Bayesian State Space Modeling of Physical Processes in Industrial Hygiene.
Exposure assessment models are deterministic models derived from physical-chemical laws. In real workplace settings, chemical concentration measurements can be noisy and indirectly measured. In addition, inference on important parameters such as generation and ventilation rates are usually of interest since they are difficult to obtain. In this article, we outline a flexible Bayesian framework for parameter inference and exposure prediction. In particular, we devise Bayesian state space models by discretizing the differential equation models and incorporating information from observed measurements and expert prior knowledge. At each time point, a new measurement is available that contains some noise, so using the physical model and the available measurements, we try to obtain a more accurate state estimate, which can be called filtering. We consider Monte Carlo sampling methods for parameter estimation and inference under nonlinear and non-Gaussian assumptions. The performance of the different methods is studied on computer-simulated and controlled laboratory-generated data. We consider some commonly used exposure models representing different physical hypotheses. Supplementary materials for this article are available online.


Peroxisome proliferator-activated receptors as molecular targets for drug therapy.
Peroxisome proliferator-activated receptors (PPAR) are a family of nuclear receptors that regulate lipid and carbohydrate metabolism in response to extracellular fatty acids and their metabolites. They are crucial in the regulation of fat storage, besides having a potential role in insulin resistance syndrome. They have clinical relevance in understanding the cause and in development of drugs in common clinical conditions such as type 2 diabetes mellitus, cellular growth and neoplasia. Three types of receptors were identified: PPAR alpha, gamma and delta. Fibrate group of lipid lowering agents bind to the alpha isoform and glitazone group of insulin sensitizers to gamma isoform. Further advances can result in new drugs for atherosclerosis, malignancies and diabetes mellitus.


Using hydrophilic adhesive tape for collection of evidence for forensic DNA analysis.
Known exemplar samples of human DNA have traditionally been body fluids, such as blood, saliva, and semen. In each case, the presence of water is a risk for the bacterial growth, which may degrade the DNA evidence. In this study, the authors have developed a method that employed a hydrophilic adhesive tape (HAT) for collecting DNA evidence. The HAT method was used to remove surface cells from relatively hairless areas on the body. The area examined were ankle, arm, behind the ear, between fingers and back of the neck. The HAT was then dissolved in the extraction buffer. DNA typing was performed at vWA, THo1, F13A1, and FES loci using the short tandem repeat (STR) analysis. Our results show that the samples collected from ear give the best results with a success rate of 100%. All subjects tested by this method had known STR genotypes established from buccal swabs. The authors' results suggest that the HAT method can be used as a less invasive method for collecting biological evidence for forensic DNA analysis. In addition, this collection method should reduce the risk of DNA degradation due to the moisture, which is encountered using conventional collecting methods.


Expression of the genes encoding the rat renal insulin-like growth factor-I system.
Insulin-like growth factor-I (IGF-I) modulates renal function, growth, and repair. IGF-I produced in the kidney is one component of the intrarenal IGF-I system comprising the IGF-I receptor (IGF-IR) and six IGF-binding proteins (IGFBP). Because of the physiologic importance of IGF-I and its potential therapeutic properties, the renal sites of mRNA synthesis for IGF-I, IGF-IR, and IGFBP-I through IGFBP-5 were characterized in rat kidney by in situ hybridization. Anatomical heterogeneity was prominent. IGF-I mRNA was present in the thick ascending limb of Henle in the outer medulla, whereas IGF-IR mRNA was diffusely present at low levels throughout the kidney. IGFBP-I mRNA was localized to cells within the distal convoluted tubules as well as the thick ascending limb of Henle. IGFBP-2 mRNA was expressed in glomeruli, medullary ray collecting ducts, pelvic smooth muscle and uroepithelium, and the papilla tip; IGFBP-3 mRNA was localized to the cortical interstitium, whereas IGFBP-4 mRNA was expressed in proximal tubules, medullary ray collecting ducts, and glomeruli. IGFBP-5 was strongly positive throughout the medulla with lesser expression in the distal convoluted tubules and glomeruli. This study highlights the complexity of the intrarenal IGF-I system. The striking heterogeneity of IGFBP gene expression suggests that the various IGFBP may have diverse modulatory effects on the action of IGF-I or discrete effects of their own.


Evaluating the Impact of Intensive Case Management for Severe Vocational Injuries on Work Incapacity and Costs.
Purpose This study investigates the impact of an intensive case management program on sick leave days, permanent work incapacity levels and treatment costs for severe vocational injuries set up by the French National Insurance Fund in five health insurance districts. Methods The method employed relies on a four-step matching procedure combining Coarsened Exact Matching and Propensity Score Matching, based on an original administrative dataset. Average Treatment effects on the Treated were estimated using a parametric model with a large set of covariates. Results After one-year follow-up, workers in the treatment group had higher sickness absence rates, with 22 extra days, and the program led to 2.7 (95% CI 2.3-3.1) times more diagnoses of permanent work incapacity in the treatment group. With an estimated yearly operational cost of 2,722 € per treated worker, the average total extra treatment cost was 4,569 € for treated workers, which corresponds to a cost increase of 29.2% for the insurance fund. Conclusions The higher costs found for the treatment group are mainly due to longer sick leave duration for the moderate severity group, implying higher cash transfers in the form of one-off indemnities. Even though workers in the treated group have more diagnoses of permanent work incapacity, the difference of severity between groups is small. Our results on longer sick leave duration are partly to be explained by interactions between the case managers and the occupational physicians that encouraged patients to stay longer off-work for better recovery, despite the higher costs that this represented for the insurance fund and the well-documented adverse side effects of longer periods off-work.


Prenatal mood and anxiety disorders and associated cytokine changes.
We examined whether women with prenatal mood and anxiety disorders would exhibit differential pro- and anti-inflammatory marker trajectories during the prenatal and postpartum periods compared to women without these disorders. Approximately 179 pregnant women participated in a longitudinal study conducted in two urban areas. Blood samples for inflammatory markers were collected at six study visits. The Structured Clinical Interview for the DSM-IV (SCID) was administered to participants scoring above cutoffs on anxiety and depression. Pregnant women with SCID Axis I diagnoses of mood and/or anxiety disorders were compared to other participants on inflammatory markers. Multilevel modeling tested associations between SCID diagnoses and within-person interleukin (IL)6 and IL10 trajectories. Prenatal SCID diagnoses were associated with linear, quadratic and cubic change in IL6 from prenatal to postpartum timepoints. Women with a prenatal SCID diagnosis had steeper decreases and increases in IL6 during prenatal and postpartum periods. SCID diagnoses were associated with lower IL10 in mid-pregnancy to postpartum (b = -0.078, SE = 0.019; p = .015). Future studies would benefit from a larger sample size and a larger number of participants with SCID diagnoses. Future research should also examine whether different prenatal Axis 1 diagnoses are associated with different patterns of immune response in pregnancy. Pregnant women with prenatal mood and anxiety disorders had greater fluctuations in IL6 across prenatal and postpartum periods and lower IL10 through pregnancy and postpartum. They may have different proinflammatory states that remain after birth without a reciprocal anti-inflammatory response.


T cells expressing the lupus susceptibility allele Pbx1d enhance autoimmunity and atherosclerosis in dyslipidemic mice.
Patients with systemic lupus erythematosus (SLE) present a high incidence of atherosclerosis, which contributes significantly to morbidity and mortality in this autoimmune disease. An impaired balance between regulatory (Treg) and follicular helper (Tfh) CD4+ T cells is shared by both diseases. However, whether there are common mechanisms of CD4+ T cell dysregulation between SLE and atherosclerosis remains unclear. Pre-B cell leukemia transcription factor 1 isoform d (Pbx1d) is a lupus susceptibility gene that regulates Tfh cell expansion and Treg cell homeostasis. Here, we investigated the role of T cells overexpressing Pbx1d in low-density lipoprotein receptor-deficient (Ldlr-/-) mice fed with a high-fat diet, an experimental model for atherosclerosis. Pbx1d-transgenic T cells exacerbated some phenotypes of atherosclerosis, which were associated with higher autoantibody production, increased Tfh cell frequency, and impaired Treg cell regulation, in Ldlr-/- mice as compared with control T cells. In addition, we showed that dyslipidemia and Pbx1d-transgenic expression independently impaired the differentiation and function of Treg cells in vitro, suggesting a gene/environment additive effect. Thus, our results suggest that the combination of Pbx1d expression in T cells and dyslipidemia exacerbates both atherosclerosis and autoimmunity, at least in part through a dysregulation of Treg cell homeostasis.


Lipocortin (Annexin) I heterotetramer binds to purine RNA and pyrimidine DNA.
Lipocortin I-like protein with a molecular weight of 94,000 Da as judged by Western analysis was found to bind to ssDNA rather than to dsDNA in a Ca(2+)-dependent manner. This protein was also bound to [(32)P]poly(rA) and [(32)P]poly(rG) as measured by EMSA. Poly(rG), poly(rA), poly(dC), and poly(dT) were competitive against binding of either [(32)P]poly(rA) or [(32)P]poly(rG), while poly(rC), poly(rU), and poly(dA) were less effective binding competitors. The binding of this protein to poly(rA) or poly(rG) was inhibited by immunoprecipitable anti-lipocortin I (calpactin II) and anti-S100 protein antibodies, but not by an anti-Ig antibody. Phospholipids such as phosphatidylserine and phosphatidylinositol enhanced the binding of lipocortin I to poly(rA). Taken together, our present observations suggest that the lipocortin I-S100 protein heterotetramer binds to either purine RNAs or pyrimidine ssDNAs in a Ca(2+)- and phospholipid-dependent manner.


