy of reconstructive spinal surgery in both primary and revision patients indicated improved gait. Gait endurance was improved in the revision group, and gait speed for the primary was not significantly different from able-bodied at 2 years postoperation. Clinically, it would appear that rehabilitation strategies to improve gait endurance and gait speed could be implemented to further improve the gait of these patients.


Time Course and Diagnostic Accuracy of Glial and Neuronal Blood Biomarkers GFAP and UCH-L1 in a Large Cohort of Trauma Patients With and Without Mild Traumatic Brain Injury.
Glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) have been widely studied and show promise for clinical usefulness in suspected traumatic brain injury (TBI) and concussion. Understanding their diagnostic accuracy over time will help translate them into clinical practice. To evaluate the temporal profiles of GFAP and UCH-L1 in a large cohort of trauma patients seen at the emergency department and to assess their diagnostic accuracy over time, both individually and in combination, for detecting mild to moderate TBI (MMTBI), traumatic intracranial lesions on head computed tomography (CT), and neurosurgical intervention. This prospective cohort study enrolled adult trauma patients seen at a level I trauma center from March 1, 2010, to March 5, 2014. All patients underwent rigorous screening to determine whether they had experienced an MMTBI (blunt head trauma with loss of consciousness, amnesia, or disorientation and a Glasgow Coma Scale score of 9-15). Of 3025 trauma patients assessed, 1030 met eligibility criteria for enrollment, and 446 declined participation. Initial blood samples were obtained in 584 patients enrolled within 4 hours of injury. Repeated blood sampling was conducted at 4, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, and 180 hours after injury. Diagnosis of MMTBI, presence of traumatic intracranial lesions on head CT scan, and neurosurgical intervention. A total of 1831 blood samples were drawn from 584 patients (mean [SD] age, 40 [16] years; 62.0% [362 of 584] male) over 7 days. Both GFAP and UCH-L1 were detectible within 1 hour of injury. GFAP peaked at 20 hours after injury and slowly declined over 72 hours. UCH-L1 rose rapidly and peaked at 8 hours after injury and declined rapidly over 48 hours. Over the course of 1 week, GFAP demonstrated a diagnostic range of areas under the curve for detecting MMTBI of 0.73 (95% CI, 0.69-0.77) to 0.94 (95% CI, 0.78-1.00), and UCH-L1 demonstrated a diagnostic range of 0.30 (95% CI, 0.02-0.50) to 0.67 (95% CI, 0.53-0.81). For detecting intracranial lesions on CT, the diagnostic ranges of areas under the curve were 0.80 (95% CI, 0.67-0.92) to 0.97 (95% CI, 0.93-1.00)for GFAP and 0.31 (95% CI, 0-0.63) to 0.77 (95% CI, 0.68-0.85) for UCH-L1. For distinguishing patients with and without a neurosurgical intervention, the range for GFAP was 0.91 (95% CI, 0.79-1.00) to 1.00 (95% CI, 1.00-1.00), and the range for UCH-L1 was 0.50 (95% CI, 0-1.00) to 0.92 (95% CI, 0.83-1.00). GFAP performed consistently in detecting MMTBI, CT lesions, and neurosurgical intervention across 7 days. UCH-L1 performed best in the early postinjury period.


An in vitro assessment of the accuracy of new and in-use torque-limiting devices.
Recent studies have shown that torque-limiting devices (TLDs) do not meet their torque targets and are affected by factors such as the use of the TLDs and the sterilization processes used. The purpose of this in vitro study was to investigate the accuracy of TLDs currently in use in the Advance Education Program in Prosthodontics at the New York University College of Dentistry. Five new and 46 in-use TLDs (Nobel BioCare) from the implant kits of the graduate students were evaluated. One investigator was trained and calibrated before testing and after every 10 evaluations. A 3-jaw chuck was mounted on the center of a cap testing device by using the provided mounting screws. A LOCATOR torque driver was clamped into the chuck, and a torque wrench driver was attached to it. The device was placed on a flat table with direct overhead lighting that allowed the investigator to have a consistent view of the notches on the TLDs. A piece of cardboard was attached to the device to ensure that the investigator could not see the readouts. The blinded researcher inserted the wrench and applied the appropriate torque force at the designated notches while another researcher recorded the results. Two readings were made for each TLD at 15, 35, and 45 Ncm. A 2-way ANOVA and an intraclass correlation coefficient to test for intraclinician reliability were performed by using a statistical software program (α=.05). Two TLDs were damaged and not tested. The 2-way ANOVA demonstrated no significant difference (P>.05) between graduate students in year 1, 2, and 3 or between the autoclaved and new TLDs. The intraclass correlation coefficient was 0.861 for 15 Ncm, 0.589 for 35 Ncm, and 0.764 for 45 Ncm. In this in vitro study, new and used TLDs all met the recommended torque values. No significant differences were found among groups, suggesting that autoclaving and use did not affect the accuracy of the TLDs tested.


