Baccharis dracunculifolia, the main botanical source of Brazilian green propolis, displays antiulcer activity.
Baccharis dracunculifolia is the most important botanical source of Southeastern Brazilian propolis, known as green propolis for its colour. In a previous study, we described the gastric protective effect of the hydroalcoholic extract of Brazilian green propolis. We therefore wanted to investigate the possibility of using B. dracunculifolia extract for antiulcer treatment. This study was undertaken to evaluate the anti-ulcerogenic property of hydroalcoholic extract of B. dracunculifolia aerial parts. The HPLC analysis of the chemical composition of B. dracunculifolia extract used in this study revealed the presence mainly of cinnamic acid derivates and flavonoids. Doses of 50, 250 and 500 mg/kg of B. dracunculifolia crude extract and positive controls (omeprazole or cimetidine) significantly diminished the lesion index, the total lesion area and the percentage of lesion compared with negative control groups. The percentage of ulcer inhibition was significantly higher in groups treated with B. dracunculifolia, cimetidine or omeprazole, with all protocols used, compared with negative control groups. Regarding the model of gastric secretion, reductions in the volume of gastric juice and total acidity were observed, as well as an increase in the gastric pH. These results were similar to results from studies carried out with green propolis extract. Although more investigations are required, our results suggest that B. dracunculifolia has potential to be used as a phytotherapic preparation for the treatment of gastric ulcer.


Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group.
Angioedema is defined as localized and self-limiting edema of the subcutaneous and submucosal tissue, due to a temporary increase in vascular permeability caused by the release of vasoactive mediator(s). When angioedema recurs without significant wheals, the patient should be diagnosed to have angioedema as a distinct disease. In the absence of accepted classification, different types of angioedema are not uniquely identified. For this reason, the European Academy of Allergy and Clinical Immunology gave its patronage to a consensus conference aimed at classifying angioedema. Four types of acquired and three types of hereditary angioedema were identified as separate forms from the analysis of the literature and were presented in detail at the meeting. Here, we summarize the analysis of the data and the resulting classification of angioedema.


Quality Improvement in Acute Ischemic Stroke Care in Taiwan: The Breakthrough Collaborative in Stroke.
In the management of acute ischemic stroke, guideline adherence is often suboptimal, particularly for intravenous thrombolysis or anticoagulation for atrial fibrillation. We sought to improve stroke care quality via a collaborative model, the Breakthrough Series (BTS)-Stroke activity, in a nationwide, multi-center activity in Taiwan. A BTS Collaborative, a short-term learning system for a large number of multidisciplinary teams from hospitals, was applied to enhance acute ischemic stroke care quality. Twenty-four hospitals participated in and submitted data for this stroke quality improvement campaign in 2010-2011. Totally, 14 stroke quality measures, adopted from the Get With The Guideline (GWTG)-Stroke program, were used to evaluate the performance and outcome of the ischemic stroke patients. Data for a one-year period from 24 hospitals with 13,181 acute ischemic stroke patients were analyzed. In 14 hospitals, most stroke quality measures improved significantly during the BTS-activity compared with a pre-BTS-Stroke activity period (2006-08). The rate of intravenous thrombolysis increased from 1.2% to 4.6%, door-to-needle time ≤60 minutes improved from 7.1% to 50.8%, symptomatic hemorrhage after intravenous thrombolysis decreased from 11.0% to 5.6%, and anticoagulation therapy for atrial fibrillation increased from 32.1% to 64.1%. The yearly composite measures of five stroke quality measures revealed significant improvements from 2006 to 2011 (75% to 86.3%, p<0.001). The quarterly composite measures also improved significantly during the BTS-Stroke activity. In conclusion, a BTS collaborative model is associated with improved guideline adherence for patients with acute ischemic stroke. GWTG-Stroke recommendations can be successfully applied in countries besides the United States.


Lead sorption performance on active silica derived from fly ash.
The object of this study was to estimate the sorption property of active silica derived from fly ash after separation of silica and aluminum. The specific surface area of active silica enlarged to 115 m(2)/g was compared with the original fly ash (4 m(2)/g). Field emission scanning electron microscopy displayed the active silica, which looked like a honeycomb or curly layer with many lamellae that formed many mesopores. The uptake kinetics indicated that the residual concentration of Pb(2+) in the aqueous solution decreased rapidly from the initial 1.25 mg/L to less than 10 μg/L within 45 min. The removal efficiency of Pb(2+) on active silica was pH dependent. The increase in pH value promoted Pb(2+) removal because the negative surface provided more electrostatic attraction sites. A stepwise non-linear isotherm was obtained because the lamellae of active silica provided a heterogeneous surface with various kinds of active sites. The maximum sorption amount of Pb on active silica was more than 90 mg/g, which was better than some pristine-activated carbon.


Thermo-sensitive transient receptor potential vanilloid channel-1 regulates intracellular calcium and triggers chromogranin A secretion in pancreatic neuroendocrine BON-1 tumor cells.
Transient receptor potential channels (TRPs) regulate tumor growth via calcium-dependent mechanisms. The (thermosensitive) capsaicin receptor TRPV1 is overexpressed in numerous highly aggressive cancers. TRPV1 has potent antiproliferative activity and is therefore potentially applicable in targeted therapy of malignancies. Recently, we characterized TRPM8 functions in pancreatic neuroendocrine tumors (NETs), however, the role of TRPV1 is unknown. Here, we studied the expression and the role of TRPV1 in regulating intracellular Ca(2+) and chromogranin A (CgA) secretion in pancreatic NET BON-1 cell line and in primary NET cells (prNET). TRPV1 expression was detected by RT-PCR, Western blot and immunofluorescence. Intracellular free Ca(2+) ([Ca(2+)](i)) was measured by fura-2; TRPV1 channel currents by the planar patch-clamp technique. Nonselective cation currents were analyzed by a color-coded plot method and CgA secretion by ELISA. Pancreatic BON-1 cells and NETs express TRPV1. Pharmacological blockade of TRPs by La(3+) (100 μM) or by ruthenium-red (RuR) or by capsazepine (CPZ) (both at 10 μM) suppressed the capsaicin (CAP)- or heat-stimulated increase of [Ca(2+)](i) in NET cells. CAP (20 μM) also increased nonselective cation channel currents in BON-1 cells. Furthermore, CAP (10 μM) stimulated CgA secretion, which was inhibited by CPZ or by RuR (both 10 μM). La(3+) potently reduced both stimulated and the basal CgA secretion. Our study shows for the first time that TRPV1 is expressed in pancreatic NETs. Activation of TRPV1 translates into changes of intracellular Ca(2+), a known mechanism triggering the secretion of CgA. The clinical relevance of TRPV1 activation in NETs requires further investigations.


Comparison of BGM and PLC/PRC/5 cell lines for total culturable viral assay of treated sewage.
The objective of this study was to compare PLC/PRF/5 and BGM cell lines for use in a total culturable viral assay (TCVA) of treated sewage effluents. Samples were collected before and after chlorination from an activated sludge wastewater treatment plant and from the effluent of a high-rate enhanced flocculation system, followed by UV light disinfection. Cell monolayers were observed for cytopathic effect (CPE) after two passages of 14 days each. Monolayers exhibiting viral CPE were tested for the presence of adenoviruses and enteroviruses by PCR or reverse transcription-PCR. Eight percent of the samples exhibited CPE on BGM cells, and 57% showed CPE on PLC/PRF/5 cells. Only enteroviruses were detected on the BGM cells, while 30% and 52% of the samples were positive for enteroviruses and adenoviruses, respectively, on the PLC/PRF/5 cells. Thirty percent of the samples were positive for both adenoviruses and enteroviruses in chlorinated activated sludge effluent. Thirty percent of the samples were positive for adenoviruses in the UV treatment effluent, but no enteroviruses were detected. In conclusion, the PLC/PRF/5 cells were more susceptible than BGM cells to viruses found in treated sewage. The use of BGM cells for TCVA may underestimate viral concentration in sewage effluent samples. The PLC/PRF/5 cells were more susceptible to adenoviruses, which is important in the evaluation of UV disinfection systems because adenoviruses are highly resistant to UV inactivation.


Ocular Injury Caused by the Sprayed Venom of the Asian Giant Hornet (Vespa mandarinia).
This report presents the details of a case of sight-threatening injury in the right eye of a 77-year-old man which was caused by the venom of the Asian giant hornet (Vespa mandarinia). The patient was not stung, rather the venom was sprayed into his eye. Although the injured eye was washed as a first aid treatment, persistent corneal defect, corneal endothelial decompensation, iris atrophy, pupil dilation, and mature cataract were observed and a hand movement visual acuity was recorded 8 weeks after the injury. Since a slight a-wave was detected in his electroretinogram (ERG) result after the corneal epithelial defect had healed, we performed cataract surgery and Descemet stripping automated endothelial keratoplasty (DSAEK). After the DSAEK, the cornea of the right eye became clearer; however, the visual acuity of his right eye did not improve. Fundus examination revealed branch retinal artery occlusion but no optic disc atrophy. ERG showed that the a-wave amplitude of the injured eye recorded after the surgery was almost half of that of the fellow eye. The iris atrophy and mature cataract show that the sprayed Vespa venom of the Asian giant hornet can permeate into the intraocular area even without stinging. Whether the venom directly affects retinal function is unclear, but the decreased a-wave of the injured eye shows that the venom caused damage of retinal function in some way. Irrigation of the anterior chamber as well as eye washing is needed as a first aid treatment in similar cases.


Development of Fluorescent Assay for Monitoring of Dehalogenase Activity.
The rapid accumulation of sequence data and powerful protein engineering techniques providing large mutant libraries have greatly heightened interest in efficient methods for biochemical characterization of proteins. Herein is reported a continuous assay for screening of enzymatic activity. The assay is developed and tested with the model enzymes haloalkane dehalogenases and relies upon a fluorescent change of a derivative of 8-hydroxypyrene-1,3,6-trisulphonic acid due to the pH drop associated with the dehalogenation reactions. The assay is performed in a microplate format using a purified enzyme, cell-free extract or intact cells, making the analysis quick and simple. The method exhibits high sensitivity with a limit of detection of 0.06 mM. The assay is successfully validated with gas chromatography and then applied for screening of 12 haloalkane dehalogenases with the environmental pollutant bis(2-chloroethyl) ether and chemical warfare agent sulfur mustard. Six enzymes exhibited detectable activity with both substrates. The within-day variability of the assay for five replicates (n = 5) was 21%.