Social environments, risk-taking and injury in farm adolescents.
Farm environments are especially hazardous for young people. While much is known about acute physical causes of traumatic farm injury, little is known about social factors that may underlie their aetiology. In a nationally representative sample of young Canadians aged 11-15 years, we described and compared farm and non-farm adolescents in terms of the qualities of their social environments, engagement in overt multiple risk-taking as well as how such exposures relate aetiologically to their reported injury experiences. Cross-sectional analysis of survey reports from the 2014 (Cycle 7) Canadian Health Behaviour in School-Aged Children study was conducted. Children (n=2567; 2534 weighted) who reported living or working on farms were matched within schools in a 1:1 ratio with children not living or working on farms. Scales examining quality of social environments and overt risk-taking were compared between the two groups, stratified by gender. We then related the occurrence of any serious injury to these social exposures in direct and interactive models. Farm and non-farm children reported social environments that were quite similar, with the exception of overt multiple risk-taking, which was demonstrably higher in farm children of both genders. Engagement in overt risk-taking, but not the other social environmental factors, was strongly and consistently associated with risks for serious injury in farm as well as non-farm children, particularly among males. Study findings highlight the strength of associations between overt multiple risk-taking and injury among farm children. This appears to be a normative aspect of adolescent farm culture.


Alpha-difluoromethylornithine inhibits N-nitrosomethylbenzylamine-induced esophageal carcinogenesis in zinc-deficient rats: effects on esophageal cell proliferation and apoptosis.
Sustained, increased cell proliferation induced by dietary zinc deficiency in rats plays a critical role in esophageal carcinogenesis. It is the determining factor that converts an otherwise nontumorigenic dose of N-nitrosomethylbenzylamine (NMBA) into a highly tumorigenic one. We studied whether the increased esophageal cell proliferation and susceptibility to NMBA-induced carcinogenesis induced by zinc deficiency can be inhibited by alpha-difluoromethylornithine (DFMO), an enzyme-activated, irreversible inhibitor of ornithine decarboxylase (the first enzyme in polyamine synthesis). Weanling rats were divided into four groups: Zn+/DFMO-, Zn+/DFMO+, Zn-/DFMO-, and Zn-/DFMO+. They were fed ad libitum either a zinc-sufficient (Zn+, 75 ppm zinc) or a zinc-deficient (Zn-, 4 ppm zinc) diet and given either deionized water (DFMO-) or 1% DFMO in deionized water (DFMO+). After 5 weeks, 5-19 animals from each group were sacrificed after in vivo 5-bromo-2'-deoxyuridine labeling to detect cells in S phase. The remaining animals in each group were given a single intragastric dose of NMBA at 2 mg/kg and sacrificed 12 weeks later for tumor incidence analysis. At week 5, DFMO treatment greatly decreased (by 48-82%) the levels of putrescine and spermidine in rat esophagus, colon, and liver, irrespective of dietary zinc intake. The increased esophageal cell proliferation induced by dietary zinc deficiency, as measured by the labeling index, the number of labeled cells, and the total number of cells, was substantially reduced by DFMO. This was accompanied by an increase in the rate of apoptosis. In addition, the expression of bax protein, an apoptosis accelerator, was markedly stronger in esophagi from Zn-/DFMO+ animals that showed increased apoptosis, whereas increased expression of bcl-2, an inhibitor of apoptosis, was only seen in the highly proliferative, zinc-deficient esophagus (Zn-/DFMO-). At week 12 after NMBA dosing, DFMO reduced the incidence of esophageal tumors from 80 to 4% in zinc-deficient rats. Our data showed that DFMO effectively inhibited the increased esophageal cell proliferation induced by dietary zinc deficiency and reduced the incidence of esophageal tumors induced by a single dose of NMBA in zinc-deficient animals. Our results also indicate a role for increased apoptosis in the mechanism(s) whereby DFMO brings about the inhibition of cell proliferation and tumor induction. These findings support a role for DFMO as a chemopreventive agent.


Sintilimab, stereotactic body radiotherapy and granulocyte-macrophage colony stimulating factor as second-line therapy for advanced non-small cell lung cancer: safety run-in results of a multicenter, single-arm, phase II trial.
The SWORD trial is the first multicenter, single arm, phase II study assessing the safety and efficacy of a PD-1 inhibitor (Sintilimab), stereotactic body radiotherapy (SBRT) and granulocyte-macrophage colony stimulating factor (GM-CSF) in advanced non-small cell lung cancer (NSCLC) without sensitizing driver mutations. A safety run-in phase was conducted to determine the tolerability of the experimental treatment. Twenty metastatic NSCLC patients who failed first-line chemotherapy were enrolled, and they received SBRT (8 Gy × 3) to one lesion, followed by Sintilimab (200 mg d1, every 3 weeks, until disease progression, unacceptable toxicity, or up to 35 cycles) and GM-CSF (125 μg/m2 d1-d14, cycle 1) within 2 weeks after SBRT. In addition, blood and tissue samples were serially collected for translational research. Median age of the patients was 61 and all of them had more than 5 lesions at baseline. The sites of SBRT included lung (n = 11), mediastinal lymph node (n = 5), liver (n = 1), abdominal lymph node (n = 1), pleural nodule (n = 1) and vertebra (n = 1). No patients had dose-limiting toxicities (DLTs) and 18 patients experienced treatment-related adverse event (TRAE). The most common TRAEs were fatigue (50%), fever (30%), and ostealgia (20%), and they all were grade 1. Only 2 grade 3 TRAEs were observed, including elevation of liver enzymes in one and transient acute heart failure in another. No grade 4 or 5 AE was observed. Sintilimab, SBRT and GM-CSF for advanced NSCLC is safe with manageable TRAEs and the trial continues to recruit participants. Trial registration ClinicalTrials.gov, NCT04106180. Registered 26 September 2019, SBRT in Combination With Sintilimab and GM-CSF for the Treatment of Advanced NSCLC-Tabular View-ClinicalTrials.gov.


Severe infectious complications following frontal sinus fracture: the impact of operative delay and perioperative antibiotic use.
The purpose of this study was to investigate whether a delay in operative management of frontal sinus fractures is associated with increased risk of serious infections. Retrospective chart review was performed of 242 consecutive patients with surgically managed frontal sinus fractures who presented to the R Adams Cowley Shock Trauma Center between 1996 and 2011. Collected patient characteristics included demographics, surgical management, hospital course, and complications. All computed tomographic imaging was reviewed to evaluate involvement of the posterior table and nasofrontal outflow tract. Serious infections included meningitis, encephalitis, brain abscess, frontal sinus abscess, and osteomyelitis. Delayed operative interventions were defined as procedures performed more than 48 hours after admission. Adjusted relative risk estimates were obtained using multivariable regression. There were 14 serious infections (5.8 percent). All patients with serious infections had both involvement of the posterior table and nasofrontal outflow tract injury. The cumulative incidence of serious infection in these patients was 10.8 percent. After adjustments for confounding, multivariable regression showed that operative delay beyond 48 hours was independently associated with a 4.03-fold (p < 0.05) increased risk for serious infection; external cerebrospinal fluid drainage catheter use and local soft-tissue infection conferred a 4.09-fold (p < 0.05) and 5.10-fold (p < 0.001) increased risk, respectively. Antibiotic use beyond 48 hours postoperatively was not associated with fewer infections. Delay in operative management of frontal sinus fractures in patients requiring operative intervention is associated with an increased risk for serious infections. Continued antibiotic prophylaxis beyond the perioperative period provides little benefit in preventing serious infections. Risk, II.


Sequential concentration of bacteria and viruses from marine waters using a dual membrane system.
The ability to rapidly and effectively concentrate diverse microbes is an essential component for monitoring water quality at recreational beaches. The purpose of this study was to develop a 0.45 microm pore size dual membrane system, which can sequentially concentrate both viruses and bacteria. The top PVDF membrane was used to filter bacteria by physical straining while the bottom HA membrane retained viruses through adsorption. The recovery of this system was assessed using test organisms: enterococci and somatic coliphage. Volumes of 100 to 400 mL of unspiked and sewage-spiked beach water were filtered through both types of membranes. The PVDF membrane recovered statistically equivalent amounts of enterococci when compared to traditional membranes. All of the coliphage passed through the PVDF membrane, while 22% passed through the HA membrane. Increasing the volume from 100 to 400 mL did not significantly influence recoveries. Up to 35% of coliphage was eluted from the bottom membrane using beef extract solution. Rinsing bottom membranes with 0.5 mmol L(-1) H(2)S0(4) was found to deactivate somatic coliphage. This research demonstrates the potential of using a dual membrane adsorption system for the concentration of both bacteria and viruses from recreational beaches. A proposed bi-layer filtration system can be designed for simultaneous bacteria and virus filtration. Future experiments should focus on measurements utilizing additional bacteria and viruses.


[Effect of a pH change in the medium and cytoplasm of cultured cells on the rhythm of protein synthesis].
A circahoral rhythm of protein syntheses similar to that in monolayer hepatocytes was discovered in cell culture of Chinese hamster fibroblasts. Studies on the effects of pH changes in the culture medium and cultured cells on different parameters of protein synthesis showed some pH-dependent changes of predecessor pool and of its incorporation intensity into proteins. At the same time changes in a relative incorporation of the predecessor into proteins (with a correction for the pool) were insignificant. This value characterizing the productivity of protein synthesis does not seem to be directly associated with pH changes in the cells. The mean period of the rhythm of protein synthesis and intracellular pH was not changed with medium pH alterations.


Granulomatous hypersensitivity to Schistosoma mansoni egg antigens in human schistosomiasis. II. In vitro granuloma modulation induced by polyclonal idiotypic antibodies.
We have previously reported on Id/anti-Id-receptor interactions in clinical human schistosomiasis. These findings support a hypothesis that anti-SEA cross-reactive Id develop in some patients during the course of a chronic infection and participate in regulation of anti-SEA cellular immune responses. We report here on experiments that extend those observations to the regulation of granulomatous hypersensitivity measured by an in vitro granuloma model. T cells from chronic intestinal schistosomiasis patients were stimulated in vitro with anti-SEA Id and assayed in an autologous in vitro granuloma assay for modulation of granuloma formation. These anti-SEA Id-reactive T cells were capable of regulating autologous in vitro granuloma formation. Both CD4 and CD8 T cells could be activated to regulate granuloma formation. This regulatory activity, initiated with stimulatory anti-SEA idiotypic antibodies, was antigenically specific and was dependent on the presence of intact F(ab')2 Ig molecules. The ability to elicit this regulatory activity appears to be dose dependent and is more easily demonstrated in chronically infected intestinal patients or SEA-sensitized individuals. These data support the hypothesis that anti-SEA cross-reactive Id are important in regulating granulomatous hypersensitivity in chronic intestinal schistosomiasis patients and these cross-reactive Id appear to play a major role in cell-cell interactions that result in the regulation of anti-SEA cellular immune responses.