An assessment of the relationship between the World Health Organization HIV drug resistance early warning indicators and HIV drug resistance acquisition.
The World Health Organization (WHO)'s HIV drug resistance (HIVDR) early warning indicators (EWIs) measure antiretroviral therapy (ART)-site factors associated with HIVDR prevention, without HIVDR laboratory testing. We assessed the relationship between EWIs and HIVDR acquisition using data from British Columbia, Canada. Eligible patients were ART-naïve, were ≥ 19 years old, had initiated ART between 1 January 2000 and 31 December 2012, had ≥ 15 months of follow-up, and were without transmitted HIVDR. Patients were followed for acquired HIVDR until 31 March 2014, the last contact date, or death. We built logistic regression models to assess the associations and predictive ability of individual indicators and of the EWI Score (the number of indicators for which a patient did not meet the criteria) on HIVDR acquisition (to any class of HIVDR, lamivudine (3TC)/emtricitabine (FTC), nonnucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs) or protease inhibitors (PIs)]). All explored EWIs were associated with at least one class of HIVDR, with the exception of 'ART prescribing practices'. We observed a dose-response relationship between acquiring HIVDR to any antiretroviral class and an increasing EWI score in our predictive logistic regression model. The area under the curve was 0.848 (excellent discrimination). The adjusted odds ratios for acquiring any class of HIVDR for an EWI score of 1, 2 and ≥ 3 versus 0 were 2.30 [95% confidence Interval (CI) 1.21-4.38], 3.35 (95% CI: 1.86-6.03) and 7.26 (95% CI: 4.18-12.61), respectively. Several EWIs were associated with and predictive of HIVDR, supporting the WHO EWIs as a component of the HIVDR prevention method in settings where HIVDR testing is not routinely or widely available.


[Photodynamic therapy in angioid streaks].
To evaluate the efficacy and safety of photodynamic therapy in choroidal neovascularization associated with angioid streaks. We performed a retrospective study of eleven eyes (eight patients) with subfoveal, juxtafoveal or extrafoveal neovascularization, which received at least one session of photodynamic therapy. Treatment efficacy was evaluated by visual acuity (VA) testing, color photography and fluorescein angiography. The mean follow-up was 13.2 months. Ten eyes presented subfoveal neovascularization, one eye presented juxtafoveal and another eye extrafoveal neovascularization. VA was unchanged in two patients, increased in one patient, and decreased in eight patients following photodynamic therapy. Nine eyes presented conversion to a fibrotic disciform lesion, whereas leakage persisted in two eyes after one session of photodynamic therapy. Recurrence of choroidal neovascularization appeared in three eyes. Photodynamic therapy in choroidal neovascularization related to angioid streaks does not appear to alter the course of this disease, but it does slow its progression.


Insulin resistance and cardiovascular risk factors in 3- to 5-year-old overweight or obese children.
The increasing rate of overweight and obesity is alarming. The complications of overweight and obesity at a young age are largely unknown. We aimed to assess the prevalence of insulin resistance (IR) and cardiovascular risk factors among overweight and obese children aged 3-5 years. The study population consisted of 75 children (29 overweight, 46 obese). We performed anthropometry and bioelectrical impedance analysis as an indicator of body composition. IR was determined by the updated Homeostasis Model Assessment of Insulin Resistance (HOMA2-IR). Cardiovascular risk factors were defined by the presence of increased serum triglycerides, blood pressure, and HOMA2-IR and by a decreased serum HDL cholesterol. An elevated HOMA2-IR was found in 7.7% of the children. HOMA2-IR was correlated with body mass index (r = 0.63), waist circumference (r = 0.62) and percentage body fat (r = 0.58) (all p < 0.001). Cardiovascular risk factors were present in 6.9% (triglycerides) to 74.3% (hypertension) of the children. IR and cardiovascular risk factors are already evident in many 3- to 5-year-old overweight and obese children. IR is strongly related to body composition.


Population stochastic modelling (PSM)--an R package for mixed-effects models based on stochastic differential equations.
The extension from ordinary to stochastic differential equations (SDEs) in pharmacokinetic and pharmacodynamic (PK/PD) modelling is an emerging field and has been motivated in a number of articles [N.R. Kristensen, H. Madsen, S.H. Ingwersen, Using stochastic differential equations for PK/PD model development, J. Pharmacokinet. Pharmacodyn. 32 (February(1)) (2005) 109-141; C.W. Tornøe, R.V. Overgaard, H. Agersø, H.A. Nielsen, H. Madsen, E.N. Jonsson, Stochastic differential equations in NONMEM: implementation, application, and comparison with ordinary differential equations, Pharm. Res. 22 (August(8)) (2005) 1247-1258; R.V. Overgaard, N. Jonsson, C.W. Tornøe, H. Madsen, Non-linear mixed-effects models with stochastic differential equations: implementation of an estimation algorithm, J. Pharmacokinet. Pharmacodyn. 32 (February(1)) (2005) 85-107; U. Picchini, S. Ditlevsen, A. De Gaetano, Maximum likelihood estimation of a time-inhomogeneous stochastic differential model of glucose dynamics, Math. Med. Biol. 25 (June(2)) (2008) 141-155]. PK/PD models are traditionally based ordinary differential equations (ODEs) with an observation link that incorporates noise. This state-space formulation only allows for observation noise and not for system noise. Extending to SDEs allows for a Wiener noise component in the system equations. This additional noise component enables handling of autocorrelated residuals originating from natural variation or systematic model error. Autocorrelated residuals are often partly ignored in PK/PD modelling although violating the hypothesis for many standard statistical tests. This article presents a package for the statistical program R that is able to handle SDEs in a mixed-effects setting. The estimation method implemented is the FOCE(1) approximation to the population likelihood which is generated from the individual likelihoods that are approximated using the Extended Kalman Filter's one-step predictions.


Low-dose aminoglutethimide in postmenopausal breast cancer: effects on adrenal and thyroid hormone secretion.
Aminoglutethimide is effective in the treatment of breast cancer in postmenopausal patients as a result of its inhibition of aromatase. Its use is complicated by a number of endocrine side-effects which include the inhibition of thyroxine synthesis and inhibition of 11-steroid and 21-steroid hydroxylases. When aminoglutethimide is used at the conventional daily dose of 1000 mg in combination with 40 mg of hydrocortisone these effects can result in clinically significant hypothyroidism and increases in the serum levels of oestrone in response to stimulation of adrenocorticotropic hormone (ACTH). In the current study it was found that with twice daily treatment at the low dose of 125 mg aminoglutethimide plus 20 mg hydrocortisone there was no significant increase in oestrone levels after ACTH stimulation. In addition there was little effect on thyroid function: serum levels of triiodothyronine and thyroxine were unaffected whilst there was a marginally significant (P less than 0.05) increase in thyroid-levels were confined to those patients with pretreatment values greater than 2.5 mU/L, the most marked effect being in 1 patient whose pretreatment level was already outside the normal range.


