The refocused INADEQUATE MAS NMR experiment in multiple spin-systems: interpreting observed correlation peaks and optimising lineshapes.
The robustness of the refocused INADEQUATE MAS NMR pulse sequence for probing through-bond connectivities has been demonstrated in a large range of solid-state applications. This pulse sequence nevertheless suffers from artifacts when applied to multispin systems, e.g. uniformly labeled (13)C solids, which distort the lineshapes and can potentially result in misleading correlation peaks. In this paper, we present a detailed account that combines product-operator analysis, numerical simulations and experiments of the behavior of a three-spin system during the refocused INADEQUATE pulse sequence. The origin of undesired anti-phase contributions to the spectral lineshapes are described, and we show that they do not interfere with the observation of long-range correlations (e.g. two-bond (13)C-(13)C correlations). The suppression of undesired contributions to the refocused INADEQUATE spectra is shown to require the removal of zero-quantum coherences within a z-filter. A method is proposed to eliminate zero-quantum coherences through dephasing by heteronuclear dipolar couplings, which leads to pure in-phase spectra.


Sleep quality, internet addiction and depressive symptoms among undergraduate students in Nepal.
Evidence on the burden of depression, internet addiction and poor sleep quality in undergraduate students from Nepal is virtually non-existent. While the interaction between sleep quality, internet addiction and depressive symptoms is frequently assessed in studies, it is not well explored if sleep quality or internet addiction statistically mediates the association between the other two variables. We enrolled 984 students from 27 undergraduate campuses of Chitwan and Kathmandu, Nepal. We assessed sleep quality, internet addiction and depressive symptoms in these students using Pittsburgh Sleep Quality Index, Young's Internet Addiction Test and Patient Health Questionnaire-9 respectively. We included responses from 937 students in the data analysis after removing questionnaires with five percent or more fields missing. Via bootstrap approach, we assessed the mediating role of internet addiction in the association between sleep quality and depressive symptoms, and that of sleep quality in the association between internet addiction and depressive symptoms. Overall, 35.4%, 35.4% and 21.2% of students scored above validated cutoff scores for poor sleep quality, internet addiction and depression respectively. Poorer sleep quality was associated with having lower age, not being alcohol user, being a Hindu, being sexually active and having failed in previous year's board examination. Higher internet addiction was associated with having lower age, being sexually inactive and having failed in previous year's board examination. Depressive symptoms were higher for students having higher age, being sexually inactive, having failed in previous year's board examination and lower years of study. Internet addiction statistically mediated 16.5% of the indirect effect of sleep quality on depressive symptoms. Sleep quality, on the other hand, statistically mediated 30.9% of the indirect effect of internet addiction on depressive symptoms. In the current study, a great proportion of students met criteria for poor sleep quality, internet addiction and depression. Internet addiction and sleep quality both mediated a significant proportion of the indirect effect on depressive symptoms. However, the cross-sectional nature of this study limits causal interpretation of the findings. Future longitudinal study, where the measurement of internet addiction or sleep quality precedes that of depressive symptoms, are necessary to build upon our understanding of the development of depressive symptoms in students.


Extreme events in multilayer, interdependent complex networks and control.
We investigate the emergence of extreme events in interdependent networks. We introduce an inter-layer traffic resource competing mechanism to account for the limited capacity associated with distinct network layers. A striking finding is that, when the number of network layers and/or the overlap among the layers are increased, extreme events can emerge in a cascading manner on a global scale. Asymptotically, there are two stable absorption states: a state free of extreme events and a state of full of extreme events, and the transition between them is abrupt. Our results indicate that internal interactions in the multiplex system can yield qualitatively distinct phenomena associated with extreme events that do not occur for independent network layers. An implication is that, e.g., public resource competitions among different service providers can lead to a higher resource requirement than naively expected. We derive an analytical theory to understand the emergence of global-scale extreme events based on the concept of effective betweenness. We also articulate a cost-effective control scheme through increasing the capacity of very few hubs to suppress the cascading process of extreme events so as to protect the entire multi-layer infrastructure against global-scale breakdown.


Importance of coastal primary production in the northern Baltic Sea.
In this study, we measured depth-dependent benthic microalgal primary production in a Bothnian Bay estuary to estimate the benthic contribution to total primary production. In addition, we compiled data on benthic microalgal primary production in the entire Baltic Sea. In the estuary, the benthic habitat contributed 17 % to the total annual primary production, and when upscaling our data to the entire Bothnian Bay, the corresponding value was 31 %. This estimated benthic share (31 %) is three times higher compared to past estimates of 10 %. The main reason for this discrepancy is the lack of data regarding benthic primary production in the northern Baltic Sea, but also that past studies overestimated the importance of pelagic primary production by not correcting for system-specific bathymetric variation. Our study thus highlights the importance of benthic communities for the northern Baltic Sea ecosystem in general and for future management strategies and ecosystem studies in particular.


A further evaluation of the effects of K+ depolarization on glutamate-evoked [3H]dopamine release from striatal slices.
Exogenous glutamate will evoke dopamine (DA) release from striatal slices in vitro. To further characterize glutamate-evoked DA release from striatal slices, experiments were designed to: 1) determine if sufficient endogenous glutamate can be released in vitro to presynaptically mediate [3H]DA release in the absence of Mg++ and 2) reevaluate how K+ depolarization affects glutamate-evoked [3H]DA release. Removal of Mg++ to potentiate N-methyl-D-aspartate (NMDA) receptor-mediated DA release increased 15 mM K(+)-evoked [3H]DA release to about 200% of control. The potentiation of this release was probably not mediated by NMDA receptors because it was not blocked by the glutamate receptor antagonists MK-801, 6,7-dinitroquinoxalinedione (DNQX) or kynurenate. Furthermore, the removal of Mg++ increased DA release substantially (200%) in the presence of 5 microM sulpiride and 10 microM nomifensine, indicating that DA reuptake and DA D2 autoreceptors are not primarily responsible for increased DA release. In the absence of Mg++, depolarization produced by 20 mM or greater [K+] inhibited DA released by exogenous glutamate, whereas a much higher [K+] was necessary to evoke endogenous glutamate release. In the presence of 1.5 mM Mg++, a reduction of the "Mg++ blockade" of NMDA receptors by 15 mM K+ depolarization during glutamate-evoked DA release was evaluated with and without the DA reuptake inhibitor nomifensine and the DA D2 antagonist sulpiride. DA released by K+ depolarization (Mg++ present) was markedly increased by 1 mM glutamate, but this effect was only partially reversed by kynurenate or high concentrations of either MK-801 (25 microM) or DNQX (100 microM).(ABSTRACT TRUNCATED AT 250 WORDS)


Conservation performance of different conservation governance regimes in the Peruvian Amazon.
State-controlled protected areas (PAs) have dominated conservation strategies globally, yet their performance relative to other governance regimes is rarely assessed comprehensively. Furthermore, performance indicators of forest PAs are typically restricted to deforestation, although the extent of forest degradation is greater. We address these shortfalls through an empirical impact evaluation of state PAs, Indigenous Territories (ITs), and civil society and private Conservation Concessions (CCs) on deforestation and degradation throughout the Peruvian Amazon. We integrated remote-sensing data with environmental and socio-economic datasets, and used propensity-score matching to assess: (i) how deforestation and degradation varied across governance regimes between 2006-2011; (ii) their proximate drivers; and (iii) whether state PAs, CCs and ITs avoided deforestation and degradation compared with logging and mining concessions, and the unprotected landscape. CCs, state PAs, and ITs all avoided deforestation and degradation compared to analogous areas in the unprotected landscape. CCs and ITs were on average more effective in this respect than state PAs, showing that local governance can be equally or more effective than centralized state regimes. However, there were no consistent differences between conservation governance regimes when matched to logging and mining concessions. Future impact assessments would therefore benefit from further disentangling governance regimes across unprotected land.


Inhalation of honey reduces airway inflammation and histopathological changes in a rabbit model of ovalbumin-induced chronic asthma.
Honey is widely used in folk medicine to treat cough, fever, and inflammation. In this study, the effect of aerosolised honey on airway tissues in a rabbit model of ovalbumin (OVA)-induced asthma was investigated. The ability of honey to act either as a rescuing agent in alleviating asthma-related symptoms or as a preventive agent to preclude the occurrence of asthma was also assessed. Forty New Zealand white rabbits were sensitized twice with mixture of OVA and aluminium hydroxide on days 1 and 14. Honey treatments were given from day 23 to day 25 at two different doses (25% (v/v) and 50% (v/v) of honey diluted in sterile phosphate buffer saline. In the aerosolised honey as a rescue agent group, animals were euthanized on day 28; for the preventive group, animals were further exposed to aerosolised OVA for 3 days starting from day 28 and euthanized on day 31. The effects of honey on inflammatory cell response, airway inflammation, and goblet cell hyperplasia were assessed for each animal. Histopathological analyses revealed that aerosolised honey resulted in structural changes of the epithelium, mucosa, and submucosal regions of the airway that caused by the induction with OVA. Treatment with aerosolised honey has reduced the number of airway inflammatory cells present in bronchoalveolar lavage fluid and inhibited the goblet cell hyperplasia. In this study, aerosolised honey was used to effectively treat and manage asthma in rabbits, and it could prove to be a promising treatment for asthma in humans. Future studies with a larger sample size and studies at the gene expression level are needed to better understand the mechanisms by which aerosolised honey reduces asthma symptoms.