Statistical validation of a global model for the distribution of the ultimate number of citations accrued by papers published in a scientific journal.
A central issue in evaluative bibliometrics is the characterization of the citation distribution of papers in the scientific literature. Here, we perform a large-scale empirical analysis of journals from every field in Thomson Reuters' Web of Science database. We find that only 30 of the 2,184 journals have citation distributions that are inconsistent with a discrete lognormal distribution at the rejection threshold that controls the False Discovery Rate at 0.05. We find that large, multidisciplinary journals are over-represented in this set of 30 journals, leading us to conclude that, within a discipline, citation distributions are lognormal. Our results strongly suggest that the discrete lognormal distribution is a globally accurate model for the distribution of "eventual impact" of scientific papers published in single-discipline journal in a single year that is removed sufficiently from the present date.


Myoid gonadal stromal tumor with epithelial differentiation (? testicular myoepithelioma).
A 46-year-old man presented with a cytologically bland testicular tumor composed of spindle cells that showed both epitheliallike (ie, true desmosomes and tonofilamentlike structures) and myogenous differentiation (ie, thin filaments with focal densities and alpha-smooth muscle actin immunoreactivity). Tumor cells were immunoreactive for vimentin and S-100 protein but negative for cytokeratin and desmin. Peritubular myoid cells are present in the normal testis; contain subplasmalemmal micropinocytotic vesicles; show thin filaments with focal densities; and are reactive with desmin, vimentin, and alpha-smooth muscle actin. They have no desmosomes and lie outside the basement membrane of the seminiferous tubules; thus they are not true myoepithelial cells (a cell type not present in the testis). Paradoxically, the current tumor appeared to show bidirectional differentiation, mimicking both a peritubular myoid spindle cell and an epitheliallike cell (possibly similar to the granulosa cell or rete testis epithelial cell). Although the findings suggest myoepithelial differentiation, the cytogenesis of this tumor remains uncertain.


Effectiveness of telehealth in preventive care: a study protocol for a randomised controlled trial of tele-exercise programme involving older people with possible sarcopenia or at risk of fall.
Continuous loss of muscle mass and strength are the consequences of the ageing process, which increase the risk of falls among older people. Falls can lead to severe consequences such as bone fractures and hampered physical and psychological well-being. Regular exercise is the key to reversing muscle atrophy and relieving sarcopenia. However, the frailty of older people and the recent COVID-19 pandemic may affect their confidence to leave home to attend classes in the community. A feasible and effective alternative should be explored. The primary objective is to evaluate the effectiveness of tele-exercise (TE) in relation to physical functioning and exercise adherence among community-dwelling older people at risk of falls in comparison with a community-based group (CB). The secondary objective includes evaluating older people's experience with tele-exercise, emphasizing their psychological welfare, social well-being, and acceptance of the telehealth approach. The design, conduct, and report follow the SPIRIT guidelines (Standard Protocol Items: recommended items to address in a Clinical Trial Protocol and Related Documents). Older people will be recruited from 10 local community centres in Hong Kong and randomly allocated into two groups. All participants will attend the exercise training 3 days per week for 3 months but the mode of delivery will differ, either online as the tele-exercise group (TE) or face-to-face as the community-based group (CB). The outcome measures include muscle strength, physical function, exercise adherence and dropout rate, psychological and social well-being will be assessed at the baseline, and the 3rd, 6th and 12th month. Some participants will be invited to attend focus group interviews to evaluate their overall experience of the tele-exercise training. Tele-exercise reduces the barriers to exercise, such as time constraints, inaccessibility to facilities, and the fear of frail older people leaving their homes. Promoting an online home-based exercise programme for older people can encourage them to engage in regular physical activity and increase their exercise adherence even when remaining at home. The use of telehealth can potentially result in savings in cost and time. The final findings will provide insights on delivering exercise via telehealth to older people and propose an exercise delivery and maintenance model for future practice. Chinese Clinical Trial Registry ( https://www.chictr.org.cn/hvshowprojectEN.html?id=219002&v=1.1 ), registration number: ChiCTR2200063370. Registered on 5 September 2022.


Novel diagnostic tests to detect Helicobacter pylori infection: A pediatric perspective.
Because of the widespread problem of Helicobacter pylori infections, there is an increased need for rapid, reliable and inexpensive diagnostic tests. Five recently developed tests that offer potential advantages because they are less invasive or permit easier acquisition of samples than available tests are assessed. The tests assessed are whole blood, saliva and urine assays that measure systemic antibody response to H pylori, stool tests that measure H pylori antigens and string tests that recover H pylori organisms.


Humanistic and Economic Burden of Geographic Atrophy: A Systematic Literature Review.
Geographic atrophy (GA), the advanced form of dry age-related macular degeneration, can result in irreversible blindness over time. We performed a systematic literature review to assess the humanistic and economic burden of GA. Predefined search terms were used to identify studies in PubMed, Embase, and Cochrane Library; conference abstracts also were searched. Of 1111 unique studies identified, 25 studies on humanistic burden, 4 on economic burden, and 3 on both humanistic and economic burden of GA were included. Vision-related functioning and health-related quality of life (HRQOL) are poor in patients with GA. HRQOL is commonly measured using the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25); patients with GA have significantly lower composite and subscale scores for near activities, distance activities, dependency, driving, social functioning, mental health, role difficulties, color vision, and peripheral vision than individuals without GA. Driving is a particular concern, and inability to drive affects dependency. Vision-related quality of life (VRQOL) declines as GA progresses. While we identified only 7 reports describing the economic burden of GA, its direct costs may be substantial. In a US study, mean cost to the payer per patient with GA was $11,533 in the year after diagnosis. A multinational study estimated annualized total direct costs of €1772 per patient with GA, mainly driven by diagnostic tests and procedures (€1071). Patients with GA are at increased risk of falls and fractures, potentially increasing direct costs. Only one study evaluated indirect costs, estimating ~$24.4 billion in yearly lost wages among people with severe vision loss due to GA or drusen ≥125 μm. GA represents a significant humanistic burden. Evidence on the economic impact of GA is limited; characterizing the economic burden of GA requires further research. Interventions that reduce GA-related disability may improve HRQOL and reduce indirect costs.


Excess Folic Acid Supplementation before and during Pregnancy and Lactation Alters Behaviors and Brain Gene Expression in Female Mouse Offspring.
Use of folic acid (FA) during early pregnancy protects against birth defects. However, excess FA has shown gender-specific neurodevelopmental toxicity. Previously, we fed the mice with 2.5 times the recommended amount of FA one week prior to mating and during the pregnancy and lactation periods, and detected the activated expression of Fos and related genes in the brains of weaning male offspring, as well as behavioral abnormalities in the adults. Here, we studied whether female offspring were affected by the same dosage of FA. An open field test, three-chamber social approach and social novelty test, an elevated plus-maze, rotarod test and the Morris water maze task were used to evaluate their behaviors. RNA sequencing was performed to identify differentially expressed genes in the brains. Quantitative real time-PCR (qRT-PCR) and Western blots were applied to verify the changes in gene expression. We found increased anxiety and impaired exploratory behavior, motor coordination and spatial memory in FA-exposed females. The brain transcriptome revealed 36 up-regulated and 79 down-regulated genes in their brains at weaning. The increase of Tlr1; Sult1a1; Tph2; Acacb; Etnppl; Angptl4 and Apold1, as well as a decrease of Ppara mRNA were confirmed by qRT-PCR. Among these genes; the mRNA levels of Etnppl; Angptl4andApold1 were increased in the both FA-exposed female and male brains. The elevation of Sult1a1 protein was confirmed by Western blots. Our data suggest that excess FA alteres brain gene expression and behaviors in female offspring, of which certain genes show apparent gender specificity.


Commensurability oscillations of hole-flux composite fermions.
We report the observation of commensurability oscillations of hole-flux composite fermions near a filling factor of ν=1/2 in a high-mobility two-dimensional hole system confined to a GaAs quantum well and subjected to a weak, strain-induced, unidirectional periodic potential modulation. The oscillations, which are consistent with ballistic transport of fully spin-polarized composite fermions in a weak periodic effective magnetic field, are surprisingly strong and exhibit up to third-order minima. We extract a ballistic mean-free path of about 0.1 μm for the hole-flux composite fermions.


Molecular analysis of the pyrimidine deoxyribonucleoside kinase gene of wild-type and acyclovir-resistant strains of varicella-zoster virus.
The pyrimidine deoxyribonucleoside kinase (dPK) genes from five wild-type and four acyclovir-resistant varicella-zoster virus (VZV) strains were studied. One of the acyclovir-resistant strains was isolated from a patient receiving chronic acyclovir therapy. Acyclovir-resistant strains expressed the 1.8 kb VZV dPK transcript but lacked dPK activity. To determine the basis for the lack of enzyme activity the dPK gene from each strain was cloned and its DNA sequence determined. The VZV dPK gene was found to be highly conserved among strains, with greater than 99% nucleotide and amino acid homology. Each acyclovir-resistant VZV strain differed from its wild-type parent in only a single amino acid. The dPK genes from the acyclovir-resistant strains contained either point mutations near the putative thymidine-binding site of the enzyme or ones that resulted in the premature termination of protein synthesis. Single point mutations were sufficient to render these strains dPK-negative and highly resistant to acyclovir. The molecular basis for acyclovir resistance at the dPK locus of VZV is similar to that previously noted to render herpes simplex viruses resistant to acyclovir.