The pharynx of Caenorhabditis elegans.
The anatomy of the pharynx of Caenorhabditis elegans has been reconstructed from electron micrographs of serial sections. The pharynx is used for pumping food into the gut, and is composed of 34 muscle cells, 9 marginal cells, 9 epithelial cells, 5 gland cells and 20 neurones. Three regions of specialization in the cuticle lining of the pharyngeal lumen may aid in the accumulation of food particles. A basement membrane isolates the pharynx from the rest of the animal, making the pharyngeal nervous system a nearly self-contained unit which is composed primarily of five classes of motor neurones and six classes of interneurones. Three other classes have also been described, which by their morphology appear to be neurosecretory and motor, motor and interneuronal, and lastly one pair that only innervates three of the marginal cells. Some classes of neurone have free endings just under the cuticle lining the lumen of the pharynx, suggesting that these are mechano- or proprio-receptive endings. The connectivity of these neurones has been described at the level of individual synaptic regions, and after combining this information with video taped observations of the pharynx pumping, some interpretations of how these neurones function have been offered.


A large-scale genetic analysis reveals a strong contribution of the HLA class II region to giant cell arteritis susceptibility.
We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05 × 10(-40), OR = 1.73). A multivariate model including class II amino acids of HLA-DRβ1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1(∗)04. An omnibus test on polymorphic amino acid positions highlighted DRβ1 13 (p = 4.08 × 10(-43)) and HLA-DQα1 47 (p = 4.02 × 10(-46)), 56, and 76 (both p = 1.84 × 10(-45)) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 × 10(-6), OR = 1.38), LRRC32 (rs10160518, p = 4.39 × 10(-6), OR = 1.20), and REL (rs115674477, p = 1.10 × 10(-5), OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function.


Can Angiotensin-Converting Enzyme Inhibitors Reduce the Incidence, Severity, and Duration of Radiation Proctitis?
To determine whether participants taking angiotensin-converting enzyme inhibitors (ACEIs) and treated with radical radiation therapy with neoadjuvant/adjuvant hormone therapy have less incidence, severity, and duration of radiation proctitis. A propensity score analysis of 817 patients who underwent radical radiation therapy with neoadjuvant or adjuvant hormone therapy as primary line management in a cohort study during 2009 to 2013 was conducted. Patients were stratified as follows: group 1, hypertensive patients taking ACEIs (as a study group); group 2, nonhypertensive patients not taking ACEIs; and group 3, hypertensive patients not taking ACEIs (both as control groups). The incidence, severity, and duration of proctitis were the main outcome. χ(2) tests, Mann-Whitney U tests, analysis of variance, risk ratio (RR), confidence interval (CI), Kaplan-Meier plots, and log-rank tests were used. The mean age of the participants was 68.91 years, with a follow-up time of 3.38 years. Based on disease and age-matched comparison, there was a statistically significant difference of proctitis grading between the 3 groups: χ(2) (8, n=308) = 72.52, P<.001. The Mann-Whitney U test indicated that grades of proctitis were significantly lower in hypertensive patients taking ACEIs than in nonhypertensive patients not taking ACEIs and hypertensive patients not taking ACEIs (P<.001). The risk ratio (RR) of proctitis in hypertensive patients taking ACEIs was significantly lower than in hypertensive patients not taking ACEIs (RR 0.40, 95% CI 0.30-0.53, P<.001) and in nonhypertensive patients not taking ACEIs (RR 0.58, 95% CI 0.44-0.77, P<.001). Time to event analysis revealed that hypertensive patients taking ACEIs were significantly different from the control groups (P<.0001). Furthermore, hypertensive patients taking ACEIs had significantly faster resolution of proctitis (P<.0001). Patients who were taking ACEIs were significantly less likely to have high-grade proctitis after radical radiation therapy with neoadjuvant or adjuvant hormone therapy (P<.001). The intake of ACEIs was significantly associated with a reduced risk of radiation-induced proctitis and also with acceleration of its resolution.


Metabolic syndrome and risk of esophageal adenocarcinoma in elderly patients in the United States: An analysis of SEER-Medicare data.
Metabolic syndrome (MetS) is associated with cancer risk and increases the risk of Barrett esophagus, which is the precursor lesion of esophageal adenocarcinoma (EA), primarily in the absence of gastroesophageal reflux disease (GERD). However, to the authors' knowledge, little is known regarding whether MetS is associated with the risk of EA. Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database, the authors evaluated whether MetS was associated with EA. A total of 3167 cases of EA were compared with individually matched population controls (5:1); a subset of 575 EA cases were able to be individually matched with 575 Barrett esophagus controls. MetS was defined using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes in the period 1 to 3 years before the diagnosis of EA or control selection. Unconditional logistic regression was used to estimate adjusted odds ratios and 95% confidence intervals. Potential effect modification by GERD symptoms and sex was examined in stratified models. EA was found to be significantly associated with MetS (odds ratio, 1.16; 95% confidence interval, 1.06-1.26) compared with population controls. In males, the association was restricted to those individuals without prior GERD; however, in females, MetS was found to be associated with EA regardless of GERD status. Effect modification by sex was observed (P for interaction = .01). MetS was not found to be associated with EA risk when compared with Barrett esophagus controls. In this older population, MetS was found to be associated with an increased risk of EA in males without GERD and females regardless of GERD status. Given the lack of an association when compared with Barrett esophagus controls, MetS may impact EA risk by primarily increasing the risk of the precursor lesion, Barrett esophagus. Cancer 2017;123:657-665. © 2016 American Cancer Society.