Coffee consumption and risk of hospitalized miscarriage before 12 weeks of gestation.
In order to analyse the association between drinking coffee in pregnancy and risk of spontaneous abortion, a case-controlled study was conducted in Milan, Northern Italy. Cases were 782 women with spontaneous abortion within the 12th week of gestation. The control group was recruited from women who gave birth at term (> 37 weeks gestation) to healthy infants on randomly selected days at the same hospitals where cases had been identified: 1543 controls were interviewed. A total of 561 (72%) cases of spontaneous abortion and 877 (57%) controls reported coffee drinking during the first trimester of the index pregnancy. The corresponding multivariate odds ratios of spontaneous abortion, in comparison with non-drinkers, were 1.2, 1.8 and 4.0, respectively, for drinkers of 1, 2 or 3, and 4 or more cups of coffee per day. No relationship emerged between maternal decaffeinated coffee, tea and cola drinking in pregnancy, as well as paternal coffee consumption, and risk of spontaneous abortion. With regard to duration in years of coffee drinking, the estimated multivariate odds ratios of spontaneous abortion were, in comparison with non-coffee drinkers, 1.1 (95% confidence interval (CI) 0.9-1.4) and 1.9 (95% CI 1.5-2.6) for women reporting a duration of coffee consumption < or = 10 or > 10 years. In conclusion, coffee drinking early in pregnancy was associated with an increased risk of abortion. This has biological implications, but epidemiological inference on the causality is difficult and still open to debate.


Catechol Groups Enable Reactive Oxygen Species Scavenging-Mediated Suppression of PKD-NFkappaB-IL-8 Signaling Pathway by Chlorogenic and Caffeic Acids in Human Intestinal Cells.
Chlorogenic acid (CHA) and caffeic acid (CA) are phenolic compounds found in coffee, which inhibit oxidative stress-induced interleukin (IL)-8 production in intestinal epithelial cells, thereby suppressing serious cellular injury and inflammatory intestinal diseases. Therefore, we investigated the anti-inflammatory mechanism of CHA and CA, both of which inhibited hydrogen peroxide (H₂O₂)-induced IL-8 transcriptional activity. They also significantly suppressed nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcriptional activity, nuclear translocation of the p65 subunit, and phosphorylation of IκB kinase (IKK). Additionally, upstream of IKK, protein kinase D (PKD) was also suppressed. Finally, we found that they scavenged H₂O₂-induced reactive oxygen species (ROS) and the functional moiety responsible for the anti-inflammatory effects of CHA and CA was the catechol group. Therefore, we conclude that the presence of catechol groups in CHA and CA allows scavenging of intracellular ROS, thereby inhibiting H₂O₂-induced IL-8 production via suppression of PKD-NF-κB signaling in human intestinal epithelial cells.


Optical detection of honeybees by use of wing-beat modulation of scattered laser light for locating explosives and land mines.
An instrument is demonstrated that can be used for optical detection of honeybees in a cluttered environment. The instrument uses a continuous-wave diode laser with a center wavelength of 808 nm and an output power of 28 mW as the laser transmitter source. Light scattered from moving honeybee wings will produce an intensity-modulated signal at a characteristic wing-beat frequency (170-270 Hz) that can be used to detect the honeybees against a cluttered background. The optical detection of honeybees has application in the biological detection of land mines and explosives, as was recently demonstrated.


Prevalence and persistence of chromosomal damage and susceptible genotypes of metabolic and DNA repair genes in Chinese vinyl chloride-exposed workers.
Vinyl chloride (VC) was classified as a group 1 carcinogen by IARC in 1987. Although the relationship between VC exposure and liver cancer has been established, the mechanism of VC-related carcinogenesis remains largely unknown. Previous epidemiological studies have shown that VC exposure is associated with increased genotoxicity in humans. To explore chromosomal damage and its progression, and their association to genetic susceptibility, we investigated 402 workers exposed to VC, a 77 VC-exposed cohort and 141 unexposed subjects. We measured the frequencies of cytokinesis-block micronucleus (CBMN) to reflect chromosomal damage and conducted genotyping for six xenobiotic metabolisms and five DNA repair genes' polymorphism. Data indicate that 95% of the control workers had CBMN frequencies </=3 per thousand, whereas VC-exposed workers had the 3.73-fold increase compared with the controls. Among the cohort workers who were followed from 2004 to 2007, the mean CBMN frequency was higher in 2007 than in 2004 with ratio of 2.08. Multiple Poisson regression analysis showed that mean CBMN frequencies were significantly elevated for the intermediate and high exposure groups than the low. Exposed workers with CYP2E1 or XRCC1 variance showed a higher CBMN frequency than their wild-type homozygous counterparts, so did workers with GSTP1 or ALDH2 genotype. This study provides evidence that cumulative exposure dose of VC and common genetic variants in genes relevant to detoxification of carcinogens are the major factors that modulate CBMN induction in VC-exposed workers.


Transmission modes of the mammalian gut microbiota.
Mammals house a diversity of bacteria that affect health in various ways, but the routes by which bacterial lineages are transmitted between hosts remain poorly understood. We experimentally determined microbiota transmission modes by deriving 17 inbred mouse lines from two wild populations and monitoring their gut microbiotas for up to 11 host generations. Individual- and population-level microbiota compositions were maintained within mouse lines throughout the experiment, indicating predominantly vertical inheritance of the microbiota. However, certain bacterial taxa tended to be exchanged horizontally between mouse lines. Consistent with evolutionary theory, the degree of horizontal transmission predicted bacterial genera with pathogenic representatives responsible for human infections and hospitalizations.


The development and evaluation of an ergonomic glove.
The primary intent of this study was to determine if a hand glove could be designed on a criterion of selective protection. Force distribution patterns on the palmar side of hand were obtained from various studies to develop zones of hand that needed protection. A new design for gloves was developed based on the principle of selective protection, where protective material is introduced in varying levels over different parts of the glove, in order to provide protection where it is most needed, and at the same time preserve the desirable dexterity and strength capabilities of the barehand, optimizing the trade-off between protection and performance. Two pairs of prototype gloves incorporating different levels of protection were fabricated and tested using a battery of performance tests and an algometer test for pressure sensitivity. The test battery comprising four dexterity tasks and a maximal voluntary grip strength task was used to assess a number of glove conditions, including the two prototype gloves developed. The results indicate that the performance of the prototype gloves are comparable, and that the performance times for the double glove and the two prototype gloves tested were not significantly different. For the grip strength, the two prototype gloves were better than the double glove. The assembly task performance for the prototype II (laminar glove) was significantly lower than that of the other glove types tested. It appears that gloves of variable thickness can be developed to afford adequate protection at zones of most need. Glove manufacturers are recommended to use an ergonomic approach in the design of gloves. Such an approach, besides protecting the safety objective of gloves, could enhance productivity considerably.


Opportunities to diagnose chronic obstructive pulmonary disease in routine care in the UK: a retrospective study of a clinical cohort.
Patterns of health-care use and comorbidities present in patients in the period before diagnosis of chronic obstructive pulmonary disease (COPD) are unknown. We investigated these factors to inform future case-finding strategies. We did a retrospective analysis of a clinical cohort in the UK with data from Jan 1, 1990 to Dec 31, 2009 (General Practice Research Database and Optimum Patient Care Research Database). We assessed patients aged 40 years or older who had an electronically coded diagnosis of COPD in their primary care records and had a minimum of 3 years of continuous practice data for COPD (2 years before diagnosis up to a maximum of 20 years, and 1 year after diagnosis) and at least two prescriptions for COPD since diagnosis. We identified missed opportunites to diagnose COPD from routinely collected patient data by reviewing patterns of health-care use and comorbidities present before diagnosis. We assessed patterns of health-care use in terms of lower respiratory consultations (infective and non-infective), lower respiratory consultations with a course of antibiotics or oral steroids, and chest radiography. If these events did not lead to a diagnosis of COPD, they were deemed to be missed opportunities. This study is registered with ClinicalTrials.gov, number NCT01655667. We assessed data for 38,859 patients. Opportunities for diagnosis were missed in 32,900 (85%) of 38,859 patients in the 5 years immediately preceding diagnosis of COPD; in 12,856 (58%) of 22,286 in the 6-10 years before diagnosis, in 3943 (42%) of 9351 in the 11-15 years before diagnosis; and in 95 (8%) of 1167 in the 16-20 years before diagnosis. Between 1990 and 2009, we noted decreases in the age at diagnosis (0·05 years of age per year, 95% CI 0·03-0·07) and yearly frequency of lower respiratory prescribing consultations (rate ratio 0·982 opportunities per year, 95% CI 0·979-0·985). Prevalence of all comorbidities present at COPD diagnosis increased except for asthma and bronchiectasis, which decreased between 1990 and 2007, from 281 (33·4%) of 842 patients to 451 of 1465 (30·8%) for asthma, and from 53 of 842 (6·3%) to 53 of 1465 (3·6%) for bronchiectasis. In the 2 years before diagnosis, of 6897 patients who had had a chest radiography, only 2296 (33%) also had spirometry. Opportunities to diagnose COPD at an earlier stage are being missed, and could be improved by case-finding in patients with lower respiratory tract symptoms and concordant long-term comorbidities. UK Department of Health, Research in Real Life.


Stretchable impedance sensor for mammalian cell proliferation measurements.
This paper presents the fabrication and testing of a novel stretchable electric cell-substrate impedance sensing (ECIS) lab on a chip device. This is the first time that ECIS electrodes were fabricated on a stretchable polydimethylsiloxane (PDMS) substrate and ECIS measurements were performed on mammalian cells exposed to cyclic strain. The stretchable ECIS biosensors simulate in vitro the dynamic environment of organisms, such as pulsation, bending and stretching, which enables investigations on cell behavior that undergoes mechanical stimuli in biological tissue. Usually cell-based assays used in cell mechanobiology rely on endpoint cell tests, which provide a limited view on dynamic cellular mechanisms. The ECIS technique is a label-free, real-time and noninvasive method to monitor the cellular response to mechanical stimuli. Bovine aortic endothelial cells (BAECs) have been used in this research because the BAECs are exposed in vivo to cyclic physiologic elongation produced by blood circulation in the arteries. These innovative stretchable ECIS biosensors were used to analyze the proliferation of BAECs under different cyclic mechanical stimulations. The results of fluorescence based cell proliferation assays confirmed that the stretchable ECIS sensors were able to analyze in real-time the BAEC proliferation. The novel stretchable ECIS sensor has the ability to analyse cell proliferation, determine the cell number and density, and apply mechanical stimulation at the same time.