Outcomes of hypercalcemia of malignancy in patients with solid cancer: a national inpatient analysis.
Hypercalcemia of malignancy (HCM) is present in one-third of cancer patients and is associated with a significant mortality risk of 50% within 1 month of diagnosis. We aimed to study the impact and outcomes of HCM in hospitalized patients with solid cancer. We analyzed data captured in the National Inpatient Sample database of the Agency of Healthcare Research and Quality. The study included all hospitalizations in adult solid cancer patients between January 2012 and September 2015 with hypercalcemia. All encounters associated with HCM were identified using the ICD-9 code (275.42) for hypercalcemia. Encounters with other known causes of hypercalcemia were excluded. The co-primary outcomes were incidence of HCM and inpatient mortality. During the study period, 7,501,209 hospitalizations met our inclusion criteria. Approximately 1.7% (n = 126,875) of these hospitalizations were related to HCM. This corresponds to approximately 1 in 59 solid malignancy associated hospitalizations. The mean age of patients with HCM was 65.7 years; 49% were females; 69% were Caucasians; 73% had metastatic disease and 22% received a palliative care consult. When compared to those without HCM, those hospitalized with HCM had a significantly longer mean hospital length of stay (7.3 days vs. 5.6 days, p < 0.001), higher inpatient mortality (12.3% vs. 5.5%, adjusted OR 1.76 (95% CI 1.69-1.84), p < 0·0001), and a greater likelihood of discharge to other facilities (27.4% vs. 16.2%, p < 0.0001). Although HCM accounts for < 2% of all hospitalizations in patients with solid cancer, those with HCM display higher mortality than those without HCM.


Effect of salicylates on intestinal secretion in calves given (intestinal loops) Escherichia coli heat-stable enterotoxin.
The inhibitory effect of salicylates on intestinal secretion in 1- to 5-day-old calves given Escherichia coli heat-stable enterotoxin (ST)-induced intestinal fluid response was investigated. Purified ST was diluted in isotonic saline solution to obtain 1:10, 1:25, 1:50, 1:75, and 1:100 dilutions. Each dilution (1 ml) was inoculated into ligated loops in the distal part of the jejunum of each calf. Acetylsalicylic acid (aspirin) given orally (100 mg/kg) at 4 hours before ST was inoculated did not substantially alter the intestinal fluid response to ST. Sodium salicylate (IV) infusion, begun simultaneously when, or at 1 hour after, ST was inoculated, significantly (P less than 0.05) decreased fluid accumulation in those loops inoculated with ST dilutions of 1:25 or greater. The sodium and potassium concentrations of the accumulated fluid did not differ significantly between or within treatment groups. These results indicate that sodium salicylate infusion may be beneficial in treating enterotoxic colibacillosis in calves. Aspirin given orally at the dose used in the present study, would not have any beneficial effect.


Increased glucose uptake capacity of Rous-transformed cells and the relevance of deprivation derepression.
The increased rate of glucose uptake found in cells transformed by Rous sarcoma virus was shown to be enhanced relative to the changes in uptake induced in nontransformed cells by deprivation of glucose (deprivation derepression). Glucose-specific uptake sites were distinguished from glucose-galactose sites in nontransformed cells, and the capacities for glucose uptake and for galactose uptake were increased to about the same extent by the exclusion of glucose from the cell culture medium. Deprivation derepression occurred without a requirement for new RNA or protein synthesis, suggesting that preexisting inactivate uptake sites were activated. Deprivation derepression could be mimicked by the treatment of cells with adenosine triphosphatase activators, and adenosine triphosphate levels were reduced in glucose-deprived cells and in cells treated with adenosine triphosphatase activators. Cells transformed by the Bryan strain of Rous sarcoma virus were unresponsive to addition of high concentrations of glucose, to glucose starvation, or to treatment with adenosine triphosphatase activators, and the relative capacity for glucose uptake in these transformed cells was enhanced much more than the capacity of galactose uptake. It was concluded that cells infected by the Bryan strain of rous sarcoma virus in the process of transformation selectively synthesize more sites specific for glucose uptake. Lower levels of adenosine triphosphate found in transformed cells possibly contribute to a chronic derepression of uptake sites.


[Role of bronchoalveolar lavage and transbronchial biopsy in the diagnosis of pneumonia in patients with organ transplantation].
Pneumonia in patients with organ transplantation constitutes a very frequent cause of mortality, as a result precocious aetiologic diagnosis is indispensable. The bronchoscopic techniques, bronchoalveolar lavage (BAL) and transbronchial biopsy (TBB), constitute fundamental procedures for these diagnoses. We begin this study with the aim of evaluating the profitability obtained with these procedures. 36 bronchoscopies were performed on 29 patients with organ transplantation, in all of them we realized BAL and in 20 TBB. We confirm the presence of pneumonia in 30 (in 15 of them we had performed TBB), the BAL was diagnostic in 20 cases (66.6%) and the TBB in 7 (46.6%). With both, BAL and TBB, we obtained a sensitivity of 80% and a specificity of 75%. We isolated 10 bacteria, 8 Citomegalovirus (CMV), 6 Pneumocystis carinii and 2 Aspergillus fumigatus. The BAL and the TBB contributed significantly in the aetiologic diagnosis of pneumonia in patients with organ transplantation, consequently we consider them basic tools in the management of these infections.


Prevalence of allergen sensitization, most important allergens and factors associated with atopy in children.
Knowledge of the profile of allergen sensitization among children is important for planning preventive measures. The objective of this study was to assess the prevalence and profile of sensitization to inhaled allergens and food among children and adolescents in an outpatient population in the city of Palmas. Cross-sectional study at outpatient clinics in Palmas, Tocantins, Brazil. Ninety-four patients aged 1-15 years who were attending two pediatric outpatient clinics were selected between September and November 2008. All of the subjects underwent clinical interviews and skin prick tests. A positive skin prick test was observed in 76.6% of the participants (72.3% for inhalants and 28.9% for food allergens). The most frequent allergens were Dermatophagoides pteronyssinus (34%), cat epithelium (28.7%), dog epithelium (21.3%), Dermatophagoides farinae (19.1%), Blomia tropicalis (18.1%), cow's milk (9.6%) and grasses (9.6%). A positive skin prick test correlated with a history of atopic disease (odds ratio, OR = 5.833; P = 0.002), a family history of atopic disease (OR = 8.400; P < 0.001), maternal asthma (OR = 8.077; P = 0.048), pet exposure (OR = 3.600; P = 0.012) and cesarean delivery (OR = 3.367; P = 0.019). Dermatophagoides pteronyssinus was the most frequent aeroallergen and cow's milk was the most prevalent food allergen. There was a positive correlation between a positive skin prick test and several factors, such as a family history of atopic disease, maternal asthma, pet exposure and cesarean delivery.


Morphometry of liver parenchyma in needle biopsy specimens from patients with alcoholic liver disease: preliminary variables for the diagnosis and prognosis of cirrhosis.
The diagnosis of liver cirrhosis depends on assessing fibrosis and architectural alterations of the liver. In a needle biopsy specimen the connective tissue is often inadequately sampled, which leads to an uncertain diagnosis. Parenchymal features alone are currently insufficient. We, therefore, carried out a comprehensive morphometric study to detect parenchymal structures that may be useful in the diagnosis and prognosis of cirrhosis. Five human liver biopsy specimens were selected from each of four alcoholic disease groups: fatty liver, alcoholic hepatitis, cirrhosis with greater-than-5-yr survival, and cirrhosis with less-than-2-yr survival. Volume fractions (Vv) and surface densities (Sv) were determined stereologically for parenchymal and hepatocellular compartments in electron micrographs. The differences between noncirrhosis and cirrhosis were (a) a doubling of the Vv of parenchymal interstitial space, (b) a nearly 25% increase in the Sv of hepatocyte plasma membrane, (c) a nearly 50% increase in the Sv of hepatocyte RER, and (d) a decrease in the Sv of the outer mitochondrial membrane. The significant difference between the greater than 5-yr and the less than 2-yr survivors of cirrhosis was the marked decrease in hepatocyte nuclear Vv in the latter group. Statistical analysis of our data showed that optimal sampling is achieved with as few as three micrographs from one block of tissue per biopsy specimen.


Optimizing vessel healing following drug eluting stent implantation with biodegradable polymer DES.
The introduction of coronary drug eluting stents (DES) more than 10 years ago drastically decreased the occurrence of restenosis, compared with first generation bare metal stents (BMS). However, the optimism created by the first studies was soon shadowed by the demonstration of higher rates of late and very late stent thrombosis (ST). The research performed in this phenomenon highlighted the causative role played by incomplete stent strut coverage, hypersensitivity reactions caused by the drug eluting polymer, and neoatherosclerosis, all markers of an inadequate vascular response to DES implantation. Over the following years, new development in stent and eluting polymer technologies have been incorporated in second generation DES to optimize the process of vessel healing and, thus, to avoid these complications. Furthermore, it is envisaged that adequate vessel healing would be followed by less dependence on double antiplatelet, a limiting aspect for DES use in different clinical scenarios. In this review, we focused on the use of biodegradable eluting polymers to increase DES safety, revisiting the rationale for its use and the synergic action with other changes in stent technology aimed to optimize vessel healing after DES implantation.


Endometrial bleeding.
Abnormal bleeding is a significant health problem, especially during adolescence and before menopause when anovulatory cycles are common. Curettage is rarely necessary to investigate or treat menstrual problems in adolescents, and its use should also be minimized in women younger than 40 years. In every age group, medical treatment is the initial choice, but surgical treatment by endometrial destruction or hysterectomy is sometimes required. Benign causes of bleeding include fibroids and possibly adenomyosis, but the indications for treatment in each case depend upon the extent of bleeding, not the extent of the lesion. Breakthrough bleeding (BTB) with combined oral contraceptives commonly leads to discontinuation of the method. As BTB tends to improve with time, in the first 3 months of pill use, unless there are obvious underlying causes, women should be reassured that it will likely settle. BTB is often the reason for discontinuing progestogen-only contraception, and there is a need for effective means of treating unscheduled bleeding. Bleeding occurs in approximately 3% of post-menopausal women, and the use of hormones increases the likelihood of bleeding by >5-fold. Knowledge of the underlying mechanisms of bleeding is essential to the development of effective treatment.


Single-spin resonance in a van der Waals embedded paramagnetic defect.
A plethora of single-photon emitters have been identified in the atomic layers of two-dimensional van der Waals materials1-8. Here, we report on a set of isolated optical emitters embedded in hexagonal boron nitride that exhibit optically detected magnetic resonance. The defect spins show an isotropic ge-factor of ~2 and zero-field splitting below 10 MHz. The photokinetics of one type of defect is compatible with ground-state electron-spin paramagnetism. The narrow and inhomogeneously broadened magnetic resonance spectrum differs significantly from the known spectra of in-plane defects. We determined a hyperfine coupling of ~10 MHz. Its angular dependence indicates an unpaired, out-of-plane delocalized π-orbital electron, probably originating from substitutional impurity atoms. We extracted spin-lattice relaxation times T1 of 13-17 μs with estimated spin coherence times T2 of less than 1 μs. Our results provide further insight into the structure, composition and dynamics of single optically active spin defects in hexagonal boron nitride.