Mental contrasting with implementation intentions (MCII) improves physical activity and weight loss among stroke survivors over one year.
Stroke is the most common cause of physical impairment, and having already had a stroke dramatically increases the risk of having another one. Although greater physical activity lowers rates of stroke recurrence, patients often fail to act in line with this recommendation. The present intervention tested whether teaching the self-regulation strategy of mental contrasting (MC) with implementation intentions (II; MCII) improves stroke patients' physical activity and weight loss over 1 year compared with 2 information-only, control interventions. Participants were 183 stroke survivors who were capable of adhering to physical activity recommendations (age: M = 57 years; body mass index (BMI): M = 30). Patients were randomized to 3 conditions: unstructured information (n = 61), structured information (n = 62), and structured information plus MCII (n = 60). Patients' physical activity was assessed 50 weeks after they had left the rehabilitation hospital using the Baecke Inventory (Baecke, Burema, & Frijters, 1982), and by diaries provided at 2 consecutive weekends after 0, 10, 20, 30, 40, and 50 weeks. Diaries were also used to assess weight change. MCII participants were more physically active after the 50 weeks (Baecke Inventory: 2.74 vs. 2.59, p < .05; diary: 62.45 vs. 54.11, p = .03) and lost more weight (2.15 kg, p = .02) compared with participants in the control conditions. Teaching the MCII self-regulation strategy enhanced long-term physical activity in stroke patients relative to health information on its own. MCII thus qualifies as an effective intervention technique to improve secondary stroke prevention. (PsycINFO Database Record


How true outcomes-based commissioning can really 'liberate' healthcare services.
Healthcare systems all over the world face the challenge of variable care quality, inefficiency and increasing costs. A potential solution is value-based healthcare, where the aim is to achieve the best outcomes at the lowest cost. However, the measurement of outcomes that really reflect what matters most to patients is currently rudimentary. The International Consortium for Health Outcomes Measurement (ICHOM) has been developed to create globally consistent sets of outcomes that reflect what matters most to patients. Incorporating such sets of outcomes into capitated outcome-based and incentivised contracts will incentivise better outcomes and greater cost efficiency.


Service utilization and cost of implementing a comprehensive HIV prevention and care program among people who inject drugs in Delhi, India.
WHO, UNODC, and UNAIDS recommend a comprehensive package for prevention, treatment, and care of HIV among people who inject drugs (PWID). We describe the uptake of services and the cost of implementing a comprehensive package for HIV prevention, treatment, and care services in Delhi, India. A cohort of 3774 PWID were enrolled for a prospective HIV incidence study and provided the comprehensive package: HIV and hepatitis testing and counseling, hepatitis B (HB) vaccination, syndromic management of sexually transmitted infections, clean needles-syringes, condoms, abscess care, and education. Supplementary services comprising tea and snacks, bathing facilities, and medical consultations were also provided. PWID were referred to government services for antiretroviral therapy (ART), TB care, opioid substitution therapy, and drug dependence treatment/rehabilitation. The project spent USD 1,067,629.88 over 36 months of project implementation: 1.7% on capital costs, 3.9% on participant recruitment, 26.7% for project management, 49.9% on provision of services, and 17.8% on supplementary services. Provision of HIV prevention and care services cost the project USD 140.41/PWID/year. 95.3% PWID were tested for HIV. Of the HIV-positive clients, only 17.8% registered for ART services after repeated follow-up. Reasons for not seeking ART services included not feeling sick, need for multiple visits to the clinic, and long waiting times. 61.8% of the PWID underwent HB testing. Of the 2106 PWID eligible for HB vaccination, 81% initiated the vaccination schedule, but only 29% completed all three doses, despite intensive follow-up by outreach workers. PWID took an average of 8 clean needles-syringes/PWID/year over the project duration, with a mid-project high of 16 needles-syringes/PWID/year. PWID continued to also procure needles from other sources, such as chemists. One hundred five PWID were referred to OST services and 267 for rehabilitation services. A comprehensive HIV prevention, treatment, and care package is challenging to implement. Extensive efforts are needed to ensure the uptake of and retention in services for PWID; peer educators and outreach workers are required on a continuous basis. Services need to be tailored to client needs, considering clinic timing and distance from hotspots. Programs may consider provision of ART services at selected drop-in centers to increase uptake.


Structural requirements for TLR4-mediated LPS signalling: a biological role for LPS modifications.
Cells of the mucosal lining are the first to encounter invading bacteria during infection, and as such, they have developed numerous ways of detecting microbial intruders. Recently, we showed that epithelial cells recognize lipopolysaccharide (LPS) through the CD14-Toll-like receptor (TLR)-4 complex. Here, we identify the substructures of LPS that are recognized by the TLR4 receptor complex. In contrast to lipid A, the O-antigen does not mediate an inflammatory response; rather it interferes with the lipid A recognition. An Escherichia coli strain genetically modified to express penta-acylated lipid A not only showed reduced immunogenicity, but was also found to inhibit pro-inflammatory signalling induced by wild-type E. coli (hexa-acylated lipid A) as well as LPS from other bacteria of the Enterobacteriaceae family. Furthermore, penta-acylated LPS from Pseudomonas aeruginosa acted as an antagonist to hexa-acylated E. coli LPS, as did E. coli, as shown by its inhibitory effect on IL-8 production in stimulated cells. Hypo-acylated lipid A, such as that of P. aeruginosa, is found in several species within the gut microflora as well as in several bacteria causing chronic infections. Thus, our results suggest that the composition of the microflora may be important in modulating pro-inflammatory signalling in epithelial cells under normal as well as pathologic conditions.