Resilience does matter: evidence from a 10-year cohort record linkage study.
To examine 10-year mortality and hospital use among individuals categorised as resilient and vulnerable to the impact of chronic pain. A cohort record linkage study. Grampian, Scotland. 5858 individuals from the Grampian Pain Cohort, established in 1996, were linked, by probability matching, with national routinely collected datasets. HRs for subsequent 10-year mortality and ORs/incidence rate ratios for subsequent 10-year hospital use, each with adjustment for potential confounding variables. 36.5% of those with high pain intensity reported a low pain-related disability (categorised resilient) and 7.1% of those reporting low pain intensity reported a high pain-related disability (categorised vulnerable). Sex, age, housing, employment and long-term limiting illness were independently associated with being vulnerable or resilient. After adjustment for these variables, individuals in the resilient group were 25% less likely to die within 10 years of the survey compared with non-resilient individuals: HR 0.75, 95% CI 0.62 to 0.91 and vulnerable individuals were 45% more likely to die than non-vulnerable individuals: HR 1.45, 95% CI 1.01 to 2.11. Resilient individuals were less likely to have had an outpatient or day-case visit for anaesthetics: OR 0.46, 95% CI 0.27 to 0.79, but no other clinical specialities. Vulnerable individuals were significantly less likely to have had any outpatient or day-case visit (OR 0.43, 0.25 to 0.75); but more likely to have had a psychiatric visit (OR 1.96, 1.06 to 3.61). No significant differences in likelihood of any inpatient visits were found. Resilient individuals have a better 10-year survival than non-resilient individuals indicating that resilience is a phenomenon worth researching. Further research is needed to explore who is likely to become resilient, why and how, as well as to tease out the internal and external factors that influence resilience.


Morphine produces potent antinociception, sedation, and hypothermia in humanized mice expressing human mu-opioid receptor splice variants.
Morphine is a strong painkiller acting through mu-opioid receptor (MOR). Full-length 7-transmembrane (TM) variants of MOR share similar amino acid sequences of TM domains in rodents and humans; however, interspecies differences in N- and C-terminal amino acid sequences of MOR splice variants dramatically affect the downstream signaling. Thus, it is essential to develop a mouse model that expresses human MOR splice variants for opioid pharmacological studies. We generated 2 lines of fully humanized MOR mice (hMOR; mMOR mice), line #1 and #2. The novel murine model having human OPRM1 genes and human-specific variants was examined by reverse-transcription polymerase chain reaction and the MinION nanopore sequencing. The differences in the regional distribution of MOR between wild-type and humanized MOR mice brains were detected by RNAscope and radioligand binding assay. hMOR; mMOR mice were characterized in vivo using a tail-flick, charcoal meal, open field, tail suspension, naloxone precipitation tests, and rectal temperature measurement. The data indicated that wild-type and humanized MOR mice exhibited different pharmacology of morphine, including antinociception, tolerance, sedation, and withdrawal syndromes, suggesting the presence of species difference between mouse and human MORs. Therefore, hMOR; mMOR mice could serve as a novel mouse model for pharmacogenetic studies of opioids.


Surface line defect solitons in square optical lattice.
We study the surface line defect gap solitons (SLDGSs) in an interface between a line defect of two-dimensional (2D) square optical lattice and the uniform media with focusing saturable nonlinearity. Some unique properties are revealed that the surface line defect of square optical lattice can profoundly affect the shape and stability of soliton. Stable soltion for the case of negative defect can exist in both of the semi-infinite gap and the first gap; unlike in the square lattice without defect, soliton can only exist in the semi-infinite gap. For the case of the positive defect, the solitons exist in the semi-inifite gap and stably exist in the low power region.


The impact of Ontario's end-of-life care strategy on end-of-life care in the community.
This article describes the impacts of the Ministry of Health and Long-Term Care's End-of-Life Care Strategy on the quality of end-of-life (EOL) care services delivered by home care providers across the province of Ontario. We compared key home care services one year before the strategy's implementation with those one year after. In addition, we conducted a qualitative survey of all community care access centres, the main providers of home care, and nearly all EOL Care Network directors to assess improvements to EOL care at the system and client level. Results showed that the number of clients of EOL care served increased by 3,537 over the baseline year. Moreover, the total number of nursing visits, shift nursing hours and personal support hours increased by 26%, 31% and 47%, respectively, compared with the baseline year. The qualitative analysis indicated that increased collaborations and communication have enhanced integration, coordination and consistency of EOL care. Anecdotally, clients and families feel more supported navigating the healthcare system, and more of their wishes are being met. The strategy appeared to improve EOL care on multiple levels. However, several barriers and challenges remain. Further investments and research are needed to achieve reliable quality EOL care for all Ontarians.


Quality of colonoscopy services for physicians in the Iowa research network.
Primary care physicians initiate colorectal cencer (CRC) screening and manage health care issues that present from these procedures. Quality of colonoscopy services can be determined by a set of indicators. The purpose of this study was to identify the quality of colonoscopy services provided for patients of family physicians in the Iowa Research Network (IRENE). Quality of services was delineated by (1) presence of a colonoscopy report on the medical record, if the medical record indicated a colonoscopy had been completed, (2) cecal intubation rate, (3) adenoma detection rate, and (4) the content of the colonoscopy report. Medical record review was conducted in 14 IRENE offices. Of 581 medical records indicating a colonoscopy had been completed, 89 (15%) did not have a colonoscopy report. The main reasons for having the colonoscopy were screening and obvious blood in the stool. Polyp detection rate for all colonoscopies was 35%, and the adenoma detction rate for screening colonoscopis for men was 31% and for women was 19%. Depth of insertion to the cecum was reached for 92%. Items least mentioned in the report were the time to complete the procedure and current medications. Only 223 (45%) reports listed the follow-up interval for next colonoscopy. Quality of colonoscopy services for this group of IRENE physicians was comparable to recommended standards of depth of insertion and adenoma detection rate. Improvements are warranted to have all colonoscopy reports and follow-up interval of next colonoscopy on a patient's medical record.


Variables associated with physical fighting among US high-school students.
Violence among adolescents is an important public health problem in the United States. This study was conducted to estimate the prevalence of having been engaged in physical fighting on school property and associated factors of the behavior among school-going adolescents in the United States. This study was based on secondary analysis of the United States Youth Risk Behavior Survey (YRBS) conducted in 2005. The sampling frame included all private and public school in the country, stratified by region and urbanicity based on the US census bureau data. Frequencies and proportions were obtained for the outcome and explanatory variables. Logistic regression analysis was used to estimate the level of association between explanatory variables and the outcome (having been involved in a physical fight). Of the 13,857 respondents, 13.5% (18.2% for males and 8.8% for females) reported physical fighting onschool property in the last 12 months to the survey. Males were more likely to have been in a physical fight than females (OR = 2.23; 95% CI [1.89, 2.63]). Respondents aged 17 years or older were less likely to report physical fighting than those who were 14 years or younger. Compared to Whites, American Indians or Alaska Natives, Blacks, Native Hawaii or other Pacific Islanders, and Hispanics were more likely to report physical fighting on school property (OR = 2.11; 95% CI [1.22, 3.66], OR = 1.72; 95% CI [1.42, 2.0], OR = 2.18; 95% CI [1.01, 4.79], and OR = 1.74; 95% CI [1.41, 2.16] respectively). Physical fighting on school property was also positively associated with cigarette smoking (OR = 1.70; 95% CI [1.37, 2.10]), drinking alcohol (OR = 1.45; 95% CI [1.20, 1.76]), use of illegal drugs (OR = 1.73; 95% CI [1.42, 2.12]), having had property stolen or deliberately damaged on school property (OR = 2.06; 95% CI [1.74, 2.44]), having been threatened or injured with a weapon on school property (OR = 2.63; 95% CI [2.06, 3.34]), and playing videogame three or more hours a day (OR = 1.29; 95% CI [1.07, 1.56]). These findings suggest that physical fighting among US High School students is widespread and positively associated with victimization (having been threatened or injured with a weapon on school property) and other risky behaviors such as smoking, alcohol and drugs use. Intervention programs to prevent/control those risky behaviors as well as further attention on the association between physical fighting and victimization at school through longitudinal research are warranted.


Distribution of the presynaptic calcium sensors, synaptotagmin I/II and synaptotagmin III, in the goldfish and rodent retinas.
Synaptic vesicle exocytosis is triggered by rises in calcium up to 100 microM at the site of vesicle fusion. The synaptic vesicle proteins synaptotagmin 1 and 2 (Syt I and Syt II) bind calcium at similarly high concentrations and have been proposed as the calcium sensors for fast neurotransmitter release. However, 1 microM calcium produces tonic transmitter release at photoreceptor and bipolar cell synapses in the goldfish retina, suggesting that these synapses use a higher affinity calcium sensor. Immunofluorescent staining with a panel of Syt I/II antibodies detected Syt I/II in both photoreceptor and bipolar cell terminals of the rodent retina. By contrast, no staining of either photoreceptor or protein kinase C (PKC)-labeled bipolar cell terminals was detected in the goldfish retina with any of the Syt I/II antibodies. The high affinity calcium sensor synaptotagmin 3 (Syt III) was localized to the synaptic layers of both goldfish and rodent retinas; however, while Syt III was associated with PKC-labeled bipolar cell terminals in the goldfish retina, it did not co-localize with PKC in the mouse retina. These results suggest that, unlike in their mammalian counterparts, synaptic vesicle exocytosis in goldfish photoreceptor and bipolar cell terminals utilizes a calcium sensor other than Syt I/II, possibly Syt III.