Improving preventive service delivery through office systems.
Rates of childhood immunizations and other preventive services are lower in many practices than national goals and providers' own estimates. Office systems have been used in adult settings to improve the delivery of preventive care, but their effectiveness in pediatric practices is unknown. This study was designed to determine whether a group of primary care practices in 1 community could implement office-based quality improvement systems that would significantly improve their delivery of childhood preventive services. The study was part of a larger community-wide intervention study reported in a preceding study. All the major providers of primary care to children in 1 community were recruited and agreed to participate (N = 8 practices). Project staff worked on-site with improvement teams in each practice to develop tailored systems to assess and improve the delivery of immunizations and screening for anemia, tuberculosis, and lead exposure. Office-based quality improvement systems typically involved some combination of chart prescreening, risk assessment forms, Post-it prompts, flow-sheets, reminder/recall systems, and patient education materials. Office systems also often involved redistributing responsibilities among office staff. All 8 participating practices created improvement teams. Project staff met with the practices 10 to 15 times over 12 months. After the period of office assistance, the overall rates for all preventive services except tuberculosis screening increased by amounts that were both clinically and statistically significant. Absolute percent improvements included: complete immunizations at 12 months, 7%; complete immunizations at 24 months, 12%; anemia screening, 30%; lead screening, 36%. The amount of improvement achieved varied considerably between practices. Office systems and the principles of quality improvement that underlie them seem to be effective in improving the delivery of childhood preventive services. Important predisposing factors may exist within practices that affect the likelihood that an individual practice will make significant improvements. prevention, immunizations, improvement, office systems, primary care.


The regulator of MAT2 (ROM2) protein binds to early maturation promoters and represses PvALF-activated transcription.
The regulation of maturation (MAT)- and late embryogenesis (LEA)-specific gene expression in dicots involves factors related to ABI3, a seed-specific component of the abscisic acid signal transduction pathways from Arabidopsis. In French bean (Phaseolus vulgaris), the ABI3-like factor, PvALF, activates transcription from MAT promoters of phytohemagglutinin (DLEC2) and beta-phaseolin (PHS beta) genes. We describe the regulator of MAT2 (ROM2) as a basic leucine zipper (bZIP) DNA binding protein that recognizes motifs with symmetric (ACGT) and asymmetric (ACCT) core elements present in both MAT promoters. ROM2 antagonizes trans-activation of the DLEC2 promoter by PvALF in transient expression assays. Repression was abolished by mutations that prevented binding of ROM2 to the DLEC2 seed enhancer region. Moreover, a hybrid protein composed of a PvALF activation domain and the DNA binding and dimerization domain of ROM2 activated gene expression, indicating that ROM2 recognizes the DLEC2 enhancer in vivo; consequently, ROM2 functions as a DNA binding site-dependent repressor. Supershift analysis of nuclear proteins, using a ROM2-specific antibody, revealed an increase in ROM2 DNA binding activity during seed desiccation. A corresponding increase in ROM2 mRNA coincided with the period when DLEC2 mRNA levels declined in embryos. These results demonstrate developmental regulation of the ROM2 repressor and point to a role for this factor in silencing DLEC2 transcription during late embryogenesis.


Capsaicin administration inhibits the abducent branch but excites the thyroarytenoid branch of the recurrent laryngeal nerves in the rat.
Our recent study showed that both inspiratory and expiratory activities of the recurrent laryngeal nerve (RLN) were enhanced by capsaicin administration in the rat (Lu IJ, Ku LC, Lin JT, Lee KZ, and Hwang JC. Chin J Physiol 45: 143-154, 2002). There are two intralaryngeal branches of the RLN: one innervates the thyroarytenoid (TA) muscle and the other innervates the abductor (Abd) muscles. To examine whether these two intralaryngeal branches respond similarly to capsaicin administration, their discharges as well as activities of the phrenic nerve (PNA) and the superior laryngeal nerve (SLNA) were monitored in anesthetized and ventilated rats at normocapnia in hyperoxia. The low dose of capsaicin (0.625 microg/kg) produced a cardiopulmonary chemoreflex, showing apnea, a decrease in PNA, hypotension, and bradycardia, and significant decreases in SLNA and the activity of the Abd branch. Concurrently, there was an increase in the intralaryngeal TA activity during both apnea and the recovery from apnea. The high dose of capsaicin (1.25 microg/kg) evoked larger chemoreflexive responses and laryngeal nerve activities. In addition, both doses of capsaicin initiated a similar delay in the onset of Abd activity and SLNA but an earlier onset for the TA branch to commence during inspiration. A bilateral vagotomy abolished the laryngeal responses to capsaicin administration. However, PNA and blood pressure were enhanced with capsaicin administration after the vagotomy. These results suggest that laryngeal adduction in response to capsaicin administration is vagal afferent dependent and that it may also represent reflexive protection for the airway and lungs.


The MOF-driven synthesis of supported palladium clusters with catalytic activity for carbene-mediated chemistry.
The development of catalysts able to assist industrially important chemical processes is a topic of high importance. In view of the catalytic capabilities of small metal clusters, research efforts are being focused on the synthesis of novel catalysts bearing such active sites. Here we report a heterogeneous catalyst consisting of Pd4 clusters with mixed-valence 0/+1 oxidation states, stabilized and homogeneously organized within the walls of a metal-organic framework (MOF). The resulting solid catalyst outperforms state-of-the-art metal catalysts in carbene-mediated reactions of diazoacetates, with high yields (>90%) and turnover numbers (up to 100,000). In addition, the MOF-supported Pd4 clusters retain their catalytic activity in repeated batch and flow reactions (>20 cycles). Our findings demonstrate how this synthetic approach may now instruct the future design of heterogeneous catalysts with advantageous reaction capabilities for other important processes.


Chamomile, a novel and selective COX-2 inhibitor with anti-inflammatory activity.
Inducible cyclooxygenase (COX-2) has been implicated in the process of inflammation and carcinogenesis. Chamomile has long been used in traditional medicine for the treatment of inflammatory diseases. In this study we aimed to investigate whether chamomile interferes with the COX-2 pathway. We used lipopolysaccharide (LPS)-activated RAW 264.7 macrophages as an in vitro model for our studies. Chamomile treatment inhibited the release of LPS-induced prostaglandin E(2) in RAW 264.7 macrophages. This effect was found to be due to inhibition of COX-2 enzyme activity by chamomile. In addition, chamomile caused reduction in LPS-induced COX-2 mRNA and protein expression, without affecting COX-1 expression. The non-steroidal anti-inflammatory drug, sulindac and a specific COX-2 inhibitor, NS398, were shown to act similarly in LPS-activated RAW 264.7 cells. Our data suggest that chamomile works by a mechanism of action similar to that attributed to non-steroidal anti-inflammatory drugs. These findings add a novel aspect to the biological profile of chamomile which might be important for understanding the usefulness of aqueous chamomile extract in the form of tea in preventing inflammation and cancer.


Meta-Analytic Bayesian Model For Differentiating Intestinal Tuberculosis from Crohn's Disease.
Distinguishing intestinal tuberculosis (ITB) from Crohn's disease (CD) is difficult, although studies have reported clinical, endoscopic, imaging, and laboratory findings that help to differentiate these two diseases. We aimed to produce estimates of the predictive power of these findings and construct a comprehensive model to predict the probability of ITB vs. CD. A systematic literature search for studies differentiating ITB from CD was conducted in MEDLINE, PUBMED, and EMBASE from inception until September 2015. Fifty-five distinct meta-analyses were performed to estimate the odds ratio of each predictive finding. Estimates with a significant difference between CD and ITB and low to moderate heterogeneity (I2<50%) were incorporated into a Bayesian prediction model incorporating the local pretest probability. Thirty-eight studies comprising 2,117 CD and 1,589 ITB patients were included in the analyses. Findings in the model that significantly favored CD included male gender, hematochezia, perianal disease, intestinal obstruction, and extraintestinal manifestations; endoscopic findings of longitudinal ulcers, cobblestone appearance, luminal stricture, mucosal bridge, and rectal involvement; pathological findings of focally enhanced colitis; and computed tomographic enterography (CTE) findings of asymmetrical wall thickening, intestinal wall stratification, comb sign, and fibrofatty proliferation. Findings that significantly favored ITB included fever, night sweats, lung involvement, and ascites; endoscopic findings of transverse ulcers, patulous ileocecal valve, and cecal involvement; pathological findings of confluent or submucosal granulomas, lymphocyte cuffing, and ulcers lined by histiocytes; a CTE finding of short segmental involvement; and a positive interferon-γ release assay. The model was validated by gender, clinical manifestations, endoscopic, and pathological findings in 49 patients (27 CD, 22 ITB). The sensitivity, specificity, and accuracy for diagnosis of ITB were 90.9%, 92.6%, and 91.8%, respectively. A Bayesian model based on the meta-analytic results is presented to estimate the probability of ITB and CD calibrated to local prevalence. This model can be applied to patients using a publicly available web application.


Prevalence of monoclonal gammopathy of undetermined significance: a systematic review.
Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma cell disorder that is associated with a lifelong risk of multiple myeloma. We conducted a systematic review of all studies investigating the prevalence and incidence of MGUS in the online database PubMed. The review was conducted from January 6, 2009, through January 15, 2010. The following MeSH search headings were used: monoclonal gammopathy, benign and prevalence; monoclonal gammopathy, benign and incidence; paraproteinemia and prevalence; and paraproteinemia and incidence. Articles were limited to those written in English and published by January 2009. Fourteen studies that met prespecified criteria were included and systematically assessed to identify the most accurate prevalence estimates of MGUS based on age, sex, and race. On the basis of our systematic review, we estimate that the crude prevalence of MGUS in those older than 50 years is 3.2% in a predominantly white population. Studies in white and Japanese populations demonstrate a clear increase in prevalence with age. The prevalence is also affected by sex: 3.7% and 2.9% in white men and women, respectively; and 2.8% and 1.6% in Japanese men and women, respectively. Additionally, MGUS is significantly more prevalent in black people (5.9%-8.4%) than in white people (3.0%-3.6%). We conclude that MGUS is a common premalignant plasma cell disorder in the general population of those older than 50 years. The prevalence increases with age and is affected by race, sex, family history, immunosuppression, and pesticide exposure. These results are important for counseling, clinical care, and the design of clinical studies in high-risk populations.