Wounding: the primary mode of Seoul virus transmission among male Norway rats.
In rodent populations, males are more likely to be infected with hantaviruses and to engage in aggression than are females. To assess the relationship between aggression and Seoul virus infection, Norway rats were trapped in Baltimore, Maryland and wounding, infection status, and steroid hormone concentrations were examined. Older males and males with high-grade wounds were more likely to have IgG antibody to Seoul, to shed virus in saliva, urine, and feces, and to have viral RNA in organs than either juveniles or adult males with less severe wounds. In contrast, neither age nor wounding predicted virus shedding among females. Although viral antigen was not identified in the brain, viral protein was detected in the gonads and adrenal glands of adult males. Males with more severe wounds had higher testosterone concentrations than males with no or low-grade wounds. Because wounding, testosterone, and virus shedding are associated among males, aggression may be the primary mode of Seoul virus transmission among male, but not female, Norway rats.


Weight Loss and the Prevention of Weight Regain: Evaluation of a Treatment Model of Exercise Self-Regulation Generalizing to Controlled Eating.
For decades, behavioral weight-loss treatments have been unsuccessful beyond the short term. Development and testing of innovative, theoretically based methods that depart from current failed practices is a priority for behavioral medicine. To evaluate a new, theory-based protocol in which exercise support methods are employed to facilitate improvements in psychosocial predictors of controlled eating and sustained weight loss. Women with obesity were randomized into either a comparison treatment that incorporated a print manual plus telephone follow-ups (n = 55) or an experimental treatment of The Coach Approach exercise-support protocol followed after 2 months by group nutrition sessions focused on generalizing self-regulatory skills from an exercise support to a controlled eating context (n = 55). Repeated-measures analysis of variance contrasted group changes in weight, physical activity, fruit and vegetable intake, mood, and exercise- and eating-related self-regulation and self-efficacy over 24 months. Regression analyses determined salient interrelations of change scores over both the weight-loss phase (baseline-month 6) and weight-loss maintenance phase (month 6-month 24). Improvements in all psychological measures, physical activity, and fruit and vegetable intake were significantly greater in the experimental group where a mean weight loss of 5.7 kg (6.1% of initial body weight) occurred at month 6, and was largely maintained at a loss of 5.1 kg (5.4%) through the full 24 months of the study. After establishing temporal intervals for changes in self-regulation, self-efficacy, and mood that best predicted improvements in physical activity and eating, a consolidated multiple mediation model suggested that change in self-regulation best predicted weight loss, whereas change in self-efficacy best predicted maintenance of lost weight. Because for most participants loss of weight remained greater than that required for health benefits, and costs for treatment administration were comparatively low, the experimental protocol was considered successful. After sufficient replication, physician referral and applications within health promotion and wellness settings should be considered.


The HIV-1 leader RNA conformational switch regulates RNA dimerization but does not regulate mRNA translation.
The untranslated leader RNA is the most conserved part of the human immunodeficiency virus type I (HIV-1) genome. It contains many regulatory motifs that mediate a variety of steps in the viral life cycle. Previous work showed that the full-length leader RNA can adopt two alternative structures: a long distance interaction (LDI) and a branched multiple-hairpin (BMH) structure. The BMH structure exposes the dimer initiation site (DIS) hairpin, whereas this motif is occluded in the LDI structure. Consequently, these structures differ in their capacity to form RNA dimers in vitro. The BMH structure is dimerization-competent, due to DIS hairpin formation, but also presents the splice donor (SD) and RNA packaging (Psi) hairpins. In the LDI structure, an extended RNA packaging (Psi(E)) hairpin is folded, which includes the splice donor site and gag coding sequences. The gag initiation codon is engaged in a long distance base pairing interaction with sequences in the upstream U5 region in the BMH structure, thus forming the evolutionarily conserved U5-AUG duplex. Therefore, the LDI-BMH equilibrium may affect not only the process of RNA dimer formation but also translation initiation. In this study, we designed mutations in the 3'-terminal region of the leader RNA that alter the equilibrium of the LDI-BMH structures. The mutant leader RNAs are affected in RNA dimer formation, but not in their translation efficiency. These results indicate that the LDI-BMH status does not regulate HIV-1 RNA translation, despite the differential presentation of the gag initiation codon in both leader RNA structures.


Quality of life in nursing homes following the group-living principle: a pilot study measuring the quality of life from the subjective perspective of dependent-living elderly.
The purpose of this study was to analyze the subjective quality of life in elderly people in nursing homes following the group-living principle. The Nottingham Health Profile (NHP) was employed. A comparison with the German representative subsample of elderly living independently age-group over 75 was conducted. Psychometric properties and appropriateness were analyzed. The mean NHP scale scores suggest an acceptable perception of residents' quality of life (n = 145). Our findings indicate that with exception of the NHP scale physical mobility, the perceived quality of life of group-living nursing home residents and independently living elderly over 75 years (German reference values) are nearly on the same level. With the exception of the subscale social isolation, the results of the current study show that the NHP is suitable for assessing the subjective quality of life in nursing home environments. The results of the first pilot study in the research field of subjective quality of life in group-living nursing homes are presented. The study focused on very old people with age-specific reduced physical and mental abilities. The NHP should also be considered as a reliable, valid and useful alternative to resident satisfaction surveys.