Mapping pneumonia research: A systematic analysis of UK investments and published outputs 1997-2013.
The burden of pneumonia continues to be substantial, particularly among the poorest in global society. We describe here the trends for UK pneumonia R&D investment and published outputs, and correlate with 2013 global mortality. Data related to awards to UK institutions for pneumonia research from 1997 to 2013 were systematically sourced and categorised by disease area and type of science. Investment was compared to mortality figures in 2010 and 2013 for pneumonia, tuberculosis and influenza. Investment was also compared to publication data. Of all infectious disease research between 2011 and 2013 (£917.0 million), £28.8 million (3.1%) was for pneumonia. This was an absolute and proportionate increase from previous time periods. Translational pneumonia research (33.3%) received increased funding compared with 1997-2010 where funding was almost entirely preclinical (87.5%, here 30.9%), but high-burden areas such as paediatrics, elderly care and antimicrobial resistance received little investment. Annual investment remains volatile; publication temporal trends show a consistent increase. When comparing investment to global burden with a novel 'investment by mortality observed' metric, tuberculosis (£48.36) and influenza (£484.21) receive relatively more funding than pneumonia (£43.08), despite investment for pneumonia greatly increasing in 2013 compared to 2010 (£7.39). Limitations include a lack of private sector data and the need for careful interpretation of the comparisons with burden, plus categorisation is subjective. There has been a welcome increase for pneumonia funding awarded to UK institutions in 2011-2013 compared with 1997-2010, along with increases for more translational research. Published outputs relating to pneumonia rose steadily from 1997 to 2013. Investment relative to mortality for pneumonia has increased, but it remains low compared to other respiratory infections and clear inequities remain. Analyses that measure investments in pneumonia can provide an insight into funding trends and research gaps. Pneumonia continues to be a high-burden illness around the globe. This paper shows that although research funding is increasing in the UK (between 1997 and 2013), it remains poorly funded compared to other important respiratory infectious diseases such as tuberculosis and influenza. Publications about pneumonia have been steadily increasing over time, indicating continuing academic and clinical interest in the topic. Though global mortality of pneumonia is declining, it should still be an area of high priority for funders, policymakers and researchers.


Hierarchical molecular tagging to resolve long continuous sequences by massively parallel sequencing.
Here we demonstrate the use of short-read massive sequencing systems to in effect achieve longer read lengths through hierarchical molecular tagging. We show how indexed and PCR-amplified targeted libraries are degraded, sub-sampled and arrested at timed intervals to achieve pools of differing average length, each of which is indexed with a new tag. By this process, indices of sample origin, molecular origin, and degree of degradation is incorporated in order to achieve a nested hierarchical structure, later to be utilized in the data processing to order the reads over a longer distance than the sequencing system originally allows. With this protocol we show how continuous regions beyond 3000 bp can be decoded by an Illumina sequencing system, and we illustrate the potential applications by calling variants of the lambda genome, analysing TP53 in cancer cell lines, and targeting a variable canine mitochondrial region.


Cardiac radionuclide imaging to assess patients with heart failure.
Heart failure (HF) is a major problem, with a high prevalence, morbidity, mortality, and cost, and is expected to become more widespread. Radionuclide imaging currently plays an important role in evaluating these patients, with much potential for increased utility. Myocardial perfusion imaging (MPI) with radiotracers is commonly used to differentiate an ischemic from a nonischemic etiology of HF and cardiomyopathy. In some instances, MPI effectively distinguishes among these, but often, standard MPI is deficient in that a nonischemic cardiomyopathy can have focal defects in tracer uptake and coronary artery disease with global balanced ischemia can result in a normal-appearing perfusion pattern. Developments in measuring quantitative blood flow promise to provide a more accurate determination of HF etiology. If coronary artery disease is established, MPI has long established use for assessment of myocardial viability and identification of patients likely to benefit from revascularization. Although a recent multicenter trial substudy has questioned the benefits of viability imaging, specific limitations of this study must be balanced against previously demonstrated utility. At the same time, viability imaging may need to be directed more skillfully toward carefully selected patients. In patients with HF who are not candidates for revascularization, myocardial remodeling often leads to poor patient outcome. Newer nuclear analyses of myocardial shape and of dyssynchronous contraction or relaxation can risk stratify patients and may help guide therapy. Investigative molecular imaging techniques promise to better understand underlying pathophysiology and guide therapy on an individual basis. Finally, recent approval of a tracer for cardiac autonomic innervation imaging should greatly expand the use of radionuclide imaging in HF, potentially guiding proper use of life saving but expensive and high-risk mechanical therapies. Given the molecular basis of much of the pathophysiology of HF, the contribution of cardiac radionuclide imaging to improve patient care should increase.


Observer and student ratings of the class environment: A preliminary investigation of convergence.
The present study examined the relationship between student and observer ratings of the class environment. More specifically, class responses on the Responsive Environmental Assessment for Classroom Teaching (REACT; Theodore J. Christ & Colleagues, 2015) were compared with observer ratings on the Classroom Strategies Assessment System-Observer Form (Reddy, Fabiano, & Dudek, 2013). This study included 38 teachers and 582 students from 5 high-poverty schools. Observational data were reported as discrepancy scores, which reflect the difference between the recommended frequency and observed frequency of specific instructional and behavioral management strategies for classroom teachers. Pearson correlations were used to evaluate the relationship between the 6 subscales included on the REACT and the 9 subscales included on the CSAS-O. Results provide preliminary evidence for the relationship between observer and student ratings of the class environment. More specifically, as discrepancy scores decreased, student ratings of the class environment tended to be more positive. The relationship between the REACT and the CSAS-O differed across subscales; however, in general, subscales that were conceptually similar tended to demonstrate stronger relationships than subscales that were conceptually distinct. Thus, the observed results also provide preliminary evidence that students are capable of discriminating between the quality of different components of the class environment. The potential use of both observer and student ratings of the class environment to provide teachers with a more robust and comprehensive reference for professional development purposes is discussed within the context of a tiered model of support. (PsycINFO Database Record


Central cord syndrome: clinical features, etiological diagnosis, and outcome in 74 dogs.
To describe the clinical and neurologic signs, diagnostic investigations, definitive or presumptive diagnosis, treatment, and outcome of dogs presented with acute onset central cord syndrome (CCS). 74 client-owned dogs evaluated for CCS at 5 referral hospitals between January 2016 and March 2021. Data were collected from the medical records of each dog, including patient signalment, physical and neurologic examination results, presence of signs of respiratory failure, diagnostic imaging findings, definitive or presumptive diagnosis, treatment and follow-up information. Descriptive statistics were calculated and bivariable analysis was performed to identify associations between selected variables. 2 neuroanatomic locations for the CCS were identified: C1-C5 spinal cord segments in 65 of 74 (88%) dogs and C6-T2 in 9 (12%) dogs. Neurolocalization did not correlate with the imaging findings in 43 (58%) dogs. Different diseases were associated with CCS. The most common condition was Hansen type I disk herniation in 27 (36%) dogs and hydrated nucleus pulposus extrusion in 16 (22%) dogs. Main lesion locations within the vertebral column associated with CCS were C3-C4 and C4-C5 intervertebral disk spaces in 21 (28%) and 18 (24%) dogs, respectively. Outcome was favorable in 69 (93%) dogs. Patients presenting with hypoventilation were 14.7 times more likely to have a poor outcome. CCS in dogs may be seen with lesions in the C1-C5 and C6-T2 spinal cord segments. Etiologies are variable. Total or partial improvement was achieved in most dogs with the appropriate treatment. Hypoventilation was associated with death.


Effect of orthodontic debonding and adhesive removal on the enamel - current knowledge and future perspectives - a systematic review.
After orthodontic treatment, brackets are debonded and residual adhesive is removed, causing iatrogenic enamel damage. The aim of this study was to review the methods of orthodontic adhesive removal, find clear evidence, and provide a rationale for this procedure. A literature search was performed in PubMed, Dentistry and Oral Sciences, Scopus, Cochrane, Google, and Google Scholar using keywords: orthodontic adhesive removal, orthodontic debonding, orthodontic clean-up. Studies concerning human enamel roughness or loss from debonding and adhesive removal were considered. Forty-four full-text articles were analyzed and 3 were rejected after detailed reading; finally 41 papers were included. Fifteen qualitative studies, 13 studies based on indices of enamel surface, and 13 quantitative studies were found. No meta-analysis could be performed due to a lack of homogenous quantitative evidence. The most popular tools were tungsten carbide burs, which were faster and more effective than Sof-Lex discs, ultrasonic tools, hand instruments, rubbers, or composite burs. They remove a substantial layer of enamel and roughen its surface, but are less destructive than Arkansas stones, green stones, diamond burs, steel burs, and lasers. Multi-step Sof-Lex discs and pumice slurry are the most predictable enamel polishing tools. Arkansas stones, green stones, diamond burs, steel burs, and lasers should not be used for adhesive removal. The use of tungsten carbide bur requires multistep polishing. Further efforts should be made to find tools and methods for complete removal of adhesive remnants, minimizing enamel loss and achieving a smooth surface.


Structural, electronic, magnetic and chemical properties of B-, C- and N-doped MgO(001) surfaces.
Doping of simple oxide materials can give rise to new exciting physical and chemical properties and open new perspectives for a variety of possible applications. Here we use density functional theory calculations to investigate the B-, C- and N-doped MgO(001) surfaces. We have found that the investigated dopants induce magnetization of the system amounting to 3, 2 and 1 μB for B, C and N, respectively. The dopants are found to be in the X(2-) state and tend to segregate to the surface. These impurity sites also present the centers of altered chemical reactivity. We probe the chemisorption properties of the doped MgO(001) surfaces with the CO molecule and atomic O. The adsorption of CO is much stronger on B- and C-doped MgO(001) compared to pure MgO(001) as the impurity sites serve as potent electron donors. The situation is similar to the case of atomic oxygen, for which we find the adsorption energy of -8.78 eV on B-doped MgO(001). The surface reactivity changes locally around the dopant atom, which is mainly restricted to its first coordination shell. The presented results suggest doped MgO as a versatile multifunctional material with possible use as an adsorbent or a catalyst.