Assessment of neurodisability and malnutrition in children in Africa.
Neurodevelopmental delay, neurodisability, and malnutrition interact to contribute a significant burden of disease in global settings. Assessments which are well integrated with plans of management or advice are most likely to improve outcomes. Assessment tools used in clinical research and programming to evaluate outcomes include developmental and cognitive tools that vary in complexity, sensitivity, and validity as well as the target age of assessment. Few tools have been used to measure socioemotional outcomes and fewer to assess the disabled child with malnutrition. There is a paucity of tools used clinically which actually provide families and professionals with advice to improve outcomes. Brain imaging, electroencephalography, audiology, and visual assessment can also be used to assess the effect of malnutrition on brain structure and function. The interaction of neurodisability and malnutrition is powerful, and both need to be considered when assessing children. Without an integrated approach to assessment and management, we will not support children and families to reach their best potential outcomes.


The dimensionality of color vision in carriers of anomalous trichromacy.
Some 12% of women are carriers of the mild, X-linked forms of color vision deficiencies called "anomalous trichromacy." Owing to random X chromosome inactivation, their retinae must contain four classes of cone rather than the normal three; and it has previously been speculated that these female carriers might be tetrachromatic, capable of discriminating spectral stimuli that are indistinguishable to the normal trichromat. However, the existing evidence is sparse and inconclusive. Here, we address the question using (a) a forced-choice version of the Rayleigh test, (b) a test using multidimensional scaling to reveal directly the dimensionality of the participants' color space, and (c) molecular genetic analyses to estimate the X-linked cone peak sensitivities of a selected sample of strong candidates for tetrachromacy. Our results suggest that most carriers of color anomaly do not exhibit four-dimensional color vision, and so we believe that anomalous trichromacy is unlikely to be maintained by an advantage to the carriers in discriminating colors. However, 1 of 24 obligate carriers of deuteranomaly exhibited tetrachromatic behavior on all our tests; this participant has three well-separated cone photopigments in the long-wave spectral region in addition to her short-wave cone. We assess the likelihood that behavioral tetrachromacy exists in the human population.


Stimulation of matrix vesicle enzyme activity in osteoblast-like cells by 1,25(OH)2D3 and transforming growth factor beta (TGF beta).
After demonstrating the presence of matrix vesicles in three osteosarcoma cell lines, MG-63, ROS 17/2.8 and MC-3T3-E1, we sought to determine whether two major enzymes localized to matrix vesicles, alkaline phosphatase and phospholipase A2, could be regulated by 1,25(OH)2D3 and/or TGF beta. Intravesicular calcification is probably dependent on these two enzymes. Alkaline phosphatase is essential for hydrolysis of phosphate-containing substrates and phospholipase A2 hydrolyzes diacylphosphatides in a calcium-mediated manner at lipid-aqueous interfaces leading to changes in membrane fluidity and possibly breakdown of the matrix vesicle. The 1,25(OH)2D3 induced increase of alkaline phosphatase in bone cells is localized to the matrix vesicle. TGF beta also increased alkaline phosphatase activity in two of the cell lines, MG-63 and ROS 17/2.8 but to a greater degree than 1,25(OH)2D3. Matrix vesicle alkaline phosphatase activity exhibited a greater response than that in the plasma membrane. TGF beta increased phospholipase A2 activity in both matrix vesicles and plasma membranes, therefore, no targeting was observed with respect to this enzyme. When TGF beta was combined with 1,25(OH)2D3, 1,25(OH)2D3 had no effect on phospholipase A2 and did not interfere with TGF beta stimulation of phospholipase A2 activity. When 1,25(OH)2D3 and TGF beta were combined, a tremendous synergy was observed in alkaline phosphatase specific activity in both plasma membranes and matrix vesicles with targeting to matrix vesicles. Therefore, TGF beta not only plays an important role in matrix formation and differentiation, but works in conjunction with 1,25(OH)2D3 to greatly potentiate the effects seen with 1,25(OH)2D3 alone.


Anaphylaxis admissions to UK critical care units between 2005 and 2009.
Anaphylaxis is a life-threatening emergency that may necessitate admission to a critical care unit. There are no reports of the frequency of admission to critical care units for patients with anaphylaxis or indeed any description of their demographic characteristics or outcomes. We analysed all physician-diagnosed cases of anaphylaxis over a 5-year period in national audit data from critical care units across the UK. Over the period 2005-2009, there were 81 paediatric and 1269 adult admissions with anaphylaxis admitted to UK critical care units (0.1% of admissions to paediatric units and 0.3% of admissions to adult units). Absolute numbers in both children and adults rose year on year. There were comparable proportions of admissions in female and male children (female = 47% and male = 53%; rate ratios (RR) = 0.88, 95% CI 0.64-1.20), but a greater proportion of adult female admissions (female = 65% and male = 35%; RR = 1.83, 95% CI 1.68-1.99). Survival to unit discharge was 95% (77/81) for children, and survival to hospital discharge was 92% (1166/1269) for adults. Each UK critical care unit is likely to see at least one anaphylaxis case per year. The number of admissions has risen in both children and adults. Although admission ratios between the sexes were comparable in children, there was a female preponderance in adult life. Survival rates were high at over 90%.


[Acute management and research of stroke in Taiwan: an update].
The presentation discussed certain issues in the management and research of cerebrovascular diseases in Taiwan. In the first part of the presentation, the acute management of stroke in Taiwan, I have revealed the results of the Taiwan Thrombolytic Therapy for Acute Ischemic Stroke (TTT-AIS) study (rt-PA). TTT-AIS was a multicentre, observational study, which enrolled 244 eligible patients with acute ischemic stroke from 23 hospitals from December 2004 to July 2008. The standard-dose group (0.9 mg/kg) had higher rates of symptomatic ICH and mortality within three months, twice that of the lower-dose group. This pattern was more prominent in older patients. Besides, significantly lower independence rate was also observed among patients ≥ 70 years old receiving standard-dose than lower-dose. This study suggests that the standard dose of alteplase 0.9 mg/kg may not be optimal for treating aged Chinese. However, the optimal dose of rt-PA for ischemic stroke in Chinese should be based on more broad and convincing evidences. Randomized trials of lower versus higher dose of rt-PA are needed. The second part of the presentation discussed about the relationship between age-related cerebral white matter lesions (leukoaraiosis) and jugular venous reflux (JVR), one of the plenty researches about cerebral venous insufficiency in Taiwan. The presentation introduced current evidences and rationales favoring venous ischemia as a role in the pathophysiology of leukoaraiosis.


The patterns of health care utilization by elderly Europeans: frailty and its implications for health systems.
To examine the patterns of health care utilization by the elderly and test the influence of functional decline. We used the three regular waves of the SHARE survey to estimate the influence of frailty on health care utilization in 10 European countries. We controlled for the main correlates of frailty and unobserved individual effects. The frail elderly increase their primary and hospital care utilization before the onset of disability. Multimorbidity moderates the effect of frailty on care utilization. The prevalence of frailty is high in most countries and is expected to increase. This renders frailty prevention and remediation efforts imperative for two complementary reasons: to promote healthier aging and to reduce the burden on health systems.


Muscle protein and amino acid turnover in rats in vivo: effects of short-term and prolonged starvation.
1. Protein loss in muscle can be caused by decreased protein synthesis, increased breakdown or both. In small animals the tracer incorporation technique is mostly used to measure protein synthesis, but for degradation measurements in vitro or ex vivo settings are required. In human and large animal studies the arteriovenous dilution technique is used because it enables the measurement of synthesis and breakdown rates simultaneously. The applicability in small animals has not yet been proven. We used a starvation model to compare both techniques. 2. A primed constant infusion of L-[2,6-(3H)]phenylalanine was given to male Lewis rats after 16, 40, 64 and 112 h starvation. Protein synthesis rates of the gastrocnemius muscle were measured by the incorporation technique and compared with hindquarter protein turnover calculated in a two- and three-compartment arteriovenous dilution model. 3. Whole-body phenylalanine rate of appearance decreased from 456 +/- 32 after 16 h to 334 +/- 34 (nmol min-1 100 g-1 body weight) after 112 h starvation. Protein synthesis rates of the gastrocnemius muscle measured by the tracer incorporation technique decreased from 3.6 +/- 0.4 after 16 h starvation to 2.2 +/- 0.3 after 64 h starvation and 1.8 +/- 0.4 (%/day) after 112 h starvation. Hindquarter protein breakdown, calculated with the tracer dilution model, increased after 112 h starvation from 28 +/- 12 to 77 +/- 15 nmol min-1 100 g-1 body weight. Using the tracer dilution model, however, the calculated protein synthesis rate across the hindquarter also increased after prolonged starvation (29 +/- 7 and 68 +/- 16 nmol min-1 100 g-1 body weight after 16 and 112 h respectively). In conjunction with this, calculated bidirectional membrane transport rates were also enhanced. Using valine and glutamine as tracers, the enhanced amino acid turnover rates were confirmed. 4. In conclusion, our results show that during short periods of starvation both methods give similar results. After prolonged starvation, however, an opposite change in disappearance rate and protein synthesis rate was observed. Assumptions made to calculate protein turnover using the arteriovenous dilution model may account for the discrepancy and care must be taken with the interpretation when using only one model in anaesthetized small animals.