Using the case mix of pressure ulcer healing to evaluate nursing home performance.
Pressure ulcer healing is an important quality measure for nursing homes, but the factors that predict healing have not been well studied. Using the Minimum Data Set, the authors identified candidate variables for a logistic regression, risk-adjustment model to predict ulcer healing. The authors then assessed model discrimination and calibration. Finally, the authors compared unadjusted with risk-adjusted performance for the individual facilities within a nursing home chain. Significant predictors of healing included mobility in bed, presence of a stage 2 ulcer (compared with a stage 4 ulcer), absence of paraplegia and quadriplegia, and absence of end-stage illness. The model C statistic was 0.67, and the calibration was acceptable. Judgments about nursing performance varied in 2 cases depending upon whether unadjusted or risk-adjusted performance was used. The model that the authors developed contains credible predictors of healing. Pressure ulcer healing may be one of many indicators used to evaluate nursing home quality.


Automated Prediction and Annotation of Small Open Reading Frames in Microbial Genomes.
Small open reading frames (smORFs) and their encoded microproteins play central roles in microbes. However, there is a vast unexplored space of smORFs within human-associated microbes. A recent bioinformatic analysis used evolutionary conservation signals to enhance prediction of small protein families. To facilitate the annotation of specific smORFs, we introduce SmORFinder. This tool combines profile hidden Markov models of each smORF family and deep learning models that better generalize to smORF families not seen in the training set, resulting in predictions enriched for Ribo-seq translation signals. Feature importance analysis reveals that the deep learning models learn to identify Shine-Dalgarno sequences, deprioritize the wobble position in each codon, and group codon synonyms found in the codon table. A core-genome analysis of 26 bacterial species identifies several core smORFs of unknown function. We pre-compute smORF annotations for thousands of RefSeq isolate genomes and Human Microbiome Project metagenomes and provide these data through a public web portal.


The Role of Statistical Learning in Understanding and Treating Spoken Language Outcomes in Deaf Children With Cochlear Implants.
Statistical learning-the ability to learn patterns in environmental input-is increasingly recognized as a foundational mechanism necessary for the successful acquisition of spoken language. Spoken language is a complex, serially presented signal that contains embedded statistical relations among linguistic units, such as phonemes, morphemes, and words, which represent the phonotactic and syntactic rules of language. In this review article, we first review recent work that demonstrates that, in typical language development, individuals who display better nonlinguistic statistical learning abilities also show better performance on different measures of language. We next review research findings that suggest that children who are deaf and use cochlear implants may have difficulties learning sequential input patterns, possibly due to auditory and/or linguistic deprivation early in development, and that the children who show better sequence learning abilities also display improved spoken language outcomes. Finally, we present recent findings suggesting that it may be possible to improve core statistical learning abilities with specialized training and interventions and that such improvements can potentially impact and facilitate the acquisition and processing of spoken language. We conducted a literature search through various online databases including PsychINFO and PubMed, as well as including relevant review articles gleaned from the reference sections of other review articles used in this review. Search terms included various combinations of the following: sequential learning, sequence learning, statistical learning, sequence processing, procedural learning, procedural memory, implicit learning, language, computerized training, working memory training, statistical learning training, deaf, deafness, hearing impairment, hearing impaired, DHH, hard of hearing, cochlear implant(s), hearing aid(s), and auditory deprivation. To keep this review concise and clear, we limited inclusion to the foundational and most recent (2005-2018) relevant studies that explicitly included research or theoretical perspectives on statistical or sequential learning. We here summarize and synthesize the most recent and relevant literature to understanding and treating language delays in children using cochlear implants through the lens of statistical learning. We suggest that understanding how statistical learning contributes to spoken language development is important for understanding some of the difficulties that children who are deaf and use cochlear implants might face and argue that it may be beneficial to develop novel language interventions that focus specifically on improving core foundational statistical learning skills.


Smartphone application of primary care guidelines used in education of medical students.
The guidelines of the German College of General Practitioners and Family Physicians (DEGAM) on frequent and important reasons for encounter in Primary Care play a central role in the teaching of Family Medicine. They were edited by the authors into an app for mobile phones, making them available at all times to General Practitioners and medical students. This study examines the issue: how useful do students consider this application within their learning process in Family Medicine? The short versions of the 15 DEGAM guidelines were processed as a web app (for all smartphone software systems) including offline utilisation, and offered to students in the Family Medicine course, during clinical attachments in General Practice, on elective compulsory courses or for their final year rotation in General Practice. The evaluation was made with a structured survey using the feedback function of the Moodle learning management system [http://www.elearning-allgemeinmedizin.de] with Likert scales and free-text comments. Feedback for evaluation came from 14 (25%) of the student testers from the Family Medicine course (9), the clinical attachment in General Practice (1), the final year rotation in General Practice (1) and elective compulsory courses (4). Students rated the app as an additional benefit to the printed/pdf-form. They use it frequently and successfully during waiting periods and before, during, or after lectures. In addition to general interest and a desire to become acquainted with the guidelines and to learn, the app is consulted with regard to general (theoretical) questions, rather than in connection with contact with patients. Interest in and knowledge of the guidelines is stimulated by the app, and on the whole the application can be said to be well suited to the needs of this user group. The students evaluated the guidelines app positively: as a modern way of familiarising them with the guidelines and expanding their knowledge, particularly through its use in waiting periods and the attractive medium smartphone. However, the latter prevents a mandatory curricular use in compulsory courses, since not all students use smartphones. It is a meaningful addition to existing teaching materials and supports evidence-based teaching in Family Medicine and is suitable for use not only in university course teaching but also during clinical training.


Matters of care in technoscience: assembling neglected things. .
This paper aims to encourage an ethos of care in the study of science and technology. It starts with a reading of Bruno Latour's notion of'matters of concern' as favouring an awareness of the ethico-political effects of constructivist accounts in STS. Introducing attention to concern brings us closer to a notion of care. However, there is a'critical' edge to care that Latour's politics of things tends to disregard. Drawing upon feminist knowledge politics, I propose to treat matters of fact and sociotechnical assemblages as 'matters of care' and argue that engaging with care requires a speculative commitment to neglected things.


Expression of sexual ornaments in a polymorphic species: phenotypic variation in response to environmental risk.
Secondary sexual traits may evolve under the antagonistic context of sexual and natural selection. In some polymorphic species, these traits are only expressed during the breeding period and are differently expressed in alternative phenotypes. However, it is unknown whether such phenotypes exhibit phenotypic plasticity of seasonal ornamentations in response to environmental pressures such as in the presence of fish (predation risk). This is an important question to understand the evolution of polyphenisms. We used facultative paedomorphosis in newts as a model system because it involves the coexistence of paedomorphs that retain gills in the adult stage with metamorphs that have undergone metamorphosis, but also because newts exhibit seasonal sexual traits. Our aim was therefore to determine the influence of fish on the development of seasonal ornamentation in the two phenotypes of the palmate newt (Lissotriton helveticus). During the entire newt breeding period, we assessed the importance of phenotype and fish presence with an information-theoretic approach. Our results showed that paedomorphs presented much less developed ornamentation than metamorphs and those ornamentations varied over time. Fish inhibited the development of sexual traits but differently between phenotypes: in contrast to metamorphs, paedomorphs lack the phenotypic plasticity of sexual traits to environmental risk. This study points out that internal and external parameters act in complex ways in the expression of seasonal sexual ornamentations and that similar environmental pressure can induce a contrasted evolution in alternative phenotypes.


Exploring the role of economics in prioritization in public health: what do stakeholders think?
Debates surrounding the use of conventional approaches in public health and the existence of perceived barriers to using the results of economic evaluations have led to questions posed as to how to establish priorities within public health schemes. The aims of this study were therefore to explore the feasibility and validity of economic evaluation techniques in developing priorities within public health programmes and consider the extent to which different presentational approaches are likely to be incorporated into decision-making, from perspectives of relevant stakeholders. An advisory board, representative of potential users of economic evaluations, was set up to identify preferences for how findings from economic evaluations might be presented to decision makers and to test the impact of different approaches, different outputs and different presentational styles. The board was divided into two groups, each of which was given three hypothetical 'scenarios' to consider. The scenarios comprised descriptions of methods and outputs, with costs, effects, target population and context of intervention constant across all scenarios. The perceived validity of estimates of effectiveness was vitally important, along with sufficient information to gauge whether designs were appropriate and to assess implementation practicalities. Cost-benefit analysis and cost-utility analysis were the preferred approaches despite their complexity, although participants required benchmarks to place net-benefit estimates from cost-benefit analyses into context. Further research is required to substantiate and build on these preliminary findings and collaborations between economists and policy makers are needed to develop clear, rigorous and standard guidance relating to economic evaluation, recognizing the diversity of public health strategies.


Novel paradigms of innate immune sensing of viral infections.
According to the existing paradigm, cellular recognition of viral infection is mediated by molecular patterns within the virus particle or produced during virus replication. However, there are various physical cellular changes indicative of infection that could also trigger innate antiviral responses. The type-I interferon response is rapidly engaged to limit viral infection and a number of studies have shown that the interferon response, or components of it, are induced by general perturbations to cellular processes. Virus entry requires membrane and cytoskeletal perturbation, and both membrane fusion or actin depolymerising agents alone are able to activate antiviral genes. Viruses cause cellular stress and change the cellular environment, and oxidative stress or endoplasmic reticulum stress will amplify antiviral signaling. Many of these responses converge on interferon regulatory factor 3, suggesting that it plays a crucial role in determining the degree to which the cell responds. This review highlights novel paradigms of viral recognition and speculates that viral infection is sensed as a danger signal.