Long-Term Follow-up of Monoclonal Gammopathy of Undetermined Significance.
Monoclonal gammopathy of undetermined significance (MGUS) occurs in approximately 3% of persons 50 years of age or older. We studied 1384 patients who were residing in southeastern Minnesota and in whom MGUS was diagnosed at the Mayo Clinic in the period from 1960 through 1994; the median follow-up was 34.1 years (range, 0.0 to 43.6). The primary end point was progression to multiple myeloma or another plasma-cell or lymphoid disorder. During 14,130 person-years of follow-up, MGUS progressed in 147 patients (11%), a rate that was 6.5 times (95% confidence interval [CI], 5.5 to 7.7) as high as the rate in the control population. The risk of progression without accounting for death due to competing causes was 10% at 10 years, 18% at 20 years, 28% at 30 years, 36% at 35 years, and 36% at 40 years. Among patients with IgM MGUS, the presence of two adverse risk factors - namely, an abnormal serum free light-chain ratio (ratio of kappa to lambda free light chains) and a high serum monoclonal protein (M protein) level (≥1.5 g per deciliter) - was associated with a risk of progression at 20 years of 55%, as compared with 41% among patients who had one adverse risk factor and 19% among patients who had neither risk factor. Among patients with non-IgM MGUS, the risk of progression at 20 years was 30% among those who had the two risk factors, 20% among those who had one risk factor, and 7% among those who had neither risk factor. Patients with MGUS had shorter survival than was expected in the control population of Minnesota residents of matched age and sex (median, 8.1 vs. 12.4 years; P<0.001). Significant differences were noted in the risk of progression between patients with IgM MGUS and those with non-IgM MGUS. Overall survival was shorter among patients with MGUS than was expected in a matched control population. (Funded by the National Cancer Institute.).


[Influence of survival processing and delay on recollection and familiarity in recognition].
The survival processing effect is a robust memory phenomenon of memory whereby encouraging participants to judge words for relevance to a survival situation produces better recall than other processing tasks such as semantic or self-reference tasks (Nairne, Thompson, & Pandeirada, 2007). The present study separated memory performance into recollection and familiarity, and estimated the contribution of these two factors to the survival processing effect as adaptive memory by using a recognition test based on the dual-process signal detection model. This study also examined the long-term persistence of the effect by delay manipulation (immediate, after a week, after five weeks) of the recognition test. Under delayed conditions (after a week and five weeks), survival processing advantage occurred on recollection, but semantic processing had no effect. In contrast, for familiarity, there was no significant difference between survival and semantic processing. These findings suggest that the survival processing effect mainly relies on recollection.


Use of potentially inappropriate medication and polypharmacy in older adults: a repeated cross-sectional study.
With age, the number of chronic conditions increases along with the use of medications. For several years, polypharmacy has been found to be on the increase in western societies. Polypharmacy is associated with an increased risk of adverse drug events (ADE). Medications called potentially inappropriate medications (PIM) have also been found to increase the risk of ADEs in an older population. In this study, which we conducted during a national information campaign to reduce PIM, we analysed the prevalence of PIM in an older adult population and in different strata of the variables age, gender, number of chronic conditions and polypharmacy and how that prevalence changed over time. This is a registry-based repeated cross-sectional study including two cohorts. Individuals aged 75 or older listed at a primary care centre in Blekinge on the 31st March 2011 (cohort 1, 15,361 individuals) or on the 31st December 2013 (cohort 2, 15,945 individuals) were included in the respective cohorts. Using a chi2 test, the two cohorts were compared on the variables age, gender, number of chronic conditions and polypharmacy. Use of five or more medications at the same time was the definition for polypharmacy. Use of PIM decreased from 10.60 to 7.04% (p-value < 0.001) between 2011 and 2013, while prevalence of five to seven chronic conditions increased from 20.55 to 23.66% (p-value < 0.001). Use of PIM decreased in all strata of the variables age, gender number of chronic conditions and polypharmacy. Except for age 80-84 and males, where it increased, prevalence of polypharmacy was stable in all strata of the variables. Use of potentially inappropriate medications had decreased in all variables between 2011 and 2013; this shows the possibility to reduce PIM with a focused effort. Polypharmacy does not increase significantly compared to the rest of the population.


Vital signs: HIV prevention through care and treatment--United States.
An estimated 1.2 million persons in the United States were living with human immunodeficiency virus (HIV) infection in 2008. Improving survival of persons with HIV and reducing transmission involve a continuum of services that includes diagnosis (HIV testing), linkage to and retention in HIV medical care, and ongoing HIV prevention interventions, including appropriately timed antiretroviral therapy (ART). CDC used three surveillance datasets to estimate recent HIV testing and HIV prevalence among U.S. adults by state, and the percentages of HIV-infected adults receiving HIV care for whom ART was prescribed, who achieved viral suppression, and who received prevention counseling from health-care providers. Published data were used to estimate the numbers of persons in the United States living with and diagnosed with HIV and, based on viral load and CD4 laboratory reports, linked to and retained in HIV care. In 2010, 9.6% of adults had been tested for HIV during the preceding 12 months (range by state: 4.9%-29.8%). Of the estimated 942,000 persons with HIV who were aware of their infection, approximately 77% were linked to care, and 51% remained in care. Among HIV-infected adults in care, 45% received prevention counseling, and 89% were prescribed ART, of whom 77% had viral suppression. Thus, an estimated 28% of all HIV-infected persons in the United States have a suppressed viral load. Prevalence of HIV testing and linkage to care are high but warrant continued effort. Increasing the percentages of HIV-infected persons who remain in HIV care, achieve viral suppression, and receive prevention counseling requires additional effort. Public health officials and HIV care providers should improve engagement at each step in the continuum of HIV care and monitor progress in every community using laboratory reports of viral load and CD4 test results.


Association of Exhaled Carbon Monoxide With Stroke Incidence and Subclinical Vascular Brain Injury: Framingham Heart Study.
Exhaled carbon monoxide (CO) is associated with cardiometabolic traits, subclinical atherosclerosis, and cardiovascular disease, but its specific relations with stroke are unexplored. We related exhaled CO to magnetic resonance imaging measures of subclinical cerebrovascular disease cross-sectionally and to incident stroke/transient ischemic attack prospectively in the Framingham Offspring study. We measured exhaled CO in 3313 participants (age 59±10 years; 53% women), and brain magnetic resonance imaging was available in 1982 individuals (age 58±10 years; 54% women). Participants were analyzed according to tertiles of exhaled CO concentration. In age- and sex-adjusted models, the highest tertile of exhaled CO was associated with lower total cerebral brain volumes, higher white-matter hyperintensity volumes, and greater prevalence of silent cerebral infarcts (P<0.05 for all). The results for total cerebral brain volume and white-matter hyperintensity volume were consistent after removing smokers from the sample, and the association with white-matter hyperintensity volume persisted after multivariable adjustment (P=0.04). In prospective analyses (mean follow-up 12.9 years), higher exhaled CO was associated with 67% (second tertile) and 97% (top tertile) increased incidence of stroke/transient ischemic attack relative to the first tertile that served as referent (P<0.01 for both). These results were consistent in nonsmokers and were partially attenuated upon adjustment for vascular risk factors. In this large, community-based sample of individuals without clinical stroke/transient ischemic attack at baseline, higher exhaled CO was associated with a greater burden of subclinical cerebrovascular disease cross-sectionally and with increased risk of stroke/transient ischemic attack prospectively. Further investigation is necessary to explore the biological mechanisms linking elevated CO with stroke.


New recreational drug 1-phenyl-2-(1-pyrrolidinyl)-1-pentanone (alpha-PVP) activates central nervous system via dopaminergic neuron.
1-phenyl-2-(1-pyrrolidinyl)-1-pentanone (α-PVP) is a new designer drug of the cathinone type. People who have taken drugs containing α-PVP or other synthetic cathinone reportedly lose consciousness, develop difficulty breathing, and at worst case, die. However, the mechanism underlying α-PVP-induced neurotoxicity is unknown. The objective of the present study was to investigate the effect of α-PVP on the central nervous system (CNS) and compare its neurotoxicity with that of methamphetamine (METH) in mice. Balb/c male mice (8 weeks old) were orally administered α-PVP (25 mg/kg) or METH (5 mg/kg). α-PVP induced a significant increase in locomotor activity, which occurred earlier than locomotor activity induced by METH. This increase was inhibited by the D1 receptor antagonist SCH23990 (50 µg/kg, i.p.) and the D2 receptor antagonist sulpiride (50 mg/kg, i.m.). The extracellular concentration of dopamine (DA) in the striatum, determined by in vivo microdialysis increased immediately after α-PVP administration. These results suggest that α-PVP stimulates DA release, causing an increase in locomotor activity, and that this stimulatory effect of α-PVP on CNS is mediated, at least in part, by the D1 and D2 receptors.