In vivo time-resolved microtomography reveals the mechanics of the blowfly flight motor.
Dipteran flies are amongst the smallest and most agile of flying animals. Their wings are driven indirectly by large power muscles, which cause cyclical deformations of the thorax that are amplified through the intricate wing hinge. Asymmetric flight manoeuvres are controlled by 13 pairs of steering muscles acting directly on the wing articulations. Collectively the steering muscles account for <3% of total flight muscle mass, raising the question of how they can modulate the vastly greater output of the power muscles during manoeuvres. Here we present the results of a synchrotron-based study performing micrometre-resolution, time-resolved microtomography on the 145 Hz wingbeat of blowflies. These data represent the first four-dimensional visualizations of an organism's internal movements on sub-millisecond and micrometre scales. This technique allows us to visualize and measure the three-dimensional movements of five of the largest steering muscles, and to place these in the context of the deforming thoracic mechanism that the muscles actuate. Our visualizations show that the steering muscles operate through a diverse range of nonlinear mechanisms, revealing several unexpected features that could not have been identified using any other technique. The tendons of some steering muscles buckle on every wingbeat to accommodate high amplitude movements of the wing hinge. Other steering muscles absorb kinetic energy from an oscillating control linkage, which rotates at low wingbeat amplitude but translates at high wingbeat amplitude. Kinetic energy is distributed differently in these two modes of oscillation, which may play a role in asymmetric power management during flight control. Structural flexibility is known to be important to the aerodynamic efficiency of insect wings, and to the function of their indirect power muscles. We show that it is integral also to the operation of the steering muscles, and so to the functional flexibility of the insect flight motor.


Positively biased processing of self-relevant social feedback.
Receiving social feedback such as praise or blame for one's character traits is a key component of everyday human interactions. It has been proposed that humans are positively biased when integrating social feedback into their self-concept. However, a mechanistic description of how humans process self-relevant feedback is lacking. Here, participants received feedback from peers after a real-life interaction. Participants processed feedback in a positively biased way, i.e., they changed their self-evaluations more toward desirable than toward undesirable feedback. Using functional magnetic resonance imaging we investigated two feedback components. First, the reward-related component correlated with activity in ventral striatum and in anterior cingulate cortex/medial prefrontal cortex (ACC/MPFC). Second, the comparison-related component correlated with activity in the mentalizing network, including the MPFC, the temporoparietal junction, the superior temporal sulcus, the temporal pole, and the inferior frontal gyrus. This comparison-related activity within the mentalizing system has a parsimonious interpretation, i.e., activity correlated with the differences between participants' own evaluation and feedback. Importantly, activity within the MPFC that integrated reward-related and comparison-related components predicted the self-related positive updating bias across participants offering a mechanistic account of positively biased feedback processing. Thus, theories on both reward and mentalizing are important for a better understanding of how social information is integrated into the human self-concept.


The smart house for older persons and persons with physical disabilities: structure, technology arrangements, and perspectives.
Smart houses are considered a good alternative for the independent life of older persons and persons with disabilities. Numerous intelligent devices, embedded into the home environment, can provide the resident with both movement assistance and 24-h health monitoring. Modern home-installed systems tend to be not only physically versatile in functionality but also emotionally human-friendly, i.e., they may be able to perform their functions without disturbing the user and without causing him/her any pain, inconvenience, or movement restriction, instead possibly providing him/her with comfort and pleasure. Through an extensive survey, this paper analyzes the building blocks of smart houses, with particular attention paid to the health monitoring subsystem as an important component, by addressing the basic requirements of various sensors implemented from both research and clinical perspectives. The paper will then discuss some important issues of the future development of an intelligent residential space with a human-friendly health monitoring functional system.


Detection of secondary binding sites in proteins using fragment screening.
Proteins need to be tightly regulated as they control biological processes in most normal cellular functions. The precise mechanisms of regulation are rarely completely understood but can involve binding of endogenous ligands and/or partner proteins at specific locations on a protein that can modulate function. Often, these additional secondary binding sites appear separate to the primary binding site, which, for example for an enzyme, may bind a substrate. In previous work, we have uncovered several examples in which secondary binding sites were discovered on proteins using fragment screening approaches. In each case, we were able to establish that the newly identified secondary binding site was biologically relevant as it was able to modulate function by the binding of a small molecule. In this study, we investigate how often secondary binding sites are located on proteins by analyzing 24 protein targets for which we have performed a fragment screen using X-ray crystallography. Our analysis shows that, surprisingly, the majority of proteins contain secondary binding sites based on their ability to bind fragments. Furthermore, sequence analysis of these previously unknown sites indicate high conservation, which suggests that they may have a biological function, perhaps via an allosteric mechanism. Comparing the physicochemical properties of the secondary sites with known primary ligand binding sites also shows broad similarities indicating that many of the secondary sites may be druggable in nature with small molecules that could provide new opportunities to modulate potential therapeutic targets.


Effects of developmental arsenite exposure on hippocampal synapses in mouse offspring.
Arsenic exposure through drinking water can impair the learning and memory ability of children in China and other countries. Synaptic plasticity plays a key role in the process of learning and memory. Alterations in the expression of presynaptic and postsynaptic proteins can be used to evaluate synaptic plasticity, and further to evaluate impairment in learning and memory ability. Thereby, the aim of this study was to explore the mechanisms underlying arsenic neurotoxicity by focusing on alterations in the hippocampal synapses of mouse offspring induced by developmental arsenite exposure. Mother mice and their offspring were exposed to 0, 25, 50 or 100 mg L-1 arsenite via drinking water from the first day of gestation until postnatal day (PND) 35. The spatial learning and memory ability of PND 35 mice was evaluated using a Morris water maze. The levels of speciated arsenicals in the brain of PND 7, 14, 21 and 35 mice were analyzed by hydride generation coupled with atomic absorption spectrophotometry. Synaptic structure and protein expression of postsynaptic density protein-95 (PSD-95) and synaptophysin (SYP) in the hippocampus of PND 7, 14, 21 and 35 mice were examined. The findings from this study disclosed that the spatial learning ability of mice could be impaired by exposure to 25 mg L-1 arsenite; however spatial memory ability could not be impaired until exposure to 100 mg L-1 arsenite. The thickness of the postsynaptic density (PSD) decreased, whereas the width of the synaptic cleft widened significantly in arsenite exposure groups. Moreover, protein expression of both PSD-95 and SYP decreased significantly in arsenite exposure groups. In conclusion, the results of this study demonstrated that developmental arsenite exposure could depress the expression of synaptic proteins, subsequently cause alteration in synaptic structures, and finally contribute to arsenite-induced deficits in spatial learning and memory ability in mouse offspring.


Gamma delta T cell help of B cells is induced by repeated parasitic infection, in the absence of other T cells.
gamma delta T cells, like alpha beta T cells, are components of all well-studied vertebrate immune systems. Yet, the contribution of gamma delta T cells to immune responses is poorly characterized. In particular, it has not been resolved whether gamma delta cells, independent of any other T cells, can help B cells produce immunoglobulin and form germinal centers, anatomical foci of specialized T cell-B cell collaboration. TCR beta-/- mice, which lack all T cells except gamma delta T cells, routinely displayed higher levels of antibody than fully T cell-deficient mice. Repeated parasitic infection of TCR beta-/- mice, but not of T cell-deficient mice, increased antibody levels and induced germinal centers that contained B cells and monoclonal gamma delta cells in close juxtaposition. However, antibody specificities were more commonly against self than against the challenging pathogen. gamma delta T cell-B cell help was not induced by repeated inoculation of TCR beta-/- mice with mycobacterial antigens. In the absence of any other T cells, gamma delta T cell-B cell collaboration can be significantly enhanced by repeated infection. However, the lack of obvious enrichment for antibodies against the challenging pathogen distinguishes gamma delta T cell help from alpha beta T cell help induced under analogous circumstances. The increased production of generalized antibodies may be particularly relevant to the development of autoimmunity, which commonly occurs in patients suffering from alpha beta T cell deficiencies, such as AIDS.


Factor XIa inhibitors: A review of the patent literature.
Anticoagulants are the mainstay for prevention and/or treatment of thrombotic disorders. Each clinically used anticoagulant is associated with significant adverse consequences, especially bleeding. Factor XIa (FXIa), a key factor involved in the amplification of procoagulation signal, has been suggested as a major target for anticoagulant drug discovery because of reduced risk of bleeding. Our literature search uncovered dozens of industrial and academic patents on the discovery of novel FXIa/FXI inhibitors. Small peptidomimetics, sulfated glycosaminoglycan mimetics, polypeptides, antisense oligonucleotides, and monoclonal antibodies have been developed as inhibitors of FXIa. Although many agents are in early discovery/development phases, the activity and safety of a few have been evaluated in various animal models and in humans. FXIa is a promising drug target for development of effective anticoagulants with limited bleeding complications. Literature reveals a major trend in the number of patent applications over the last three years. These inhibitors exploit different approaches for target inhibition. Allosteric modulation of FXIa and biosynthetic inhibition of FXI are mechanistically unique. Despite initial results in patients undergoing knee anthroplasty as with antisense oligonucleotides, major advances should be realized, particularly with respect to pharmacokinetics, for FXI/FXIa inhibitors to enter the clinic.


Predictors of completion of a hepatitis B vaccination schedule in attendees at a primary health care centre.
In Australia, rates of hepatitis B (HBV) transmission continue to be higher in certain populations, including commercial sex workers and injecting drug users (IDU). This study aims to identify rates and predictors of completion of a HBV vaccination schedule in 'high-risk' attendees of a primary health care centre in Sydney. All clients who attended Kirketon Road Centre, a primary health care centre located in Kings Cross, Sydney, with no evidence of HBV immunity were included in the cohort. The study design was observational with historical controls. The main outcome measure was completion of a three-dose HBV vaccine schedule in the study period. Among 2085 clients who received a first vaccination, 1013 (49%) received a second and 435 (21%) received a third vaccination. Univariate analysis found that significant predictors of completion of the vaccine schedule were intention to administer an accelerated schedule (OR 1.49, P = 0.004), not being an IDU (OR 1.29, P = 0.02) and shorter time between first visit and first vaccine dose (OR 1.24, P for trend <0.0001); however, on multivariate analysis, not being an IDU was no longer a predictor of vaccine completion. Implementation of an accelerated vaccination schedule improved completion rates but they were still low, despite the provision of free vaccination in a service specifically targeting the needs of sex workers, IDU and other marginalised populations. Increasing HBV vaccine uptake and completion rates in Australian adults is an important public health issue not only for the prevention of HBV but also for the future application of other potential vaccines, including those against HIV and hepatitis C.