A randomised controlled trial to compare the clinical and cost-effectiveness of prism glasses, visual search training and standard care in patients with hemianopia following stroke: a protocol.
Homonymous hemianopia is a common and disabling visual problem after stroke. Currently, prism glasses and visual scanning training are proposed to improve it. The aim of this trial is to determine the effectiveness of these interventions compared to standard care. The trial will be a multicentre three arm individually randomised controlled trial with independent assessment at 6 week, 12 week and 26 week post-randomisation. Recruitment will occur in hospital, outpatient and primary care settings in UK hospital trusts. A total of 105 patients with homonymous hemianopia and without ocular motility impairment, visual inattention or pre-existent visual field impairment will be randomised to one of three balanced groups. Randomisation lists will be stratified by site and hemianopia level (partial or complete) and created using simple block randomisation by an independent statistician. Allocations will be disclosed to patients by the treating clinician, maintaining blinding for outcome assessment. The primary outcome will be change in visual field assessment from baseline to 26 weeks. Secondary measures will include the Rivermead Mobility Index, Visual Function Questionnaire 25/10, Nottingham Extended Activities of Daily Living, Euro Qual-5D and Short Form-12 questionnaires. Analysis will be by intention to treat. This study has been developed and supported by the UK Stroke Research Network Clinical Studies Group working with service users. Multicentre ethical approval was obtained through the North West 6 Research ethics committee (Reference 10/H1003/119). The trial is funded by the UK Stroke Association. Trial Registration: Current Controlled Trials ISRCTN05956042. Dissemination will consider usual scholarly options of conference presentation and journal publication in addition to patient and public dissemination with lay summaries and articles. Current Controlled Trials ISRCTN05956042.


Amplification and linear summation of synaptic effects on motoneuron firing rate.
The aim of this study was to measure the effects of synaptic input on motoneuron firing rate in an unanesthetized cat preparation, where activation of voltage-sensitive dendritic conductances may influence synaptic integration and repetitive firing. In anesthetized cats, the change in firing rate produced by a steady synaptic input is approximately equal to the product of the effective synaptic current measured at the resting potential (I(N)) and the slope of the linear relation between somatically injected current and motoneuron discharge rate (f-I slope). However, previous studies in the unanesthetized decerebrate cat indicate that firing rate modulation may be strongly influenced by voltage-dependent dendritic conductances. To quantify the effects of these conductances on motoneuron firing behavior, we injected suprathreshold current steps into medial gastrocnemius motoneurons of decerebrate cats and measured the changes in firing rate produced by superimposed excitatory synaptic input. In the same cells, we measured I(N) and the f-I slope to determine the predicted change in firing rate (Delta F = I(N) * f-I slope). In contrast to previous results in anesthetized cats, synaptically induced changes in motoneuron firing rate were greater-than-predicted. This enhanced effect indicates that additional inward current was present during repetitive firing. This additional inward current amplified the effective synaptic currents produced by two different excitatory sources, group Ia muscle spindle afferents and caudal cutaneous sural nerve afferents. There was a trend toward more prevalent amplification of the Ia input (14/16 cells) than the sural input (11/16 cells). However, in those cells where both inputs were amplified (10/16 cells), amplification was similar in magnitude for each source. When these two synaptic inputs were simultaneously activated, their combined effect was generally very close to the linear sum of their amplified individual effects. Linear summation is also observed in medial gastrocnemius motoneurons of anesthetized cats, where amplification is not present. This similarity suggests that amplification does not disturb the processes of synaptic integration. Linear summation of amplified input was evident for the two segmental inputs studied here. If these phenomena also hold for other synaptic sources, then the presence of active dendritic conductances underlying amplification might enable motoneurons to integrate multiple synaptic inputs and drive motoneuron firing rates throughout the entire physiological range in a relatively simple fashion.


Circular RNA profiling reveals circRNA1656 as a novel biomarker in high grade serous ovarian cancer.
Circular RNA (circRNA) is a class of endogenous non-coding RNAs that are closely related to the pathogenesis of many human diseases, particularly cancer. However, the characterization of circRNAs in high-grade serous ovarian cancer (HGSOC) remains unknown. This study aimed to investigate the expression profile of circRNAs in HGSOC. Expression profiles of circRNAs differential expression based on circRNAs High-throughput sequencing were identified in 3 HGSOC specimens and 3 normal ovarian tissues. A total of 710 differentially expressed circRNAs were found (354 expressions up-regulated and 356 expressions down-regulated). CircRNA sequencing data were verified by qRT-PCR in HGSOC tissue and benign ovarian lesions. Differential expression of 7 circRNAs (circRNA385, circRNA2058, circRNA3336, circRNA2606, circRNA1656, circRNA1312 and circRNA7474) in HGSOC tissue was confirmed by qRT-PCR. Among them, circRNA1656 showed the highest fold change. qRT-PCR was used to verify the expression of circRNA1656 in ovarian cancer cell lines. In order to analyze the relationship between circRNA1656 expression and clinical pathological biological characteristics of HGSOC, qRT-PCR was used to verify the expression of circRNA1656 in 60 HGSOC tissues compared with 60 benign ovarian lesions. The expression of circRNA1656 was down-regulated in HGSOC tissues and ovarian cancer cell lines, and correlated with the FIGO stage of HGSOC. circRNA1656 has the potential to serve as a novel tumor marker for HGSOC.


Photophysical properties of an alkyne-bridged bis(zinc porphyrin)-perylene bis(dicarboximide) derivative.
We report the synthesis, electrochemistry, and photophysical properties of a new donor-acceptor-donor molecule in which the meso carbon atoms of two zinc porphyrin (POR) units are linked through ethynylene bridges to the 1,7-positions of a central perylene-3,4:9,10-bis(dicarboximide) (PDI). In contrast to previously studied systems incorporating POR and PDI groups, this alkyne-based derivative shows evidence of through-bond electronic coupling in the ground state; the new chromophore exhibits absorption features similar to those of its constituent parts as well as lower energy features (at wavelengths up to ca. 1000 nm), presumably arising from donor-acceptor interactions. Transient absorption measurements show that excitation at several visible and near-IR wavelengths results in the formation of an excited-state species with a lifetime of 290 ps in 1% (v/v) pyridine in toluene. The absorption spectrum of this species resembles the sum of the spectra for the chemically generated radical cation and radical anion of the chromophore. The chromophore shows moderate two-photon absorption cross sections (2000-7000 GM) at photon wavelengths close to the onset of its low-energy one-photon absorption feature.