Apnoeic oxygenation during intubation: a systematic review and meta-analysis.
Apnoeic oxygenation during intubation is used to prevent desaturation during intubation. The aim of this review was to assess whether apnoeic oxygenation during endotracheal intubation reduced the incidence of hypoxaemia. Five major databases were systematically searched for all relevant studies published up to May 2016. All study designs with a control group and a group receiving apnoeic oxygenation were included in this review. These studies were then assessed for level of evidence and risk of bias. The data were then analysed using a meta-analysis. Eleven studies (six high quality randomised controlled trials, four low quality level two studies and one low quality level three study) were found. In the meta-analysis there was strong evidence for benefit of apnoeic oxygenation in terms of improved SpO2 in elective surgical patients, obese patients and those undergoing emergency intubation without respiratory failure. However, no significant benefit was found in patients with respiratory failure. This is the first meta-analysis to be performed on apnoeic oxygenation during intubation. Apnoeic oxygenation provides significant benefit in terms of improving SpO2 for the majority of intubations, although there appears to be no benefit in patients whose indication for intubation is respiratory failure. Apnoeic oxygenation ought to be considered for integration into intubation protocols.


Fecal Impaction Causing Pelvic Venous Compression and Edema.
Chronic constipation is a common condition which may result in fecal impaction. A 13-year-old male with chronic constipation and encopresis presented with fecal impaction for three weeks. The impaction caused abdominal pain, distension, encopresis, and decreased oral intake. He was found in severe distress with non-pitting edema of his feet and ankles along with perineal edema. The pedal edema worsened after receiving a fluid bolus, so concern arose for venous compression or a thrombus. A Duplex Ultrasound demonstrated changes in the venous waveforms of the bilateral external iliac and common femoral veins without thrombosis. Manual disimpaction and polyethylene glycol 3350 with electrolytes resolved the pedal and perineal edema. Four months later, he had soft bowel movements without recurrence of the edema. A repeat Duplex Ultrasound was normal. We present a child in whom severe fecal impaction caused pelvic venous compression resulting in bilateral pedal and perineal edema.


Predicting negative health outcomes in older general practice patients with chronic illness: Rationale and development of the PROPERmed harmonized individual participant data database.
The prevalence of multimorbidity and polypharmacy increases significantly with age and are associated with negative health consequences. However, most current interventions to optimize medication have failed to show significant effects on patient-relevant outcomes. This may be due to ineffectiveness of interventions themselves but may also reflect other factors: insufficient sample sizes, heterogeneity of population. To address this issue, the international PROPERmed collaboration was set up to obtain/synthesize individual participant data (IPD) from five cluster-randomized trials. The trials took place in Germany and The Netherlands and aimed to optimize medication in older general practice patients with chronic illness. PROPERmed is the first database of IPD to be drawn from multiple trials in this patient population and setting. It offers the opportunity to derive prognostic models with increased statistical power for prediction of patient-relevant outcomes resulting from the interplay of multimorbidity and polypharmacy. This may help patients from this heterogeneous group to be stratified according to risk and enable clinicians to identify patients that are likely to benefit most from resource/time-intensive interventions. The aim of this manuscript is to describe the rationale behind PROPERmed collaboration, characteristics of the included studies/participants, development of the harmonized IPD database and challenges faced during this process.


Selected reaction monitoring mass spectrometry for relative quantification of proteins involved in cellular life and death processes.
Monitoring of proteins involved in cellular life and death processes is of high scientific interest since it permits the elucidation of functional changes in a variety of diseases. In this study, we have developed a nanoLC-MS/MS assay for the simultaneous detection and quantification of 24 selected proteins that are known to be important for cellular homeostasis. The Selected Reaction Monitoring (SRM) assay applies heavy-labeled peptide analogues for the relative quantification of proteins with central functions in cellular stress and metabolism, including many mitochondrial proteins. The assay includes proteins involved in the quality control of mitochondrial proteins, oxidative stress, respiratory chain, and fatty acid degradation, as well as the cytosolic glyceraldehyde 3-phosphate dehydrogenase, lactate dehydrogenase and ribosomal proteins. The assay can thus quantitate the balance between mitochondrial and cytosolic pathways, which is relevant in many disease states, and can be studied by comparing patient and control samples. The measured validation parameters showed satisfactory results for the proteins included in the analysis. The linear range of the monitored proteins was 0.01-20nM, with a median precision of less than 10%. The assay performed well in monitoring proteins in both cultured human skin fibroblast cells as well as in isolated peripheral blood mononuclear cells. We therefore believe that this assay is applicable for the study of cellular stress response in various types of cell defects and disease states.


Fetal growth reference ranges in twin pregnancy: analysis of the Southwest Thames Obstetric Research Collaborative (STORK) multiple pregnancy cohort.
To generate reference charts for expected fetal growth in dichorionic diamniotic (DCDA) and monochorionic diamniotic (MCDA) twin pregnancies and to compare these with those from singleton pregnancies. This was a retrospective study of biometric measurements from serial ultrasound examinations of twin pregnancies in the second and third trimesters, from 14 weeks' gestation to term, collected by nine hospitals over a 10-year period. The measurements obtained in each fetus at each examination included head circumference (HC), biparietal diameter (BPD), abdominal circumference (AC) and femur length (FL). Multilevel mixed effects statistical models were used to evaluate growth in each biometric variable in relation to gestational age, taking account of the serial examinations and the association between the two fetuses in each pregnancy, with separate models constructed for DCDA and MCDA pregnancies. The final dataset for analysis included a total of 9866 second- and third-trimester ultrasound examinations in 1802 DCDA and 323 MCDA twin pregnancies, with a median of five (range, 1-14) scans per pregnancy. For each variable, the mean value for DCDA twins was close to the reported value in singletons at 20-30 weeks and showed a decrease relative to singletons beyond 30 weeks. The differences were greater for AC and HC, for which the mean in twins was approximately equivalent to the 30th percentile in singletons at 18 weeks, the 35th percentile at 25 weeks and the 30th percentile at 35 weeks. Fetuses in MCDA twin pregnancies displayed lower mean measurements than did those in DCDA pregnancies throughout the gestational age range considered. Ultrasound biometry shows a small but statistically significant reduction in fetal growth in twin pregnancies relative to that in singletons, particularly in the third trimester, with a more marked difference for MCDA than for DCDA pregnancies.


The effect of cactus pear (Opuntia ficus-indica) on body weight and cardiovascular risk factors: a systematic review and meta-analysis of randomized clinical trials.
Hundreds of dietary supplements are currently marketed as weight loss supplements. However, the advertised health claims of effectiveness for most of these have not been proven. The aim of this study was to critically appraise and evaluate the evidence for effectiveness of cactus pear, Opuntia ficus-indica (OFI), using data from published randomized clinical trials. We conducted electronic searches in Medline, Embase, Amed, Cinahl, and the Cochrane Library. No restrictions on age, time, or language were imposed. The risk for bias in the studies included was assessed using the Cochrane Collaboration criteria. Two reviewers independently determined the eligibility of included studies, assessed reporting quality, and extracted data. We identified seven eligible studies, of which five were included. The studies varied in design and reporting quality. Meta-analysis revealed a nonsignificant difference in body weight between OFI and controls (mean difference = -0.83 kg; 95% confidence interval, -2.49 to 0.83; I(2) = 93%). Significant reductions in body mass index, percentage body fat, systolic and diastolic blood pressures, and total cholesterol were observed. Adverse events included gastric intolerance and flu symptoms. The evidence from randomized clinical trials does not indicate that supplementation with OFI generates statistically significant effects on body weight. Consumption of OFI can cause significant reductions in percentage body fat, blood pressure, and total cholesterol. Few clinical trials evaluating the effects of OFI have been published. They vary in design and methodology, and are characterized by inconsistent quality of reporting. Further clinical trials evaluating the effects of OFI on body composition and metabolic parameters are warranted.


Variation of laminar depth in normal eyes with age and race.
To determine if laminar depth (LD) and prelaminar tissue volume (PTV) are associated with age and race in healthy human eyes. Optic nerve head images from enhanced depth imaging spectral-domain optical coherence tomography of 166 normal eyes from 84 subjects of African descent (AD) and European descent (ED) were manually delineated to identify the principal surfaces: internal limiting membrane, Bruch's membrane (BM), anterior sclera (AS), and anterior surface of the lamina cribrosa. These four surfaces defined the LD and PTV using Bruch's membrane opening (BMO) and AS for reference structures. Generalized estimating equations were used to evaluate whether the effect of age on each outcome was differential by race. When age was analyzed as a continuous variable, the interaction term between age and race was statistically significant for mean LDBMO (P = 0.015) and mean LDAS (P = 0.0062) after adjusting for axial length and BMO area. For every 1-year increase in age, the LDAS was greater on average by 1.78 μm in AD subjects and less by 1.71 μm in ED subjects. Mean PTV was lower in the older subjects (1248 × 10(6) μm(3) AD, 881 × 10(6) μm(3) ED) compared to the younger subjects (1316 × 10(6) μm(3) AD, 1102 × 10(6) μm(3) ED) in both groups. With increasing age, the LD changes differently across racial groups in normal subjects. The LD in ED subjects showed a significantly decreasing slope suggesting that the lamina moves anteriorly with age in this group.


Chaste: using agile programming techniques to develop computational biology software.
Cardiac modelling is the area of physiome modelling where the available simulation software is perhaps most mature, and it therefore provides an excellent starting point for considering the software requirements for the wider physiome community. In this paper, we will begin by introducing some of the most advanced existing software packages for simulating cardiac electrical activity. We consider the software development methods used in producing codes of this type, and discuss their use of numerical algorithms, relative computational efficiency, usability, robustness and extensibility. We then go on to describe a class of software development methodologies known as test-driven agile methods and argue that such methods are more suitable for scientific software development than the traditional academic approaches. A case study is a project of our own, Cancer, Heart and Soft Tissue Environment, which is a library of computational biology software that began as an experiment in the use of agile programming methods. We present our experiences with a review of our progress thus far, focusing on the advantages and disadvantages of this new approach compared with the development methods used in some existing packages. We conclude by considering whether the likely wider needs of the cardiac modelling community are currently being met and suggest that, in order to respond effectively to changing requirements, it is essential that these codes should be more malleable. Such codes will allow for reliable extensions to include both detailed mathematical models--of the heart and other organs--and more efficient numerical techniques that are currently being developed by many research groups worldwide.