Developing an ethical guideline for clinical teaching in Tehran University of Medical Sciences.
Clinical education is an essential part of medical trainees' education process, and curriculum planners agree that it should be based on ethical standards and principles in the medical field. Nevertheless, no explained and codified criteria have been developed for ethics in clinical teaching. This study was aimed to develop an ethical guideline for medical students and teachers as the first and most important step in respecting patients' rights in educational centers. The initial draft included the codes of ethics in clinical education and was developed based on library studies. Subsequently, it was improved through a qualitative study using semi-structured interviews and focus group sessions with medical students, patients, and medical teachers in educational hospitals affiliated to Tehran University of Medical Sciences. The improved draft was reviewed and validated by a medical expert panel to prepare the final draft. The codes derived from this study included patients' choices and rights in purely educational procedures, and special considerations for a) obtaining informed consent for educational procedures; b) performing procedures on deceased persons, patients under anesthesia and those lacking decision making capacity; c) educational visual recordings of the patients; and d) safety monitoring in clinical education. The guideline developed in this study incorporates codes of ethics into clinical training. Therefore, in addition to providing efficient education, the interests of patients and their rights are respected, and the ethical sensitivity of learners in primacy of patients' best interests will be preserved and enhanced.


All-optical processing with molecular switches.
A gradual transition from electrical to optical networks is accompanying the rapid progress of telecommunication technology. The urge for enhanced transmission capacity and speed is dictating this trend. In fact, large volumes of data encoded on optical signals can be transported rapidly over long distances. Their propagation along specific routes across a communication network is ensured by a combination of optical fibers and optoelectronic switches. It is becoming apparent, however, that the interplay between the routing electrical stimulations and the traveling optical signals will not be able to support the terabit-per-second capacities that will be needed in the near future. Electrical inputs cannot handle the immense parallelism potentially possible with optical signals. Operating principles to control optical signals with optical signals must be developed. Molecular and supramolecular switches are promising candidates for the realization of innovative materials for information technology. Binary digits can be encoded in their chemical, electrical, or optical inputs and outputs to execute specific logic functions. We have developed a simple strategy to gate optical signals with optical signals by using a photoactive molecular switch. We have demonstrated that NAND, NOR, and NOT operations can be implemented exclusively with optical inputs and optical outputs coupling from one to three switching elements. Our remarkably simple approach to all-optical switching might lead to the development of a new generation of devices for digital processing and communication technology.


Sodalis glossinidius prevalence and trypanosome presence in tsetse from Luambe National Park, Zambia.
Tsetse flies are the biological vectors of African trypanosomes, the causative agents of sleeping sickness in humans and nagana in animals. The tsetse endosymbiont Sodalis glossinidius has been suggested to play a role in tsetse susceptibility to infection. Here we investigate the prevalence of African trypanosomes within tsetse from the Luambe National Park, Zambia and if there is an association between S. glossinidius and presence of trypanosomes within the tsetse examined. Tsetse representing three species (Glossina brevipalpis, Glossina morsitans morsitans and Glossina pallidipes), were sampled from Luambe National Park, Zambia. Following DNA extraction, PCR was used to examine the tsetse for presence of trypanosomes and the secondary endosymbiont S. glossinidius. S. glossinidius infection rates varied significantly between tsetse species, with G. brevipalpis (93.7%) showing the highest levels of infection followed by G. m. morsitans (17.5%) and G. pallidipes (1.4%). ITS-PCR detected a wide variety of trypanosomes within the tsetse that were analysed. Significant differences were found in terms of trypanosome presence between the three tsetse species. A high proportion of G. m. morsitans were shown to carry T. brucei s.l. DNA (73.7%) and of these around 50% were positive for Trypanosoma brucei rhodesiense. T. vivax, T. godfreyi, T. simiae, T. simiae Tsavo and T. congolense were also detected. No association was found between the occurrence of S. glossinidius and the presence of trypanosome DNA in any of the three tsetse species tested. The current work shows that T. b. rhodesiense was circulating in Luambe National Park, representing a risk for people living in the park or surrounding area and for tourists visiting the park. The differences in trypanosome DNA presence observed between the different tsetse species tested may indicate host feeding preferences, as the PCR will not discriminate between a fly with an active/resident infection compared to a refractory fly that has fed on an infected animal. This makes it difficult to establish if S. glossinidius may play a role in the susceptibility of tsetse flies to trypanosome infection.


Monocyte function-associated antigen expression during and after pediatric cardiac surgery.
Systemic inflammatory response syndrome and infectious complications are major causes of morbidity and mortality after cardiopulmonary bypass. Recent work in adult patients suggests that the balance between proinflammatory and anti-inflammatory mediators is important. We hypothesized that the expression of different function-related receptors on circulating monocytes might reflect the net response of the inflammatory reaction. We performed a prospective and observational study in a tertiary pediatric cardiac center in a population of children (n = 40) undergoing elective cardiac surgery. Expression of receptors on the surface of monocytes was assessed before, during, and after surgical intervention. Early monocyte activation was demonstrated by changes of the expression of the chemokine receptor CCR2, which was inversely correlated with plasma levels of monocyte chemotactic protein 1 (rho = -0.54, P = .002). High levels of monocyte chemotactic protein 1 were found in children with high expression of the adhesion receptor CD11b/CD18 on circulating monocytes. The intensity of human leukocyte antigen DR expression rapidly decreased in all children after the onset of cardiopulmonary bypass ( P < .001). Low human leukocyte antigen DR expression was correlated with increased plasma levels of interleukin 10 postoperatively. Children who had signs of bacterial pneumonia postoperatively had lower levels of human leukocyte antigen DR expression before surgical intervention (relative risk, 13.3; P = .007). The expression of monocyte function-related receptors is altered after cardiac surgery. Early activation of monocytes by monocyte chemotactic protein 1 possibly released from the heart is followed by an anti-inflammatory response with suppression of monocyte human leukocyte antigen DR expression. The increased risk of bacterial infection after pediatric cardiac surgery can be anticipated by surveillance of monocyte function before surgical intervention.


Dietary galactose inhibits GDF-9 mediated follicular development in the rat ovary.
Clinical evidence suggests an association between galactosemia and premature ovarian failure, but the mechanism is still not fully understood. Growth differentiation factor-9 (GDF-9) is thought to be an obligatory growth factor during the gonadotropin-independent phase of folliculogenesis. The objective of this study was to examine the effects of galactose on initiation of folliculogenesis in the peripubertal interval and the connection between galactose toxicity and GDF-9 expression in the ovary. After immature Long-Evans rats (n = 10) were fed a diet consisting of 20% galactose for 19 days, whole body, ovary and uterine weights were measured. Serum estradiol and progesterone concentrations were measured by radioimmunoassay. Ovarian follicles were counted by morphometric analysis and GDF-9 expression was investigated by immunohistochemistry and immunoblot assay. Galactose treatment did not affect the onset of puberty as marked by the time of vaginal opening. The galactose diet significantly decreased the number of healthy growing follicles. The results of immunoblot assay showed that both bands corresponding to propeptide and mature forms of GDF-9 decreased with the galactose diet about 90 and 70%, respectively. The results of immunohistochemical staining showed that the GDF-9 positive follicle number and the ratio of GDF-9 positive to GDF negative (primordial/non-growing) follicles significantly decreased with this high galactose diet. The present study suggests that a high galactose diet inhibits follicular development, possibly through down-regulation of GDF-9 in the rat ovary, implying that GDF-9 may be involved in galactose-related ovarian toxicity.


Exfoliative cytology for diagnosing basal cell carcinoma and other skin cancers in adults.
Early accurate detection of all skin cancer types is essential to guide appropriate management, reduce morbidity and improve survival. Basal cell carcinoma (BCC) is usually localised to the skin but has potential to infiltrate and damage surrounding tissue, while cutaneous squamous cell carcinoma (cSCC) and melanoma have a much higher potential to metastasise and ultimately lead to death. Exfoliative cytology is a non-invasive test that uses the Tzanck smear technique to identify disease by examining the structure of cells obtained from scraped samples. This simple procedure is a less invasive diagnostic test than a skin biopsy, and for BCC it has the potential to provide an immediate diagnosis that avoids an additional clinic visit to receive skin biopsy results. This may benefit patients scheduled for either Mohs micrographic surgery or non-surgical treatments such as radiotherapy. A cytology scrape can never give the same information as a skin biopsy, however, so it is important to better understand in which skin cancer situations it may be helpful. To determine the diagnostic accuracy of exfoliative cytology for detecting basal cell carcinoma (BCC) in adults, and to compare its accuracy with that of standard diagnostic practice (visual inspection with or without dermoscopy). Secondary objectives were: to determine the diagnostic accuracy of exfoliative cytology for detecting cSCC, invasive melanoma and atypical intraepidermal melanocytic variants, and any other skin cancer; and for each of these secondary conditions to compare the accuracy of exfoliative cytology with visual inspection with or without dermoscopy in direct test comparisons; and to determine the effect of observer experience. We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We also studied the reference lists of published systematic review articles. Studies evaluating exfoliative cytology in adults with lesions suspicious for BCC, cSCC or melanoma, compared with a reference standard of histological confirmation. Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). Where possible we estimated summary sensitivities and specificities using the bivariate hierarchical model. We synthesised the results of nine studies contributing a total of 1655 lesions to our analysis, including 1120 BCCs (14 datasets), 41 cSCCs (amongst 401 lesions in 2 datasets), and 10 melanomas (amongst 200 lesions in 1 dataset). Three of these datasets (one each for BCC, melanoma and any malignant condition) were derived from one study that also performed a direct comparison with dermoscopy. Studies were of moderate to poor quality, providing inadequate descriptions of participant selection, thresholds used to make cytological and histological diagnoses, and blinding. Reporting of participants' prior referral pathways was particularly poor, as were descriptions of the cytodiagnostic criteria used to make diagnoses. No studies evaluated the use of exfoliative cytology as a primary diagnostic test for detecting BCC or other skin cancers in lesions suspicious for skin cancer. Pooled data from seven studies using standard cytomorphological criteria (but various stain methods) to detect BCC in participants with a high clinical suspicion of BCC estimated the sensitivity and specificity of exfoliative cytology as 97.5% (95% CI 94.5% to 98.9%) and 90.1% (95% CI 81.1% to 95.1%). respectively. When applied to a hypothetical population of 1000 clinically suspected BCC lesions with a median observed BCC prevalence of 86%, exfoliative cytology would miss 21 BCCs and would lead to 14 false positive diagnoses of BCC. No false positive cases were histologically confirmed to be melanoma. Insufficient data are available to make summary statements regarding the accuracy of exfoliative cytology to detect melanoma or cSCC, or its accuracy compared to dermoscopy. The utility of exfoliative cytology for the primary diagnosis of skin cancer is unknown, as all included studies focused on the use of this technique for confirming strongly suspected clinical diagnoses. For the confirmation of BCC in lesions with a high clinical suspicion, there is evidence of high sensitivity and specificity. Since decisions to treat low-risk BCCs are unlikely in practice to require diagnostic confirmation given that clinical suspicion is already high, exfoliative cytology might be most useful for cases of BCC where the treatments being contemplated require a tissue diagnosis (e.g. radiotherapy). The small number of included studies, poor reporting and varying methodological quality prevent us from drawing strong conclusions to guide clinical practice. Despite insufficient data on the use of cytology for cSCC or melanoma, it is unlikely that cytology would be useful in these scenarios since preservation of the architecture of the whole lesion that would be available from a biopsy provides crucial diagnostic information. Given the paucity of good quality data, appropriately designed prospective comparative studies may be required to evaluate both the diagnostic value of exfoliative cytology by comparison to dermoscopy, and its confirmatory value in adequately reported populations with a high probability of BCC scheduled for further treatment requiring a tissue diagnosis.