Monitor alarm fatigue: standardizing use of physiological monitors and decreasing nuisance alarms.
Reliance on physiological monitors to continuously "watch" patients and to alert the nurse when a serious rhythm problem occurs is standard practice on monitored units. Alarms are intended to alert clinicians to deviations from a predetermined "normal" status. However, alarm fatigue may occur when the sheer number of monitor alarms overwhelms clinicians, possibly leading to alarms being disabled, silenced, or ignored. Excessive numbers of monitor alarms and fear that nurses have become desensitized to these alarms was the impetus for a unit-based quality improvement project. Small tests of change to improve alarm management were conducted on a medical progressive care unit. The types and frequency of monitor alarms in the unit were assessed. Nurses were trained to individualize patients' alarm parameter limits and levels. Monitor software was modified to promote audibility of critical alarms. Critical monitor alarms were reduced 43% from baseline data. The reduction of alarms could be attributed to adjustment of monitor alarm defaults, careful assessment and customization of monitor alarm parameter limits and levels, and implementation of an interdisciplinary monitor policy. Although alarms are important and sometimes life-saving, they can compromise patients' safety if ignored. This unit-based quality improvement initiative was beneficial as a starting point for revamping alarm management throughout the institution.


Presence of Atrial Fibrillation at the Time of Dialysis Initiation Is Associated with Mortality and Cardiovascular Events.
Death in dialysis patients results mainly from cardiovascular and cerebrovascular diseases. To our knowledge, no prospective study has compared the rates of mortality or cardiovascular events between patients with and without atrial fibrillation (AF) at the time of dialysis initiation. This study included 1,516 patients who were initiated into dialysis between October 2011 and August 2013. Rates of mortality and cardiovascular events were compared between patients with and without AF, and between AF patients with and without warfarin (WF) treatment. The study comprised 1,025 men and 491 women with a mean age of 67.5 ± 13.1. Of these patients, 93 had AF, while 1,423 did not; 22.6% of the former group and 9.7% of the latter group died by March 2014 (p < 0.01). Cardiovascular events occurred in 34.4% of patients with AF and 15.1% of patients without (p < 0.01). Even after adjustments for various factors, AF remained an independent risk factor for mortality (hazard ratio (HR) 1.873, 95% CI 1.168-3.002, p < 0.01). It was also an independent risk factor for cardiovascular events (HR 1.872, 95% CI 1.262-2.778, p < 0.01). No difference in any parameter was noted between the groups that did and did not receive WF treatment. Patients with AF at the time of dialysis initiation show a poor prognosis and are at high risk of cardiovascular events. Therefore, AF should be taken into consideration in dialysis patients.


Projecting Cancer Incidence for 2025 in the 2 Largest Populated Cities in Vietnam.
The population size and projected demographics of Vietnam's 2 largest cities, Ho Chi Minh City (HCMC) and Hanoi, will change dramatically over the next decade. Demographic changes in an aging population coupled with income growth and changes in lifestyle will result in a very different distribution of common cancers in the future. The study aimed to project the number of cancer incidence in the 2 largest populated cities in Vietnam for the year 2025. Cancer incidence data from 2004 to 2013 collected from population-based cancer registries in these 2 cities were provided by Vietnam National Cancer Institute. Incidence cases in 2013 and the previous decades average annual percent changes of age-standardized cancer incidence rates combined with expected population growth were modeled to project cancer incidence for each cancer site by gender to 2025. A substantial double in cancer incidence from 2013 to 2025 resulted from a growing and aging population in HCMC and Hanoi. Lung, colorectum, breast, thyroid, and liver cancers, which represent 67% of the overall cancer burden, are projected to become the leading cancer diagnoses by 2025 regardless of genders. For men, the leading cancer sites in 2025 are predicted to be lung, colorectum, esophagus, liver, and pharynx cancer, and among women, they are expected to be breast, thyroid, colorectum, lung, and cervical cancer. We projected an epidemiological transition from infectious-associated cancers to a high burden of cancers that have mainly been attributed to lifestyle in both cities. We predicted that with 16.9% growth in the overall population and dramatic aging with these 2 urban centers, the burdens of cancer incidence will increase sharply in both cities over the next decades. Data on projections of cancer incidence in both cities provide useful insights for directing appropriate policies and cancer control programs in Vietnam.


The complete genome sequence of Xanthomonas albilineans provides new insights into the reductive genome evolution of the xylem-limited Xanthomonadaceae.
The Xanthomonadaceae family contains two xylem-limited plant pathogenic bacterial species, Xanthomonas albilineans and Xylella fastidiosa. X. fastidiosa was the first completely sequenced plant pathogen. It is insect-vectored, has a reduced genome and does not possess hrp genes which encode a Type III secretion system found in most plant pathogenic bacteria. X. fastidiosa was excluded from the Xanthomonas group based on phylogenetic analyses with rRNA sequences. The complete genome of X. albilineans was sequenced and annotated. X. albilineans, which is not known to be insect-vectored, also has a reduced genome and does not possess hrp genes. Phylogenetic analysis using X. albilineans genomic sequences showed that X. fastidiosa belongs to the Xanthomonas group. Order of divergence of the Xanthomonadaceae revealed that X. albilineans and X. fastidiosa experienced a convergent reductive genome evolution during their descent from the progenitor of the Xanthomonas genus. Reductive genome evolutions of the two xylem-limited Xanthomonadaceae were compared in light of their genome characteristics and those of obligate animal symbionts and pathogens. The two xylem-limited Xanthomonadaceae, during their descent from a common ancestral parent, experienced a convergent reductive genome evolution. Adaptation to the nutrient-poor xylem elements and to the cloistered environmental niche of xylem vessels probably favoured this convergent evolution. However, genome characteristics of X. albilineans differ from those of X. fastidiosa and obligate animal symbionts and pathogens, indicating that a distinctive process was responsible for the reductive genome evolution in this pathogen. The possible role in genome reduction of the unique toxin albicidin, produced by X. albilineans, is discussed.