The effect of curcumin on hypoxia in the tumour microenvironment as a regulatory factor in cancer.
Hypoxia can lead to different responses from cancer cells, including cell death or survival, partially depending on how long it is exposed. Patients with cancer and under hypoxic tumour conditions have a poorer prognosis and are at greater risk of metastasis. Physiological response to low oxygen levels is controlled by hypoxia-inducible factor (HIF)-1. Curcumin, the major component of the rhizomes of Curcuma longa L., reduces HIF-1 levels and function, inhibiting the production of vascular endothelial growth factor (VEGF). In addition, curcumin efficiently inhibits the angiogenesis of vascular endothelial cells triggered by hypoxia. One of the most compelling features that drive continued interest in curcumin is the molecules' modulation of initiation, promotion, and progression stages of cancer while concomitantly acting as a radiosensitizer and chemosensitizer for tumours. In this review, we discuss the role of curcumin in modulating hypoxia and investigate the mechanisms and regulatory factors of hypoxia in tumour tissues.


Sensitivity and Specificity of Laser-Scanning In Vivo Confocal Microscopy for Filamentous Fungal Keratitis: Role of Observer Experience.
To determine sensitivity and specificity of laser-scanning in vivo confocal microscopy (LS-IVCM) for detection of filamentous fungi in patients with microbial keratitis and to evaluate the effect of observer's imaging experience on these parameters. Retrospective reliability study. This study included 21 patients with filamentous fungal keratitis and 24 patients with bacterial keratitis (as controls). The etiology of infection was confirmed based on the response to specific therapy regardless of culture results. All patients had undergone full-thickness corneal imaging by a LS-IVCM (Heidelberg Retina Tomograph 3 with Rostock Cornea Module; Heidelberg Engineering, Heidelberg, Germany). The images were evaluated for the presence of fungal filaments by 2 experienced observers and 2 inexperienced observers. All observers were masked to the clinical and microbiologic data. The mean number of images obtained per eye was 917 ± 353. The average sensitivity of LS-IVCM for detecting fungal filaments was 71.4% ± 0% for the experienced observers and 42.9% ± 6.7% for the inexperienced observers. The average specificity was 89.6% ± 3.0% and 87.5% ± 17.7% for these 2 groups of observers, respectively. Although there was a good agreement between the 2 experienced observers (κ = 0.77), the inexperienced observers showed only a moderate interobserver agreement (κ = 0.51). The LS-IVCM sensitivity was higher in patients with fungal infections who had positive culture or longer duration of the disease. Although LS-IVCM has a high specificity for diagnosing filamentous fungal keratitis, its sensitivity is moderate and highly dependent on the level of the observer's experience and training with this imaging modality.


Quality of life philosophy IV. The brain and consciousness.
In this article we look at the brain's structure and function from a philosophical perspective. Although the brain at micro-level, with its trillions of ultra-thin nerve fibers, is one of the most complicated structures in the known universe, you can still grasp its composition if you go up to the level of the cell. How this structure functions is not quite clear. You can understand its function at fiber level, because it is fairly simple, and you can understand it at cell level, but it is already vague. Roughly speaking, you can envision a single nerve cell as a tiny, independent computer whose behavior is dependent on continuous calculations of all input. At organ level, the function can be understood as an extremely complex pattern machine. Finally, the brain"s function can be understood at the cognitive level as what provides consciousness through its ability to keep order in our complicated reality. The superior function of the brain is to connect the real us, our higher self, to the surrounding world. The brain has been developed so that it can create all possible complex patterns. The connectivity seems to imply that the patterns of the human brain are 1000-dimensional. It is our vision that these complicated patterns arise from basic patterns in the quantum matter of which everything is created. In our opinion, our consciousness" special utilization of a patterned aspect of nature is what lies behind inscrutable statements like "Man is created in God"s image". We suggest that these patterns in matter are the basic, creative force that influences all living organisms. Unfortunately, science has only just begun to understand these patterns. The Bible's description of the origin of man is two people eating from the Tree of Knowledge and as punishment they are expelled from the Garden of Eden. What does that mean? It means that, as conscious creatures, we no longer were an unproblematic, harmonious part of the world around us. The great question is why this consciousness about the world, provided by the brain, is not a gift that makes life better instead of getting us expelled from the Garden of Eden. We think that our real problem is the fact that we are still not in control of our consciousness. Instead of it serving us, we have become its slaves. If we come to understand brain and consciousness in order to solve this basic problem of our existence, we shall again be able to become a coherent part of the world, both as individuals and as a species. We share the vision that such an understanding of the problems of consciousness will make medical science holistic and will bring quality of life, health, and the ability to function to its patients.


Angiotensin II signaling in human preadipose cells: participation of ERK1,2-dependent modulation of Akt.
The renin-angiotensin system expressed in adipose tissue has been implicated in the modulation of adipocyte formation, glucose metabolism, triglyceride accumulation, lipolysis, and the onset of the adverse metabolic consequences of obesity. As we investigated angiotensin II signal transduction mechanisms in human preadipose cells, an interplay of extracellular-signal-regulated kinases 1 and 2 (ERK1,2) and Akt/PKB became evident. Angiotensin II caused attenuation of phosphorylated Akt (p-Akt), at serine 473; the p-Akt/Akt ratio decreased to 0.5±0.2-fold the control value without angiotensin II (p<0.001). Here we report that the reduction of phosphorylated Akt associates with ERK1,2 activities. In the absence of angiotensin II, inhibition of ERK1,2 activation with U0126 or PD98059 resulted in a 2.1±0.5 (p<0.001) and 1.4±0.2-fold (p<0.05) increase in the p-Akt/Akt ratio, respectively. In addition, partial knockdown of ERK1 protein expression by the short hairpin RNA technique also raised phosphorylated Akt in these cells (the p-Akt/Akt ratio was 1.5±0.1-fold the corresponding control; p<0.05). Furthermore, inhibition of ERK1,2 activation with U0126 prevented the reduction of p-Akt/Akt by angiotensin II. An analogous effect was found on the phosphorylation status of Akt downstream effectors, the forkhead box (Fox) proteins O1 and O4. Altogether, these results indicate that angiotensin II signaling in human preadipose cells involves an ERK1,2-dependent attenuation of Akt activity, whose impact on the biological functions under its regulation is not fully understood.


Effects of cholesterol oxides on cell death induction and calcium increase in human neuronal cells (SK-N-BE) and evaluation of the protective effects of docosahexaenoic acid (DHA; C22:6 n-3).
Some oxysterols are associated with neurodegenerative diseases. Their lipotoxicity is characterized by an oxidative stress and induction of apoptosis. To evaluate the capacity of these molecules to trigger cellular modifications involved in neurodegeneration, human neuronal cells SK-N-BE were treated with 7-ketocholesterol, 7α- and 7β-hydroxycholesterol, 6α- and 6β-hydroxycholesterol, 4α- and 4β-hydroxycholesterol, 24(S)-hydroxycholesterol and 27-hydroxycholesterol (50-100μM, 24h) without or with docosahexaenoic acid (50μM). The effects of these compounds on mitochondrial activity, cell growth, production of reactive oxygen species (ROS) and superoxide anions (O2(-)), catalase and superoxide dismutase activities were determined. The ability of the oxysterols to induce increases in Ca(2+) was measured after 10min and 24h of treatment using fura-2 videomicroscopy and Von Kossa staining, respectively. Cholesterol, 7-ketocholesterol, 7β-hydroxycholesterol, and 24(S)-hydroxycholesterol (100μM) induced mitochondrial dysfunction, cell growth inhibition, ROS overproduction and cell death. A slight increase in the percentage of cells with condensed and/or fragmented nuclei, characteristic of apoptotic cells, was detected. With 27-hydroxycholesterol, a marked increase of O2(-) was observed. Increases in intracellular Ca(2+) were only found with 7-ketocholesterol, 7β-hydroxycholesterol, 24(S)-hydroxycholesterol and 27-hydroxycholesterol. Pre-treatment with docosahexaenoic acid showed some protective effects depending on the oxysterol considered. According to the present data, 7-ketocholesterol, 7β-hydroxycholesterol, 24(S)-hydroxycholesterol and 27-hydroxycholesterol could favor neurodegeneration by their abilities to induce mitochondrial dysfunctions, oxidative stress and/or cell death associated or not with increases in cytosolic calcium levels.


The innovator will prevail in glucose monitoring.
As well as the expanding diabetes market for glucose-monitoring devices, there are other applications for these products and opportunities for companies with the will to innovate. One area that is explored here is the intensive care unit.


[History, principles of construction of combined vaccine and problems of vaccine prophylaxis with their use].
This problem article deals with modern trends in the creation and use of combined vaccines, the advantage and drawbacks of multicomponent preparations. The data on competition, interference and synergism in the action of individual components making up combined vaccines, on the cellular and molecular mechanisms of the interaction of antigens are presented. Specific features of the development of immunity induced by complex vaccines with due regard to the action of genetic and phenotypic signs, as well as the formation of humoral and cell-mediated immunity. The priority of Russian researchers in the development of the first combined vaccines is pointed out. On the basis of theoretical knowledge and accumulated practical experience the main principles of the construction and properties of combined vaccines have been formulated.


[Morphology of the parietal peritoneum and peritoneal exudate in peritonitis].
Biopsies of the peritoneum and cells of peritoneal exudate were examined in 36 patients with various phases and extension of acute purulent peritonitis. In 34 of them biopsy was taken before and after therapeutic treatment with low-frequency ultrasound. In all the cases the material was examined by light microscope, in 9 by means of transmission electron microscopy, in 2 by means of scanning electron microscopy. The peritoneum of 3 patients undergoing planned operation was studied as the control. It was shown that on the first day of peritonitis development there occurred active contraction of endotheliocytes of peritoneal microvessels with divergence of intercellular contacts resulting in sharp extravasation of the liquid, condensation of the blood formed elements, and formation of stases and microthrombi. The latter prevented marginal stay and emigration of leukocytes. Ultrasonic treatment facilitated the destruction of microthrombi and was accompanied by intensive leukocyte migration.