NanoMIPs Design for Fucose and Mannose Recognition: A Molecular Dynamics Approach.
Nanoscale molecularly imprinted polymers (nanoMIPs) are powerful molecular recognition tools with broad applications in the diagnosis, prognosis, and treatment of complex diseases. In this work, fully atomistic molecular dynamics (MD) simulations are used to assist the design of nanoMIPs with recognition capacity toward l-fucose and d-mannose as prototype disease biomarkers. MD simulations were conducted on prepolymerization mixtures containing different molar ratios of the monomers N-isopropylacrylamide (NIPAM), methacrylamide (MAM), and (4-acrylamidophenyl)(amino)methaniminium acetate (AB) and fixed molar ratios of the cross-linker ethylene glycol dimethacrylate (EGDMA) in explicit acetonitrile as the porogenic solvent. Prepolymerization mixtures containing ternary mixtures of NIPAM (50%), MAM (25%), and AB (25%) exhibit the best imprinting potential for both l-fucose and d-mannose, as they maximize (i) the stability of template-monomer plus template-cross-linker interactions, (ii) the number of functional monomers plus cross-linkers organized around the template, and (iii) the number of hydrogen bonds participating in template recognition. The studied prepolymerization mixtures exhibit an overall increased recognition capacity toward d-mannose over l-fucose, which is attributed to the higher hydrogen-bonding capacity of the former template. Our results are valuable to guide the synthesis of efficient nanoMIPs for sugar recognition and provide a computational framework extensible to any other template, monomer, or cross-linker combination, thus constituting a promising strategy for the rational design of molecularly imprinted materials.


An Exploration of the Effectiveness of a Peer-Led Pain Management Program (PAP) for Nursing Home Residents with Chronic Pain and an Evaluation of Their Experiences: A Pilot Randomized Controlled Trial.
Background: 80% of nursing home residents have reported chronic pain, which is often accepted by older adults as part of aging. Peer support models are being used to help individuals manage their chronic conditions and overcome the challenges of limited healthcare resources. The aims of this study were: (i) to examine the effectiveness of a 12 week peer-led pain management program (PAP) for nursing home residents and (ii) to evaluate their experiences. Methods: A cluster randomized controlled trial (RCT) was used. The 12 week pain management program was provided for the experimental group. Outcomes were measured at three time points. The participants' satisfaction and acceptance were evaluated by a semi-structured interview after the program was completed. Results: Pain self-efficacy, pain intensity, pain interference, pain knowledge, and depression levels improved after the completion of the 12 week peer-led PAP. The pain-intensity level reported at week 12 was significantly lower in the experimental group than in the control group. Semi-structured interviews showed that the nursing home residents were satisfied with the pain education that they received. Conclusions: The 12 week peer-led PAP appeared to improve the pain-related and psychological outcome measures in nursing home residents, and the feedback on the peer-led PAP from the nursing home residents was positive.


Influence of arm lengthening in reverse shoulder arthroplasty.
Reverse shoulder arthroplasty (RSA) can improve anterior active elevation (AAE) by lengthening of the deltoid and hence increasing its lever arm. However, evaluations of functional outcomes of RSA have shown variable improvements in the range of motion. The aim of our study was to correlate humeral and arm lengthening to postoperative AAE. We reviewed 183 RSAs with a minimum follow-up of 1 year. Lengthening of the humerus and the arm was evaluated in relation to the contralateral side. We observed mean humeral lengthening of 0.2 ± 1.4 cm (range, -4.7 to +5.2 cm) and mean arm lengthening of 1.6 ± 1.9 cm (range, -5.1 to +5.4 cm). Postoperative AAE was 140° ± 27° (range, 30° to 180°). We found no significant correlation between lengthening or shortening of the humerus and AAE (P = .169). Shortening of the arm led to a mean AAE value of 122°; lengthening of 0 and 1 cm, mean AAE of 140°; lengthening of greater than 1 cm to 2.5 cm, mean AAE of 144°; and lengthening of greater than 2.5 cm, mean AAE of 147°. When we compared patients with lengthening of the arm and those with shortening, the postoperative AAE was significantly greater after arm lengthening, 145° versus 122°, with a mean difference of 23° (95% confidence interval, 13° to 33°) (P < .001). This study shows that shortening of the arm reduced AAE. With respect to arm lengthening, a lengthening threshold was not found. An objective assessment of deltoid lengthening is possible preoperatively, intraoperatively, and postoperatively, and this measure seems to correlate with the functional outcome.


Repositioning for pressure ulcer prevention in adults.
A pressure ulcer (PU), also referred to as a 'pressure injury', 'pressure sore', or 'bedsore' is defined as an area of localised tissue damage that is caused by unrelieved pressure, friction or shearing forces on any part of the body. PUs commonly occur in patients who are elderly and less mobile, and carry significant human and economic impacts. Immobility and physical inactivity are considered to be major risk factors for PU development and the manual repositioning of patients in hospital or long-term care is a common pressure ulcer prevention strategy. The objectives of this review were to:1) assess the effects of repositioning on the prevention of PUs in adults, regardless of risk or in-patient setting;2) ascertain the most effective repositioning schedules for preventing PUs in adults; and3) ascertain the incremental resource consequences and costs associated with implementing different repositioning regimens compared with alternate schedules or standard practice. We searched the following electronic databases to identify reports of the relevant randomised controlled trials: the Cochrane Wounds Group Specialised Register (searched 06 September 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 8); Ovid MEDLINE (1948 to August, Week 4, 2013); Ovid EMBASE (1974 to 2013, Week 35); EBESCO CINAHL (1982 to 30 August 2013); and the reference sections of studies that were included in the review. Randomised controlled trials (RCTs), published or unpublished, that assessed the effects of any repositioning schedule or different patient positions and measured PU incidence in adults in any setting. Two review authors independently performed study selection, risk of bias assessment and data extraction. We included three RCTs and one economic study representing a total of 502 randomised participants from acute and long-term care settings. Two trials compared the 30º and 90º tilt positions using similar repositioning frequencies (there was a small difference in frequency of overnight repositioning in the 90º tilt groups between the trials). The third RCT compared alternative repositioning frequencies.All three studies reported the proportion of patients developing PU of any grade, stage or category. None of the trials reported on pain, or quality of life, and only one reported on cost. All three trials were at high risk of bias.The two trials of 30º tilt vs. 90º were pooled using a random effects model (I² = 69%) (252 participants). The risk ratio for developing a PU in the 30º tilt and the standard 90º position was very imprecise (pooled RR 0.62, 95% CI 0.10 to 3.97, P=0.62, very low quality evidence). This comparison is underpowered and at risk of a Type 2 error (only 21 events).In the third study, a cluster randomised trial, participants were randomised between 2-hourly and 3-hourly repositioning on standard hospital mattresses and 4 hourly and 6 hourly repositioning on viscoelastic foam mattresses. This study was also underpowered and at high risk of bias. The risk ratio for pressure ulcers (any category) with 2-hourly repositioning compared with 3-hourly repositioning on a standard mattress was imprecise (RR 0.90, 95% CI 0.69 to 1.16, very low quality evidence). The risk ratio for pressure ulcers (any category) was compatible with a large reduction and no difference between 4-hourly repositioning and 6-hourly repositioning on viscoelastic foam (RR 0.73, 95% CI 0.53 to 1.02, very low quality evidence).A cost-effectiveness analysis based on data derived from one of the included parallel RCTs compared 3-hourly repositioning using the 30º tilt overnight with standard care consisting of 6-hourly repositioning using the 90º lateral rotation overnight. In this evaluation the only included cost was nursing time. The intervention was reported to be cost saving compared with standard care (nurse time cost per patient €206.6 vs €253.1, incremental difference €-46.5; 95%CI: €-1.25 to €-74.60). Repositioning is an integral component of pressure ulcer prevention and treatment; it has a sound theoretical rationale, and is widely recommended and used in practice. The lack of robust evaluations of repositioning frequency and position for pressure ulcer prevention mean that great uncertainty remains but it does not mean these interventions are ineffective since all comparisons are grossly underpowered. Current evidence is small in volume and at risk of bias and there is currently no strong evidence of a reduction in pressure ulcers with the 30° tilt compared with the standard 90º position or good evidence of an effect of repositioning frequency. There is a clear need for high-quality, adequately-powered trials to assess the effects of position and optimal frequency of repositioning on pressure ulcer incidence.The limited data derived from one economic evaluation means it remains unclear whether repositioning every 3 hours using the 30º tilt is less costly in terms of nursing time and more effective than standard care involving repositioning every 6 hours using a 90º tilt.