Speaker identification utilizing noncontemporary speech.
The noncontemporariness of speech is important to both of the two general approaches to speaker identification. Ear-witness identification is one of them; in that instance, the time at which the identification is made is noncontemporary. A substantial amount of research has been carried out on this relationship and it now is well established that an auditor's memory for a voice decays sharply over time. It is the second approach to speaker identification which is of present interest. In this case, samples of a speaker's utterances are obtained at different points in time. For example, a threat call will be recorded and then sometime later (often very much later), a suspect' s exemplar recording will be obtained. In this instance, it is the speech samples that are noncontemporary and they are the materials that are subjected to some form of speaker identification. Prevailing opinion is that noncontemporary speech itself poses just as difficult a challenge to the identification process as does the listener's memory decay in earwitness identification. Accordingly, series of aural-perceptual speaker identification projects were carried out on noncontemporary speech: first, two with latencies of 4 and 8 weeks followed by 4 and 32 weeks plus two more with the pairs separated by 6 and 20 years. Mean correct noncontemporary identification initially dropped to 75-80% at week 4 and this general level was sustained for up to six years. It was only after 20 years had elapsed that a significant drop (to 33%) was noted. It can be concluded that a listener's competency in identifying noncontemporary speech samples will show only modest decay over rather substantial periods of time and, hence, this factor should have only a minimal negative effect on the speaker identification process.


Antifibrinolytic therapy for preventing oral bleeding in patients with haemophilia or Von Willebrand disease undergoing minor oral surgery or dental extractions.
Minor oral surgery or dental extractions (oral or dental procedures) are widely performed and can be complicated by hazardous oral bleeding, especially in people with an inherited bleeding disorder such as haemophilia or Von Willebrand disease (VWD). The amount and severity of singular bleedings depend on disease-related factors, such as the severity of the haemophilia, both local and systemic patient factors (such as periodontal inflammation, vasculopathy or platelet dysfunction) and intervention-related factors (such as the type and number of teeth extracted or the dimension of the wound surface). Similar to local haemostatic measures and suturing, antifibrinolytic therapy is a cheap, safe and potentially effective treatment to prevent bleeding complications in individuals with bleeding disorders undergoing oral or dental procedures. However, a systematic review of trials reporting outcomes after oral surgery or a dental procedure in people with an inherited bleeding disorder, with or without, the use of antifibrinolytic agents has not been performed to date. This is an update of a previously published Cochrane Review. Primarily, we aim to assess the efficacy of antifibrinolytic agents to prevent bleeding complications in people with haemophilia or VWD undergoing oral or dental procedures.Secondary objectives are to assess if antifibrinolytic agents can replace or reduce the need for clotting factor concentrate therapy in people with haemophilia or VWD and to establish the effects of these agents on bleeding in oral or dental procedures for each of these patient populations. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches of the Cochrane Central Register of Controlled Trials (CENTRAL), of MEDLINE and from handsearching of journals and conference abstract books. We additionally searched the reference lists of relevant articles and reviews. We searched PubMed, Embase, Cinahl and the Cochrane Library. Additional searches were performed in ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP).Date of last search of the Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register: 01 March 2019. Randomised and quasi-randomised controlled trials in people with haemophilia or VWD undergoing oral or dental procedures using antifibrinolytic agents (tranexamic acid or epsilon aminocaproic acid (EACA)) to prevent perioperative bleeding compared to no intervention or usual care with or without placebo. Two authors independently screened the titles and abstracts of all identified articles. Full texts were obtained for potentially relevant abstracts and two authors independently assessed these for inclusion based on the selection criteria. A third author verified trial eligibility. Two authors independently performed data extraction and risk of bias assessments using standardised forms. While there were no eligible trials in people with VWD identified, two randomised, double-blind, placebo-controlled trials (total of 59 participants) in people with haemophilia undergoing dental extraction were included. One trial of tranexamic acid published in 1972 included 28 participants with mild, moderate or severe haemophilia A and B and one of EACA published in 1971 included 31 people with haemophilia with factor VIII or factor IX levels less than 15%. Overall, the two included trials showed a beneficial effect of tranexamic acid and EACA, administered systemically, in reducing the number of bleedings, the amount of blood loss and the need for therapeutic clotting factor concentrates. Regarding postoperative bleeding, the tranexamic acid trial showed a risk difference (RD) of -0.64 (95% confidence interval (CI) -0.93 to - 0.36) and the EACA trial a RD of -0.50 (95% CI 0.77 to -0.22). The combined RD of both trials was -0.57 (95% CI -0.76 to -0.37), with the quality of the evidence (GRADE) for this outcome is rated as moderate. Side effects occurred once and required stopping EACA (combined RD of -0.03 (95% CI -0.08 to 0.13). There was heterogeneity between the two trials regarding the proportion of people with severe haemophilia included, the concomitant standard therapy and fibrinolytic agent treatment regimens used. We cannot exclude that a selection bias has occurred in the EACA trial, but overall the risk of bias appeared to be low for both trials. Despite the discovery of a beneficial effect of systemically administered tranexamic acid and EACA in preventing postoperative bleeding in people with haemophilia undergoing dental extraction, the limited number of randomised controlled trials identified, in combination with the small sample sizes and heterogeneity regarding standard therapy and treatment regimens between the two trials, do not allow us to conclude definite efficacy of antifibrinolytic therapy in oral or dental procedures in people with haemophilia. No trials were identified in people with VWD.