A novel approach for production of an active N-terminally truncated Ulp1 (SUMO protease 1) catalytic domain from Escherichia coli inclusion bodies.
The SUMO fusion system is widely used to facilitate recombinant expression and production of difficult-to-express proteins. After purification of the recombinant fusion protein, removal of the SUMO-tag is accomplished by the yeast cysteine protease, SUMO protease 1 (Ulp1), which specifically recognizes the tertiary fold of the SUMO domain. At present, the expression of the catalytic domain, residues 403-621, is used for obtaining soluble and biologically active Ulp1. However, we have observed that the soluble and catalytically active Ulp1403-621 inhibits the growth of E. coli host cells. In the current study, we demonstrate an alternative route for producing active Ulp1 catalytic domain from a His-tagged N-terminally truncated variant, residues 416-621, which is expressed in E. coli inclusion bodies and subsequently refolded. Expressing the insoluble Ulp1416-621 variant is advantageous for achieving higher production yields. Approximately 285 mg of recombinant Ulp1416-621 was recovered from inclusion bodies isolated from 1 L of high cell-density E. coli batch fermentation culture. After Ni2+-affinity purification of inactive and denatured Ulp1416-621 in 7.5 M urea, different refolding conditions with varying l-arginine concentration, pH, and temperature were tested. We have successfully refolded the enzyme in 0.25 M l-arginine and 0.5 M Tris-HCl (pH 7) at room temperature. Approximately 80 mg of active Ulp1416-621 catalytic domain can be produced from 1 L of high cell-density E. coli culture. We discuss the applicability of inclusion body-directed expression and considerations for obtaining high expression yields and efficient refolding conditions to reconstitute the active protein fold.


Sex differences in the vascular access of hemodialysis patients: a cohort study.
We describe differences for probability of receiving a fistula attempt, achieving fistula use, remaining catheter-free and the rate of access-related procedures as a function of sex. Prospectively collected vascular access data on incident dialysis patients from five Canadian programs using the Dialysis Measurement Analysis and Reporting System to determine differences in fistula-related outcomes between women and men. The probability of receiving a fistula attempt and the probability of fistula use were determined using binary logistic regression. Catheter and fistula procedure rates were described using Poisson regression. We studied time to fistula attempt and time to fistula use, accounting for competing risks. We included 1446 (61%) men and 929 (39%) women. Men had a lower body mass index (P < 0.001) and were more likely to have coronary artery disease (P < 0.001) and peripheral vascular disease (p < 0.001). A total of 688 (48%) men and 403 (43%) women received a fistula attempt. Women were less likely to receive a fistula attempt by 6 months {odds ratio [OR] 0.64 [95% confidence interval (CI) 0.52-0.79]} and to achieve catheter-free use of their fistula by 1 year [OR 0.38 (95% CI 0.27-0.53)]. At an average of 2.30 access procedures per person-year, there is no difference between women and men [incidence rate ratio (IRR) 0.97 (95% CI 0.87-1.07)]. Restricting to those with a fistula attempt, women received more procedures [IRR 1.16 (95% CI 1.04-1.30)] attributed to increased catheter procedures [IRR 1.50 (95% CI 1.27-1.78)]. There was no difference in fistula procedures [IRR women versus men 0.96 (95% CI 0.85-1.07)]. Compared with men, fewer women undergo a fistula attempt. This disparity increases after adjusting for comorbidities. Women have the same number of fistula procedures as men but are less likely to successfully use their fistula.


Genome sequencing and analysis of plant growth-promoting attributes from Leclercia adecarboxylata.
Plant growth-promoting bacteria are ecological alternatives for fertilization, mainly for gramineous. Since plant x bacteria interaction is genotype and strain dependent, searching for new strains may contribute to the development of new biofertilizers. We aim to characterize plant growth-promoting capacity of Leclercia adecarboxylata strain Palotina, formerly isolated by our group in corn. A single isolated colony was taken and its genome was sequenced using Illumina technology. The whole genome was compared to other Leclercia adecarboxylata strains, and their biological and growth-promoting traits, such as P solubilization and auxin production, were tested. Following that, a 4.8 Mb genome of L. adecarboxylata strain Palotina was assembled and the functional annotation was carried out. This paper is the first to report the genes associated with plant growth promotion demonstrating in vitro indole acid production by this strain. These results project the endophyte as a potential biofertilizer for further commercial exploitation.


Venous and Arterial Thromboses: Two Sides of the Same Coin?
Arterial and venous thromboses are sustained by development of intraluminal thrombi, respectively, within the venous and arterial systems. The composition and structure of arterial and venous thrombi have been historically considered as being very different. Arterial thrombi (conventionally defined as "white") have been traditionally proposed to be composed mainly of fibrin and platelet aggregates, whilst venous thrombi (conventionally defined as "red") have been proposed as mostly being enriched in fibrin and erythrocytes. This archaic dichotomy seems ever more questionable, since it barely reflects the pathophysiology of thrombus formation in vivo. Both types of thrombi are actually composed of a complex fibrin network but, importantly, also contain essentially the same blood-borne cells (i.e., red blood cells, leukocytes, and platelets), and it is only the relative content of these individual elements that differ between venous and arterial clots or, otherwise, between thrombi generated under different conditions of blood flow and shear stress. Convincing evidence now suggests that either white or red intracoronary thrombi may be present in patients with myocardial infarction and, even more importantly, red thrombi may be more prone to distal embolization during percutaneous coronary intervention than those with lower content of erythrocytes. Conversely, it is now accepted that components traditionally considered to be involved "only" in arterial thrombosis are also represented in venous thrombosis. Thus, platelets comprise important components of venous clots, although they may be present in lower amounts here than in arterial thrombi, and von Willebrand factor is also represented in both arterial and venous thrombi. Of importance, such evidence thus supports the concept that adjunctive treatment normally associated to prevention of arterial thrombosis (e.g., aspirin) may have a role also in prevention and treatment of venous thrombosis.


Risk factors for local recurrence after breast-conserving surgery.
It is not clear whether risk factors for local recurrence after breast-conserving surgery differ in women having surgery for in situ or invasive cancer. Furthermore, the Nottingham Prognostic Index (NPI) and Nottingham Histological Grade (NHG) have been little studied as determinants of local recurrence risk. In a case-control study (491 cases and 1098 controls) nested within a cohort of 7502 women who had surgery for in situ or invasive cancer of the breast, patient characteristics, tumour characteristics and treatment-related variables were evaluated as risk factors for local recurrence. Multivariate conditional logistic regression analyses showed that age below 40 years, tumour multicentricity and an unclear or unknown surgical margin were significant risk factors for local recurrence. Radiotherapy to the breast and adjuvant hormone therapy were protective. Cancer in situ was not associated with a higher risk of local recurrence than invasive cancer (odds ratio 1.0, 95 per cent confidence interval 0.8 to 1.3). NHG and NPI were not helpful in determining risk of local recurrence. Margin status, age, tumour multicentricity, and use of radiotherapy and adjuvant hormone therapy were important determinants of risk of local recurrence. With the exception of surgical margin, variables related to the quality of surgical management did not predict risk of local recurrence.


Hypertensive crisis and myocardial infarction after fluorescein angiography.
Fluorescein angiography is commonly used in evaluation of retinopathy. Adverse reactions are uncommon but severe cardiovascular difficulties seem to occur selectively in older men with hypertension and ischemic heart disease. The 54-year-old patient described had hypertensive crisis and resulting myocardial infarction after fluorescein angiography.


Objective measures of emotion related to brand attitude: a new way to quantify emotion-related aspects relevant to marketing.
With this study we wanted to test the hypothesis that individual like and dislike as occurring in relation to brand attitude can be objectively assessed. First, individuals rated common brands with respect to subjective preference. Then, they volunteered in an experiment during which their most liked and disliked brand names were visually presented while three different objective measures were taken. Participant's eye blinks as responses to acoustic startle probes were registered with electromyography (EMG) (i) and their skin conductance (ii) and their heart rate (iii) were recorded. We found significantly reduced eye blink amplitudes related to liked brand names compared to disliked brand names. This finding suggests that visual perception of liked brand names elicits higher degrees of pleasantness, more positive emotion and approach-oriented motivation than visual perception of disliked brand names. Also, skin conductance and heart rate were both reduced in case of liked versus disliked brand names. We conclude that all our physiological measures highlight emotion-related differences depending on the like and dislike toward individual brands. We suggest that objective measures should be used more frequently to quantify emotion-related aspects of brand attitude. In particular, there might be potential interest to introduce startle reflex modulation to measure emotion-related impact during product development, product design and various further fields relevant to marketing. Our findings are discussed in relation to the idea that self reported measures are most often cognitively polluted.


Effects of N-acetyl-L-cysteine on lifespan, locomotor activity and stress-resistance of 3 Drosophila species with different lifespans.
N-acetyl-L-cysteine (NAC) is a derivative of the sulphur-containing amino acid L-cysteine with potential anti-aging properties. We studied 3 Drosophila species with contrast longevity differences (D. virilis is longest-lived, D. kikkawai is shortest-lived and D. melanogaster has moderate lifespan) to test the effects of NAC at 8 different concentrations (from 10 nM to 100 mM) on the lifespan, stress-resistance and locomotor activity. Except the adverse effects of highest (10 mM and 100 mM) concentrations NAC demonstrated sexually opposite and male-biased effects on Drosophila lifespan, stress-resistance and locomotor activity and not satisfied the criteria of a geroprotector in terms of the reproducibility of lifespan extending effects in different model organisms. The concentration- and sex-dependent changes in the relative expression levels of the antioxidant genes (Cat/CG6871 and Sod1/CG11793) and genes involved in hydrogen sulfide biosynthesis (Cbs/CG1753, Eip55E/CG5345 and Nfs1/CG12264) suggest the involvement of hormetic mechanisms in the geroprotective effects of NAC.


[Methodolocical issues of naturalistic observational studies on the economic evaluation of neuroleptic treatment for schizophrenic disease].
Methodological problems of prospective natural trials are discussed. The application of adequate methods is demonstrated by analysing the effects of antipsychotic medical treatment on the probability and the costs of inpatient episodes of 307 patients with schizophrenia for 2.5 years. Selection bias is controlled by the propensity score method. Effects of medical treatment on the incidence of inpatient episodes are analysed by means of a random-effect logit model. Effects of medical treatment on the costs of inpatient episodes are analysed by means of a random-effect Tobit model. Results of the study show that antipsychotic medical treatment reduces the probability and the costs of inpatient treatment irrespective of the type of neuroleptic drugs. The hypothesis of a higher effectivity of atypical neuroleptics in comparison to conventional antipsychotics regarding the reduction of the incidence and the costs of inpatient treatment was not supported. Beyond the effects of medical treatment the study results indicate that improving social support and competence for coping with life events as well as providing community mental health services may reduce the risk and the costs of inpatient episodes.