High fat diet and exercise lead to a disrupted and pathogenic DNA methylome in mouse liver.
High-fat diet consumption and sedentary lifestyle elevates risk for obesity, non-alcoholic fatty liver disease, and cancer. Exercise training conveys health benefits in populations with or without these chronic conditions. Diet and exercise regulate gene expression by mediating epigenetic mechanisms in many tissues; however, such effects are poorly documented in the liver, a central metabolic organ. To dissect the consequences of diet and exercise on the liver epigenome, we measured DNA methylation, using reduced representation bisulfite sequencing, and transcription, using RNA-seq, in mice maintained on a fast food diet with sedentary lifestyle or exercise, compared with control diet with and without exercise. Our analyses reveal that genome-wide differential DNA methylation and expression of gene clusters are induced by diet and/or exercise. A combination of fast food and exercise triggers extensive gene alterations, with enrichment of carbohydrate/lipid metabolic pathways and muscle developmental processes. Through evaluation of putative protective effects of exercise on diet-induced DNA methylation, we show that hypermethylation is effectively prevented, especially at promoters and enhancers, whereas hypomethylation is only partially attenuated. We assessed diet-induced DNA methylation changes associated with liver cancer-related epigenetic modifications and identified significant increases at liver-specific enhancers in fast food groups, suggesting partial loss of liver cell identity. Hypermethylation at a subset of gene promoters was associated with inhibition of tissue development and promotion of carcinogenic processes. Our study demonstrates extensive reprogramming of the epigenome by diet and exercise, emphasizing the functional relevance of epigenetic mechanisms as an interface between lifestyle modifications and phenotypic alterations.


Influence of perinatal care on stillbirths in patients of low socio-economic class.
In a series of 12,587 deliveries in patients of low socio-economic class, there were 356 stillbirths; prospective analysis of these showed that 42.1% occurred in the 4.7% of cases in which the mother had received no antenatal care. When booked and unbooked patients were compared it was found that the rate of stillbirths due to infection and anoxia was significantly higher among unbooked patients, who also accounted for more intra-uterine deaths due to abruptio placentae and congenital abnormalities. We speculate that diet and nutrition might play a major part in the causation of these intra-uterine deaths.


Economic impact of failed or delayed primary repair of bladder exstrophy: differences in cost of hospitalization.
Patients with bladder exstrophy and failed primary newborn closure or who undergo delayed primary repair have suboptimal functional outcomes. We sought to determine whether these patients also have costlier, more resource intensive hospitalizations compared to patients who undergo neonatal primary closure. We reviewed hospital coding records to identify patients who underwent surgical repair of classic bladder exstrophy at The Johns Hopkins Hospital between 1997 and 2006, and obtained charge records for each hospitalization. Total hospital charges (excluding professional fees) were inflation adjusted to year 2005 dollars. Cases were identified as newborn primary repair, delayed primary repair or reclosure of failed prior repair. Results of classic exstrophy repair were analyzed in 80 patients. A total of 34 procedures were newborn primary repairs, 15 were delayed primary repairs and 31 were reclosures of failed prior repair. All of the patients undergoing delayed primary repairs and reclosures underwent osteotomy, compared to only 21% of those undergoing newborn primary repair. Overall mean inflation adjusted hospitalization charge was $66,348 +/- $26,625 (range $29,689 to $179,403). Newborn closures were significantly less costly (mean charge $53,188 +/- $15,086) than either reclosure ($71,621 +/- $19,366) or delayed primary closure ($85,278 +/- $42,354, p <0.0001). Controlling for multiple variables in a regression model showed that the primary factors associated with charges were operative time, days in intensive care unit and length of stay. Length of stay and operative times were significantly shorter in the newborn surgical group, likely accounting for the lower costs in this group (despite higher intensive care unit use). Mean hospital charges and mean length of stay increased during the study period. Primary newborn exstrophy repair is associated with lower surgical hospitalization costs compared to delayed primary repair and reclosure. Combined with previous data on clinical outcomes, these data reiterate the paramount importance of achieving a successful initial newborn closure whenever possible.


Morphological correlates of increased coupling resistance at an electrotonic synapse.
Close appositions between axonal membranes are present in the septum between adjacent axonal segments of the septate or lateral giant axons of the crayfish Procambarus. In sections the closely apposed membranes appear separated by a space or gap. The use of lanthanum indicates that there may be structures connecting the apposed membranes. The apparent gap is actually a network of channels continuous with the extracellular space. Adjacent axonal segments are electrotonically coupled at the septa. The coupling resistance is increased by mechanical injury of an axon, immersion in low Cl(-) solutions, and immersion in low Ca(++) solutions, followed by a return to normal physiological solution. Septa at which coupling resistance had been measured were examined in the electron microscope. The induced increases in coupling resistance are associated with separation of the junctional membranes (with the exception of the moderate increases during immersion in low Ca(++) solutions). Schwann cell processes are present between the separated axonal membranes. When nerve cords in low Cl(-) solutions are returned to normal physiological solution, coupling, i.e., electrotonic synapses. A model of an electrotonic synapse is proposed in which tween axonal membranes are again found. The association between the morphological and physiological findings provides further evidence that the junctions are the sites of electrotonic coupling, i.e., electrotonic, synapses. A model of an electrotonic synapse is proposed in which intercytoplasmic channels not open to the extracellular space are interlaced with a hexagonal network of extracellular channels between the apposed junctional membranes.


Patient-derived oral mucosa organoids as an in vitro model for methotrexate induced toxicity in pediatric acute lymphoblastic leukemia.
We have recently established a protocol to grow wildtype human oral mucosa organoids. These three-dimensional structures can be maintained in culture long-term, do not require immortalization, and recapitulate the multilayered composition of the epithelial lining of the oral mucosa. Here, we validate the use of this model to study the effect of Leucovorin (LV) on Methotrexate (MTX)-induced toxicity. MTX is a chemotherapeutic agent used in the treatment of pediatric acute lymphoblastic leukemia. Although effective, the use of MTX often results in severe side-effects, including oral mucositis, which is characterized by epithelial cell death. Here, we show that organoids are sensitive to MTX, and that the addition of LV reduces MTX toxicity, in both a concentration- and timing-dependent manner. Additionally, we show that a 24 hour 'pretreatment' with LV reduces MTX-induced cell death, suggesting that such a pretreatment could decrease mucositis in patients. Taken together, we provide the first in vitro model to study the effect of MTX on wildtype oral mucosa cells. Our findings underscore the relevance of the clinically applied LV regimen and highlight the potential of this model to further optimize modifications in dosing and timing of Leucovorin on oral mucosa cells.


The impact of patient protection and Affordable Care Act on trauma care: A step in the right direction.
The Patient Protection and Affordable Care Act (ACA) was implemented to guarantee financial coverage for health care for all Americans. The implementation of ACA is likely to influence the insurance status of Americans and reimbursement rates of trauma centers. The aim of this study was to assess the impact of ACA on the patient insurance status, hospital reimbursements, and clinical outcomes at a Level I trauma center. We hypothesized that there would be a significant decrease in the proportion of uninsured trauma patients visiting our Level I trauma center following the ACA, and this is associated with improved reimbursement. We performed a retrospective analysis of the trauma registry and financial database at our Level I trauma center for a 27-month (July 2012 to September 2014) period by quarters. Our outcome measures were change in insurance status, hospital reimbursement rates (total payments/expected payments), and clinical outcomes before and after ACA (March 31, 2014). Trend analysis was performed to assess trends in outcomes over each quarter (3 months). A total of 9,892 patients were included in the study. The overall uninsured rate during the study period was 20.3%. Post-ACA period was associated with significantly lower uninsured rate (p < 0.001). During the same time, there was as a significant increase in the Medicaid patients (p = 0.009). This was associated with significantly improved hospital reimbursements (p < 0.001).On assessing clinical outcomes, there was no change in hospitalization (p = 0.07), operating room procedures (p = 0.99), mortality (p = 0.88), or complications (p = 0.20). Post-ACA period was also not associated with any change in the hospital (p = 0.28) or length of stay at intensive care unit (p = 0.66). The implementation of ACA has led to a decrease in the number of uninsured trauma patients. There was a significant increase in Medicaid trauma patients. This was associated with an increase in hospital reimbursements that substantially improved the financial revenues. Despite the controversies, implementation of ACA has the potential to substantially improve the financial outcomes of trauma centers through Medicaid expansion. Economic and value-based evaluation, level III.


Cost-effectiveness of a pragmatic structured education intervention for the prevention of type 2 diabetes: economic evaluation of data from the Let's Prevent Diabetes cluster-randomised controlled trial.
Prevention of type 2 diabetes mellitus (TD2M) is a priority for healthcare systems. We estimated the cost-effectiveness compared with standard care of a structured education programme (Let's Prevent) targeting lifestyle and behaviour change to prevent progression to T2DM in people with prediabetes. Cost-effectiveness analysis alongside randomised controlled trial. 44 general practices in Leicestershire, England. 880 participants with prediabetes randomised to receive either standard care or a 6-hour group structured education programme with follow-up sessions in a primary care setting. Incremental cost utility from the UK National Health Service (NHS) perspective. Quality of life and resource use measured from baseline and during the 36 months follow-up using the EuroQoL EQ-5D and 15D instruments and an economic questionnaire. Outcomes measured using quality-adjusted life years (QALYs) and healthcare costs calculated in 2012-2013 prices. After accounting for clustering and missing data, the intervention group was found to have a net gain of 0.046 (95% CI -0.0171 to 0.109) QALYs over 3 years, adjusted for baseline utility, at an additional cost of £168 (95% CI -395 to 732) per patient compared with the standard care group. The incremental cost-effectiveness ratio is £3643/QALY with an 86% probability of being cost-effective at a willingness to pay threshold of £20 000/QALY. The education programme had higher costs and higher quality of life compared with the standard care group. The Let's Prevent programme is very likely to be cost-effective at a willingness to pay threshold of £20 000/QALY gained. ISRCTN80605705.