Cetacean noise criteria revisited in the light of proposed exposure limits for harbour porpoises.
The impact of underwater noise on marine life calls for identification of exposure criteria to inform mitigation. Here we review recent experimental evidence with focus on the high-frequency cetaceans and discuss scientifically-based initial exposure criteria. A range of new TTS experiments suggest that harbour and finless porpoises are more sensitive to sound than expected from extrapolations based on results from bottlenose dolphins. Furthermore, the results from TTS experiments and field studies of behavioural reactions to noise, suggest that response thresholds and TTS critically depend on stimulus frequency. Sound exposure levels for pure tones that induce TTS are reasonably consistent at about 100 dB above the hearing threshold for pure tones and sound pressure thresholds for avoidance reactions are in the range of 40-50 dB above the hearing threshold. We propose that frequency weighting with a filter function approximating the inversed audiogram might be appropriate when assessing impact.


Cerebral cortical microinfarcts: A novel MRI marker of vascular brain injury in patients with heart failure.
Patients with heart failure (HF) are at risk for vascular brain injury. Cerebral cortical microinfarcts (CMIs) are a novel MRI marker of vascular brain injury. This study aims to determine the occurrence of CMIs in patient with HF and their clinical correlates, including haemodynamic status. From the Heart-Brain Study, a multicenter prospective cohort study, 154 patients with clinically stable HF without concurrent atrial fibrillation (mean age 69.5 ± 10.1, 32% female) and 124 reference participants without HF (mean age 65.6 ± 7.4, 47% females) were evaluated for CMIs on 3 T MRI. CMI presence in HF was tested for associations with vascular risk profile, cardiac function and history, MRI markers of vascular brain injury and cognitive profile. CMI occurrence was higher in patient with HF (17%) than reference participants (7%); after correction for age and sex OR 2.5 [95% CI 1.1-6.0] p = .032; after additional correction for vascular risk factors OR 2.7 [1.0-7.1] p = .052. In patients with HF, CMI presence was associated with office hypertension (OR 2.7 [1.2-6.5] p = .021) and a lower cardiac index (B = -0.29 [-0.55--0.04] p = .023 independent of vascular risk factors), but not with cause or duration of HF. Presence of CMIs was not associated with cognitive performance in patients with HF. CMIs are a common occurrence in patients with HF and related to an adverse vascular risk factor profile and severity of cardiac dysfunction. CMIs thus represent a novel marker of vascular brain injury in these patients.


Human tryptophan dioxygenase: a comparison to indoleamine 2,3-dioxygenase.
In contrast to the diverse superfamily of monooxygenases, there are only two classes of heme-containing dioxygenases in humans. One is tryptophan 2,3 dioxygenase (hTDO), and the other is indoleamine 2,3-dioxygenase (hIDO), both of which catalyze the oxidative degradation of Trp to N-formyl kynurenine. Although hTDO and hIDO catalyze the same reaction, they engage in distinct physiological functions. The molecular properties of hTDO, unlike hIDO, have never been explored in the past. Here, we report the first structural and functional characterization of hTDO with resonance Raman and optical absorption spectroscopies. We show that the proximal Fe-His stretching frequency of hTDO is 229 cm(-1), 7 cm(-1) lower than that of hIDO, indicating its weaker imidazolate character as compared to hIDO. In the CO derivative of the L-Trp-bound enzyme, the Fe-CO stretching and C-O stretching frequencies are 488 and 1972 cm(-1), respectively, suggesting that L-Trp binds to the distal pocket with its C2-C3 double bond facing the heme-bound ligand, in contrast to hIDO, in which the indole NH group forms an H-bond with the heme-bound ligand. Moreover, the Km values of hTDO for D-Trp and L-Trp are similar, but the kcat value for D-Trp is 10-fold lower than that for L-Trp. In contrast, in hIDO, the Km value for D-Trp is 700-fold higher than L-Trp, whereas the kcat values are comparable for the two stereoisomers. Taken together, the data indicate that the initial deprotonation reaction of the indole NH group in hTDO is carried out by the evolutionarily conserved distal His, whereas that in hIDO is performed by the heme-bound dioxygen; in addition, the stereospecificity of hTDO is determined by the efficiency of the dioxygen chemistry, whereas that in hIDO is controlled by the substrate affinity.


Intraoral presentation of multiple malignant peripheral nerve sheath tumors associated with neurofibromatosis-1.
Neurofibromatosis-1 (NF-1) is a relatively common autosomal dominant disease characterized by multiple cutaneous fibromatoses and café au lait spots. It is associated with the mutation of NF-1 gene, a tumor suppressor gene located on chromosome 17q11.2. Hence, it can be considered as a familial cancer predisposition syndrome in which the affected individuals are at increased risk of developing malignancies. Intraoral neurofibromas associated with NF-1 are quite common, but the occurrence of malignant peripheral nerve sheath tumor (MPNST) in the oral cavity is very rare. Oral MPNST can occur either de novo or by malignant transformation of neurofibromas or very rarely can represent a metastatic lesion. Here, we present a case of MPNST involving the maxillary region, in a patient with NF-1. Since MPNST often creates a diagnostic dilemma, histopathologic criteria for the diagnosis of MPNST are also discussed.


Counseling for childbirth fear - a national survey.
Counseling by experienced midwives is offered to women with childbirth fear in most obstetric clinics in Sweden, but information about the content of such counseling is lacking. To study comprehensiveness, content and organization of the midwife-led counseling for childbirth fear in all obstetric clinics in Sweden. In this cross-sectional study, data were collected using a questionnaire sent to all obstetric clinics in Sweden (n = 45); a total of 43 clinics responded. Descriptive and one-way ANOVA was used in the analysis. All responding obstetric clinics in Sweden offer midwife-led counseling to women with childbirth fear. Major differences were found regarding the time allocated to counseling, with a range between 5.7 and 47.6 minutes per childbirth. Supplementary education for midwives and the availability of treatment options varied at the different clinics and were not associated with the size of the clinic. The midwife-led counseling conducted at the different Swedish obstetric clinics showed considerable disparities. Women with childbirth fear would benefit from care on equal terms irrespective of place of residence. Consequently, it would be valuable to develop a national healthcare program for childbirth fear.


Involuntary admission: the case of anorexia nervosa.
Involuntary treatment of psychiatric disorders has always been controversial; this is especially true for eating disorders. Patients with anorexia nervosa of life threatening severity frequently refuse psychiatric hospitalization. Ambivalence toward treatment is characteristic of eating disorders and patients are often admitted to inpatient programs under pressure from family and doctors. In this article, we report research on the positive or negative impact of involuntary admission in the treatment of eating disorders, its application and effectiveness as well as the adverse consequences of coercive treatment in eating disorders. A literature review was done. From a total of 134 publications which were retrieved from the literature search, 50 studies were directly relevant to the scope of this review and fulfilled all inclusion criteria. There are trends and arguments for both sides; for and against involuntary treatment in anorexia nervosa. The scientific literature so far is inconclusive, although in the short term, involuntary hospitalization has benefits. This review has also shown that involuntary hospitalization can have adverse long-term consequences for the patient-therapist allegiance. We conclude that in some cases, involuntary treatment can save lives of young patients with anorexia nervosa; however, in other cases, it can break the psychotherapeutic relationship and make the patient abandon treatment. It is the clinician who has to decide for whom and when to approve involuntary treatment or not.


Restoration of connexin26 protein level in the cochlea completely rescues hearing in a mouse model of human connexin30-linked deafness.
Mutations in genes coding for connexin26 (Cx26) and/or Cx30 are linked to approximately half of all cases of human autosomal nonsyndromic prelingual deafness. Cx26 and Cx30 are the two major Cx isoforms found in the cochlea, and they coassemble to form hybrid (heteromeric and heterotypic) gap junctions (GJs). This molecular arrangement implies that homomeric GJs would remain in the cochlea if one of the coassembly partners were mutated resulting in null expression. We generated mice in which extra copies of the Cx26 gene were transgenically expressed from a modified bacterial artificial chromosome in a Cx30-/- background. In the absence of the Cx30 gene, Cx26 expressed from extra alleles completely restored hearing sensitivity and prevented hair cell death in deaf Cx30-/- mice. The results indicated that hybrid GJs consisting of Cx26 and Cx30 were not essential for normal hearing in mice and suggested that up-regulation of Cx26 or slowing down its protein degradation might be a therapeutic strategy to prevent and treat deafness caused by Cx30 mutations.


Effectiveness of health voucher scheme and micro-health insurance scheme to support the poor and extreme poor in selected urban areas of Bangladesh: An assessment using a mixed-method approach.
National healthcare financing strategy recommends tax-based equity funds and insurance schemes for the poor and extreme poor living in urban slums and pavements as the majority of these population utilise informal providers resulting in adverse health effects and financial hardship. We assessed the effect of a health voucher scheme (HVS) and micro-health insurance (MHI) scheme on healthcare utilisation and out-of-pocket (OOP) payments and the cost of implementing such schemes. HVS and MHI schemes were implemented by Concern Worldwide through selected NGO health centres, referral hospitals, and private healthcare facilities in three City Corporations of Bangladesh from December 2016 to March 2020. A household survey with 1,294 enrolees, key-informant interviews, focus group discussions, consultative meetings, and document reviews were conducted for extracting data on healthcare utilisation, OOP payments, views of enrolees, and suggestions of implementers, and costs of services at the point of care. Healthcare utilisation including maternal, neonatal and child health (MNCH) services, particularly from medically trained providers, was higher and OOP payments were lower among the scheme enrolees compared to corresponding population groups in general. The beneficiaries were happy with their access to healthcare, especially for MNCH services, and their perceived quality of care was fair enough. They, however, suggested expanding the benefits package, supported by an additional workforce. The cost per beneficiary household for providing services per year was €32 in HVS and €15 in MHI scheme. HVS and MHI schemes enabled higher healthcare utilisation at lower OOP payments among the enrolees, who were happy with their access to healthcare, particularly for MNCH services. However, they suggested a larger benefits package in future. The provider's costs of the schemes were reasonable; however, there are potentials of cost containment by purchasing the health services for their beneficiaries in a competitive basis from the market. Scaling up such schemes addressing the drawback would contribute to achieving universal health coverage.