Reversible gating of endocannabinoid plasticity in the amygdala by chronic stress: a potential role for monoacylglycerol lipase inhibition in the prevention of stress-induced behavioral adaptation.
Chronic stress is the primary environmental risk factor for the development and exacerbation of affective disorders, thus understanding the neuroadaptations that occur in response to stress is a critical step in the development of novel therapeutics for depressive and anxiety disorders. Brain endocannabinoid (eCB) signaling is known to modulate emotional behavior and stress responses, and levels of the eCB 2-arachidonoylglycerol (2-AG) are elevated in response to chronic homotypic stress exposure. However, the role of 2-AG in the synaptic and behavioral adaptations to chronic stress is poorly understood. Here, we show that stress-induced development of anxiety-like behavior is paralleled by a transient appearance of low-frequency stimulation-induced, 2-AG-mediated long-term depression at GABAergic synapses in the basolateral amygdala, a key region involved in motivation, affective regulation, and emotional learning. This enhancement of 2-AG signaling is mediated, in part, via downregulation of the primary 2-AG-degrading enzyme monoacylglycerol lipase (MAGL). Acute in vivo inhibition of MAGL had little effect on anxiety-related behaviors. However, chronic stress-induced anxiety-like behavior and emergence of long-term depression of GABAergic transmission was prevented by chronic MAGL inhibition, likely via an occlusive mechanism. These data indicate that chronic stress reversibly gates eCB synaptic plasticity at inhibitory synapses in the amygdala, and in vivo augmentation of 2-AG levels prevents both behavioral and synaptic adaptations to chronic stress.


Obesity in adolescents with chronic fatigue syndrome: an observational study.
Identify the prevalence of obesity in patients with chronic fatigue syndrome (CFS) compared with healthy adolescents, and those identified with CFS in a population cohort. Cross-sectional analysis of multiple imputed data. Data from UK paediatric CFS/myalgic encephalomyelitis (CFS/ME) services compared with data collected at two time points in the Avon Longitudinal Study of Parents and Children (ALSPAC). 1685 adolescents who attended a CFS/ME specialist service between 2004 and 2014 and 13 978 adolescents aged approximately 13 years and 16 years participating in the ALSPAC study. Body mass index (BMI) (kg/m2), sex-specific and age-specific BMI Z-scores (relative to the International Obesity Task Force cut-offs) and prevalence of obesity (%). Adolescents who had attended specialist CFS/ME services had a higher prevalence of obesity (age 13 years: 9.28%; age 16 years: 16.43%) compared with both adolescents classified as CFS/ME in ALSPAC (age 13 years: 3.72%; age 16 years: 5.46%) and those non-CFS in ALSPAC (age 13 years: 4.18%; age 16 years: 4.46%). The increased odds of obesity in those who attended specialist services (relative to non-CFS in ALSPAC) was apparent at both 13 years (OR: 2.31 (1.54 to 3.48)) and 16 years, with a greater likelihood observed at 16 years (OR: 4.07 (2.04 to 8.11)). We observed an increased prevalence of obesity in adolescents who were affected severely enough to be referred to a specialist CFS/ME service. Further longitudinal research is required in order to identify the temporal relationship between the two conditions.


Practices Among Local Public Health Agencies to Support Evidence-Based Decision Making: A Qualitative Study.
Evidence-based decision making (EBDM) capacity in local public health departments is foundational to meeting both organizational and individual competencies and fulfilling expanded roles. In addition to on-the-job training, organizational supports are needed to prepare staff; yet, less is known in this area. This qualitative study explores supportive management practices instituted as part of a training and technical assistance intervention. This qualitative study used a semistructured interview guide to elicit participants' descriptions and perceptions via key informant interviews. Verbatim transcripts were coded and thematic analyses were conducted. Local public health departments in a US Midwestern state participated in the project. Seventeen middle managers and staff from 4 local health departments participated in remote, audio-recorded interviews. Following delivery of a 3½-day in-person training, the study team met with health department leadership teams for department selection of supportive agency policies and procedures to revise or newly create. Periodic remote meetings included collaborative problem-solving, sharing of informational resources, and encouragement. Included management practices instituted to support EBDM and impact on day-to-day work as described by the interview participants. Leadership and middle management practices deemed most helpful included dedicating staff; creating specific guidelines; setting expectations; and providing trainings, resources, and guidance. Health departments with a preexisting supportive organizational culture and climat e were able to move more quickly and fully to integrate supportive management practices. Workforce development included creation of locally tailored overviews for all staff members and onboarding of new staff. Staff wanted additional hands-on skill-building trainings. Several worked with partners to incorporate evidence-based processes into community health improvement plans. Ongoing on-the-job experiential learning is needed to integrate EBDM principles into day-to-day public health practice. Management practices established by leadership teams and middle managers can create supportive work environments for EBDM integration.


Antipsychotic use and myocardial infarction in older patients with treated dementia.
Antipsychotic agents (APs) are commonly prescribed to older patients with dementia. Antipsychotic use is associated with an increased risk of ischemic stroke in this population. Our study aimed to investigate the association of AP use with the risk of acute myocardial infarction (MI). A retrospective cohort of community-dwelling older patients who initiated cholinesterase inhibitor treatment was identified between January 1, 2000, and December 31, 2009, using the Quebec, Canada, prescription claims database. From this source cohort, all new AP users during the study period were matched with a random sample of AP nonusers. The risk of MI was evaluated using Cox proportional hazards models, adjusting for age, sex, cardiovascular risk factors, psychotropic drug use, and propensity scores. In addition, a self-controlled case series study using conditional Poisson regression modeling was conducted. Among the source cohort of 37,138 cholinesterase inhibitor users, 10,969 (29.5%) initiated AP treatment. Within 1 year of initiating AP treatment, 1.3% of them had an incident MI. Hazard ratios for the risk of MI after initiation of AP treatment were 2.19 (95% CI, 1.11-4.32) for the first 30 days, 1.62 (95% CI, 0.99-2.65) for the first 60 days, 1.36 (95% CI, 0.89-2.08) for the first 90 days, and 1.15 (95% CI, 0.89-1.47) for the first 365 days. The self-controlled case series study conducted among 804 incident cases of MI among new AP users yielded incidence rate ratios of 1.78 (95% CI, 1.26-2.52) for the 1- to 30-day period, 1.67 (95% CI, 1.09-2.56) for the 31- to 60-day period, and 1.37 (95% CI, 0.82-2.28) for the 61- to 90-day period. Antipsychotic use is associated with a modest and time-limited increase in the risk of MI among community-dwelling older patients treated with cholinesterase inhibitors.


Modulation of human vascular endothelial cell behaviors by nanotopographic cues.
Basement membranes possess a complex three-dimensional topography in the nanoscale and submicron range which have been shown to profoundly modulate a large menu of fundamental cell behaviors. Using the topographic features found in native vascular endothelial basement membranes as a guide, polyurethane substrates were fabricated containing anisotropically ordered ridge and groove structures and isotropically ordered pores from 200 nm to 2000 nm in size. We investigated the impact of biomimetic length-scale topographic cues on orientation/elongation, proliferation and migration on four human vascular endothelial cell-types from large and small diameter vessels. We found that all cell-types exhibited orientation and alignment with the most pronounced response on anisotropically ordered ridges > or =800 nm. HUVEC cells were the only cell-type examined to demonstrate a decrease in proliferation in response to the smallest topographic features regardless of surface order. On anisotropically ordered surfaces all cell-types migrated preferentially parallel to the long axis of the ridges, with the greatest increase in cell migration being observed on the 1200 nm pitch. In contrast, cells did not exhibit any preference in direction or increase in migration speed on isotropically ordered surfaces. Overall, our data demonstrate that surface topographic features impact vascular endothelial cell behavior and that the impact of features varies with the cell behavior being considered, topographic feature scale, surface order, and the anatomic origin of the cell being investigated.


Post-transplantation pancreatitis.
Post-transplantation pancreatitis occurs with a frequency of about 3 per cent and carries a mortality of 70 per cent. An average of 216 days following transplantation elapses before the onset of pancreatitis and tends to occur most frequently in men in the fourth decade of life. A multiplicity of factors which predispose to pancreatitis are present in the post-transplant period and may be responsible for the frequency and lethality of post-transplant pancreatitis. Among these factors are immunosuppressive therapy, consisting of azathioprine and steroids, secondary hyperparathyroidism and increased susceptibility to infection.


The impact of young age on breast cancer outcome.
We conducted a retrospective analysis in order to evaluate the impact of age on women aged less than 35 years affected by breast cancer. Between January 1972 and December 2006, 346 patients aged less than 35 years underwent adjuvant treatment at Florence University. The mean age of the patient population was 32 years (range 22-35): 76 patients were under 30 years old, the remaining were above 30 years old. In our series, 215 patients received adjuvant radiotherapy to whole breast after conservative surgery, 131 patients underwent mastectomy without subsequent radiation therapy and 323 patients had lymphadenectomy; 191 patients received adjuvant chemotherapy, 73 with anthracycline-containing regimen. With a median time of 2.5 years (range 6 months to 27.6 years) local relapses were observed in 67 cases (19.4%). At the multivariate analysis of local disease-free survival, ductal and ductal plus lobular histotypes, having more than 3 positive nodes, and age emerged as independent significant relapse predictors (p = 0.018, p = 0.0005, p = 0.003 and p = 0.024, respectively). For the DSS analysis, the median follow-up was 6.8 years (range 0.6-36.7 years). At the multivariate analysis, age (p = 0.0038), positive nodes (p = 0.0035) and distant metastases (p < 0.0001) resulted to be independent death predictors. Patients younger than 30 had a worse prognosis. At the univariate analysis also local relapse resulted to be statistically significant (p = 0.0004). Anthracycline-based chemotherapy seems to improve the outcome of these patients. However, there is an urgent need for tailored treatment investigations within the framework of randomized, controlled clinical trials.