Evaluation of atherosclerosis after cessation of cabergoline therapy in patients with prolactinoma.
The aim of the study was to determine whether atherosclerotic risk markers exist at the moment and after withdrawal of cabergoline (CAB) therapy in patients who had taken a suitable dose of CAB therapy for a suitable period of time before cessation of CAB. This study was designed as prospective cross-sectional. Out of a total of 115 patients with prolactinoma, 42 non-obese women with microprolactinoma, who met the Pituitary Society criteria (2006) for the withdrawal of long-term CAB therapy, and 30 healthy patients participated in our study. The number of patients excluded from the study were as follows: 34 patients with tumor shrinkage of less than 50%; 10 who received DA treatments for less than 2 years; 9 who were treated with bromocriptine; and 20 who had diabetes mellitus, hypertension, hyperlipidemia, obesity, renal disease, coronary arterial disease, or were tobacco smokers. The patients were evaluated for anthropometric, metabolic, and inflammatory parameters at the time of cessation of CAB therapy and at the 3rd and 12th months after the withdrawal of CAB therapy. Endothelial dysfunction was determined by flow-mediated dilation (FMD) of the brachial artery and carotid intima media thickness (IMT), which were assessed by high resolution ultrasonography (USG) by the same practitioner. At the moment of cessation of CAB therapy, the FMD percentage in patients with prolactinoma was worse than that in healthy controls (p=0.0029). After the withdrawal of CAB treatment, fibrinogen (p=0.036), mean platelet volume (MPV) (p<0.001), carotid IMT (p=0.041), and high-density lipoprotein cholesterol (HDL C) (p=0.048) were worse in the relapse patients than those in the remission patients. Furthermore, only MPV values were found to be significantly related to a relapse of hyperprolactinemia among all atherosclerotic risk markers [area under the curve: 0.830 (95% CI 0.685-0.974) (p<0.001)]. Unfavorable cardiovascular risk profiles are a problem for patients with prolactinoma during cessation and after CAB withdrawal.


Influence of safety gear on parental perceptions of injury risk and tolerance or children's risk taking.
Risk compensation theory has been shown to relate to how individuals behave in areas such as traffic safety and consumer product safety. The present study examines whether risk compensation theory applies to parents' judgments about school age children's permissible risk taking under non-safety gear and safety gear conditions for seven common play situations. The extent of the child's experience with the activity and parental beliefs about safety gear efficacy were examined as possible moderators of extent of children's risk taking allowed by parents. A telephone interview was used to obtain each parent's ratings of permissible risk taking by their child (for example, speed at which child is allowed to cycle, height allowed to climb to on a climber) under safety gear and no gear conditions, and ratings of child experience and gear efficacy. Results confirmed risk compensation operated under all seven play situations, resulting in parents reporting they would allow significantly greater risk taking by their children under safety gear than non-safety gear conditions. Children with more experience with the activities were to be allowed greater risk taking, even when not wearing safety gear. Parents who believed more strongly in the efficacy of the safety gear to prevent injuries showed greater risk compensation. No sex differences emerged in any analyses. Results highlight the need to communicate to parents that safety gear moderates injury risk but does not necessarily guarantee the prevention of injury, particularly if children are allowed greater risk taking when wearing safety gear.


Personality disorders in previously detained adolescent females: a prospective study.
This longitudinal study investigated the predictive value of trauma and mental health problems for the development of antisocial personality disorder (ASPD) and borderline personality disorder (BPD) in previously detained women. The participants were 229 detained adolescent females who were assessed for traumatic experiences and mental health problems (mean age = 15.5 years). Three to 6 years later (M = 4.5; SD = 0.6), ASPD and BPD were diagnosed with a semistructured interview. Forty percent of the women had a personality disorder (i.e., ASPD 15.8%, BPD 9.2%, or both ASPD and BPD 15.2%). Posttraumatic stress, depressive symptoms, and dissociation during detention increased the risk for BPD in adulthood. Surprisingly, neither conduct problems nor substance dependence predicted ASPD; these findings require further study because they add to the controversy surrounding ASPD in females. The high prevalence rates of personality disorders indicate the need for intervention programs that target these unwanted outcomes.


Scale-Adjusted Metrics for Predicting the Evolution of Urban Indicators and Quantifying the Performance of Cities.
More than a half of world population is now living in cities and this number is expected to be two-thirds by 2050. Fostered by the relevancy of a scientific characterization of cities and for the availability of an unprecedented amount of data, academics have recently immersed in this topic and one of the most striking and universal finding was the discovery of robust allometric scaling laws between several urban indicators and the population size. Despite that, most governmental reports and several academic works still ignore these nonlinearities by often analyzing the raw or the per capita value of urban indicators, a practice that actually makes the urban metrics biased towards small or large cities depending on whether we have super or sublinear allometries. By following the ideas of Bettencourt et al. [PLoS ONE 5 (2010) e13541], we account for this bias by evaluating the difference between the actual value of an urban indicator and the value expected by the allometry with the population size. We show that this scale-adjusted metric provides a more appropriate/informative summary of the evolution of urban indicators and reveals patterns that do not appear in the evolution of per capita values of indicators obtained from Brazilian cities. We also show that these scale-adjusted metrics are strongly correlated with their past values by a linear correspondence and that they also display crosscorrelations among themselves. Simple linear models account for 31%-97% of the observed variance in data and correctly reproduce the average of the scale-adjusted metric when grouping the cities in above and below the allometric laws. We further employ these models to forecast future values of urban indicators and, by visualizing the predicted changes, we verify the emergence of spatial clusters characterized by regions of the Brazilian territory where we expect an increase or a decrease in the values of urban indicators.


The crystal structure of thrombin-activable fibrinolysis inhibitor (TAFI) provides the structural basis for its intrinsic activity and the short half-life of TAFIa.
Mature thrombin-activable fibrinolysis inhibitor (TAFIa) is a highly unstable metallocarboxypeptidase that stabilizes blood clots by clipping C-terminal lysine residues from partially degraded fibrin. In accordance with its in vitro antifibrinolytic activity, animal studies have reported that inhibition of mature TAFI aids in the prevention of thrombosis. The level of TAFI activity is stringently regulated through (i) controlled proteolytic truncation of the zymogen (TAFI), generating the mature enzyme, TAFIa, and (ii) the short half-life of TAFIa. TAFI itself exhibits an intrinsic enzymatic activity, which is likely required to provide a baseline level of antifibrinolytic activity. The novel crystal structure presented here reveals that the active site of TAFI is accessible, providing the structural explanation for the its intrinsic activity. It also supports the notion that an "instability region" exists, in agreement with site-directed mutagenesis studies. Sulfate ions, bound to this region, point toward a potential heparin-binding site and could explain how heparin stabilizes TAFIa.


The effect of body orientation on a point-to-point movement in healthy elderly persons.
Upper limb retraining during the early phases of neurological rehabilitation often involves having individuals practice reaching in body orientations that reduce the effect of gravity on various joint motions (e.g., shoulder flexion, elbow extension). However, the efficacy of these training techniques has not been determined. The purpose of this study was to determine the effects of reducing gravity through a change in body orientation from sitting to side-lying on the kinematics of a point-to-point movement in healthy elderly persons. Nine healthy, right-hand-dominant women 62 to 66 years of age pointed to a target in two different body orientations-sitting and side-lying. A 2-dimensional kinematic analysis of the movement was performed to compare the trajectory of the hand and the interjoint coordination under the two conditions. Regardless of body orientation relative to gravity, participants produced straight hand paths and smooth, bell-shaped velocity profiles. However, they moved slower in side-lying, and the pattern of interjoint coordination varied. The shoulder and elbow moved less, whereas the scapula made a greater contribution to the overall movement. Furthermore, the temporal coordination of the joints was modified as a consequence of body position. The results indicate that point-to-point arm movements made against gravity differ from those made in a gravity-reduced plane, particularly at the joint level, illustrating that movement organization is sensitive to this contextual difference. The effect of minimizing gravity on upper limb movement needs to be explored in patient populations to determine whether training patients in gravity-reduced orientations is efficacious.


A Comparative Evaluation of Diffractive Trifocal and New Refractive/Extended Depth of Focus Intraocular Lenses for Refractive Lens Exchange.
To evaluate and compare the visual performance and quality of life (QOL) associated with refractive/extended depth of focus (EDOF) intraocular lenses (IOLs) and diffractive trifocal IOLs in refractive lens exchange patients. This was a comparative interventional study of patients undergoing implantation of Lucidis (Swiss Advanced Vision, SAV‑IOL SA, Neuchâtel, Switzerland) or AT LISA tri 839MP (Carl Zeiss Meditec AG, Germany) IOLs. Near, intermediate, and distance best corrected and uncorrected visual acuities were collected at 1 and 3 months postoperatively. The vision-related QOL was evaluated 1 and 3 months after surgery, using the National Eye Institute Visual Function Questionnaire-14 (VF-14 QOL questionnaire). A total of 74 patients underwent refractive lens exchange and IOL implantation, with 38 patients in the EDOF group and 36 in the trifocal group. Among all visual acuities, uncorrected near visual acuity was statistically significantly better with the Lucidis IOL at the first month (p = .02) and diminished at the third-month visit (p = .16). When we compared the VF-14 QOL questionnaire scores, reading small print, reading a newspaper or book, and driving at night were statistically significantly better in the Lucidis group at the first month (p = .00, for each). That difference persisted only in driving at night at the third-month visit (p = .04). Reading small print, driving at night, and doing fine handwork were the most difficult tasks in the AT LISA group at the first month, and only driving at night remained so at the third-month visit. The refractive results and visual outcomes at all distances of EDOF and trifocal IOLs were highly satisfactory. However, the EDOF design in the Lucidis IOL achieves lower rates of glare in the early period after refractive lens exchange.