Mitral valve repair for active culture positive infective endocarditis.
To describe the clinical and echocardiographic outcome after mitral valve (MV) repair for active culture positive infective MV endocarditis. Between 1996 and 2004, 36 patients (mean (SD) age 53 (18) years) with positive blood culture up to three weeks before surgery (or positive culture of material removed at operation) and intraoperative evidence of endocarditis underwent MV repair. Staphylococci and streptococci were the most common pathogens. All patients had moderate or severe mitral regurgitation (MR). Mean New York Heart Association (NYHA) class was 2.3 (1.0). Follow up was complete (mean 38 (19) months). Operative mortality was 2.8% (one patient). At follow up, endocarditis has not recurred. One patient developed severe recurrent MR and underwent valve replacement and one patient had moderate MR. There were two late deaths, both non-cardiac. Kaplan-Meier five year freedom from recurrent moderate to severe MR, freedom from repeat operation, and survival were 94 (4)%, 97 (3)%, and 93 (5)%, respectively. At the most recent review the mean NYHA class was 1.17 (0.3) (p < 0.0001). At the latest echocardiographic evaluation, left atrial diameters, left ventricular end diastolic diameter, and MV diameter were significantly reduced (p < 0.05) compared with preoperative values. MV repair for active culture positive endocarditis is associated with low operative mortality and provides satisfactory freedom from recurrent infection, freedom from repeat operation, and survival. Hence, every effort should be made to repair infected MVs and valves should be replaced only when repair is not possible.


Organometallic Halide Perovskites: Sharp Optical Absorption Edge and Its Relation to Photovoltaic Performance.
Solar cells based on organometallic halide perovskite absorber layers are emerging as a high-performance photovoltaic technology. Using highly sensitive photothermal deflection and photocurrent spectroscopy, we measure the absorption spectrum of CH3NH3PbI3 perovskite thin films at room temperature. We find a high absorption coefficient with particularly sharp onset. Below the bandgap, the absorption is exponential over more than four decades with an Urbach energy as small as 15 meV, which suggests a well-ordered microstructure. No deep states are found down to the detection limit of ∼1 cm(-1). These results confirm the excellent electronic properties of perovskite thin films, enabling the very high open-circuit voltages reported for perovskite solar cells. Following intentional moisture ingress, we find that the absorption at photon energies below 2.4 eV is strongly reduced, pointing to a compositional change of the material.


Provision of inpatient rehabilitation and challenges experienced with participation post discharge: quantitative and qualitative inquiry of African stroke patients.
The provision of rehabilitation differs between developed and developing countries, this could impact on the outcomes of post stroke rehabilitation. The aim of this paper is to present provision of in-patient stroke rehabilitation. In addition the challenges experienced by the individuals with participation post discharge are also presented. Qualitative and quantitative research methods were used to collect data. The quantitative data was collected using a retrospective survey of stroke patients admitted to hospitals over a three- to five-year period. Quantitative data was captured on a validated data capture sheet and analysed descriptively. The qualitative data was collected using interviews from a purposively and conveniently selected sample, audio-taped and analysed thematically. The qualitative data was presented within the participation model. A total of 168 medical folders were reviewed for a South African sample, 139 for a Rwandan sample and 145 for a Tanzanian sample. The mean age ranged from 62.6 (13.78) years in the South African sample to 56.0 (17.4) in the Rwandan sample. While a total of 98 % of South African stroke patients received physiotherapy, only 39.4 % of Rwandan patients received physiotherapy. From the qualitative interviews, it became clear that the stroke patients had participation restrictions. When conceptualised within the Participation Model participation restrictions experienced by the stroke patients were a lack of accomplishment, inability to engage in previous roles and a perception of having health problems. With the exception of Rwanda, stroke patients in the countries studied are admitted to settings early post stroke allowing for implementation of effective acute interventions. The participants were experiencing challenges which included a lack of transport and the physical geographic surroundings in the rural settings not being conducive to wheelchair use. Stroke patients admitted to hospitals in certain African countries could receive limited in-patient therapeutic interventions. With the exception of barriers in the physical environment, stroke patients in developing countries where resources are limited experience the same participation restrictions as their counterparts in developed countries where resources are more freely available. Rehabilitation interventions in these developing countries should therefore be community-based focussing on intervening in the physical environment.


Measurement of adherent cell mass and growth.
The characterization of physical properties of cells such as their mass and stiffness has been of great interest and can have profound implications in cell biology, tissue engineering, cancer, and disease research. For example, the direct dependence of cell growth rate on cell mass for individual adherent human cells can elucidate the mechanisms underlying cell cycle progression. Here we develop an array of micro-electro-mechanical systems (MEMS) resonant mass sensors that can be used to directly measure the biophysical properties, mass, and growth rate of single adherent cells. Unlike conventional cantilever mass sensors, our sensors retain a uniform mass sensitivity over the cell attachment surface. By measuring the frequency shift of the mass sensors with growing (soft) cells and fixed (stiff) cells, and through analytical modeling, we derive the Young's modulus of the unfixed cell and unravel the dependence of the cell mass measurement on cell stiffness. Finally, we grew individual cells on the mass sensors and measured their mass for 50+ hours. Our results demonstrate that adherent human colon epithelial cells have increased growth rates with a larger cell mass, and the average growth rate increases linearly with the cell mass, at 3.25%/hr. Our sensitive mass sensors with a position-independent mass sensitivity can be coupled with microscopy for simultaneous monitoring of cell growth and status, and provide an ideal method to study cell growth, cell cycle progression, differentiation, and apoptosis.


Relationship between bone quantitative ultrasound and mortality: a prospective study.
In a cohort of 5,201 women [72.3 +/- 5.3 years] from 58 primary care centers in Spain, followed for three years, no relationship between heel QUS parameters and overall mortality was found. However, a significant relationship between a low speed of sound (SOS) and vascular mortality was observed. An inverse relationship between mortality and bone mineral density measured by dual-energy absorption densitometry or quantitative bone ultrasound (QUS) has been described. The aim of the present study was to test this relationship in the ECOSAP cohort, a 3-year prospective study designed to assess the ability of heel QUS and clinical risk factors to predict non-vertebral fracture risk in women over 64. A cohort of 5,201 women [72.3 +/- 5.3 years] was studied. QUS was assessed with the Sahara(R) bone sonometer. Women attended follow-up visits every 6 months. Physicians recorded if the patient died and cause of death. Hazard rates (HR) of all-cause and vascular mortality per one standard deviation reduction in QUS parameters were determined. One hundred (1.9%) women died during a median of 36.1 months follow-up, for a total of 14,999 patient-years, 42 because of vascular events (both cardiovascular and cerebrovascular). After adjusting for age, none of the QUS variables showed statistically significant differences between the patients who died and the survivors. In the final multivariate model, adjusted for age, current thyroxine and hypoglycaemic drug use, chronic obstructive pulmonary disease and decreased visual acuity, SOS was marginally non-significant: (HR: 1.19; 0.97-1.45). However, each 1 SD reduction in SOS was associated with a 39% increase in vascular mortality (HR: 1.39; 1.15-1.66). In our cohort, SOS was related with vascular mortality, but not overall mortality.


The balance between GMD and OFUT1 regulates Notch signaling pathway activity by modulating Notch stability.
The Notch signaling pathway plays an important role in development and physiology. In Drosophila, Notch is activated by its Delta or Serrate ligands, depending in part on the sugar modifications present in its extracellular domain. O-fucosyltransferase-1 (OFUT1) performs the first glycosylation step in this process, O-fucosylating various EGF repeats at the Notch extracellular domain. Besides its O-fucosyltransferase activity, OFUT1 also behaves as a chaperone during Notch synthesis and is able to down regulate Notch by enhancing its endocytosis and degradation. We have reevaluated the roles that O-fucosylation and the synthesis of GDP-fucose play in the regulation of Notch protein stability. Using mutants and the UAS/Gal4 system, we modified in developing tissues the amount of GDP-mannose-deshydratase (GMD), the first enzyme in the synthesis of GDP-fucose. Our results show that GMD activity, and likely the levels of GDP-fucose and O-fucosylation, are essential to stabilize the Notch protein. Notch degradation observed under low GMD expression is absolutely dependent on OFUT1 and this is also observed in Notch Abruptex mutants, which have mutations in some potential O-fucosylated EGF domains. We propose that the GDP-fucose/OFUT1 balance determines the ability of OFUT1 to endocytose and degrade Notch in a manner that is independent of the residues affected by Abruptex mutations in Notch EGF domains.


Two Validated Ways of Improving the Ability of Decision-Making in Emergencies; Results from a Literature Review.
The aim of the current review wasto study the existing knowledge about decision-making and to identify and describe validated training tools.A comprehensive literature review was conducted by using the following keywords: decision-making, emergencies, disasters, crisis management, training, exercises, simulation, validated, real-time, command and control, communication, collaboration, and multi-disciplinary in combination or as an isolated word. Two validated training systems developed in Sweden, 3 level collaboration (3LC) and MacSim, were identified and studied in light of the literature review in order to identify how decision-making can be trained. The training models fulfilled six of the eight identified characteristics of training for decision-making.Based on the results, these training models contained methods suitable to train for decision-making.


Genetic selection of a flavivirus-refractory strain of the yellow fever mosquito Aedes aegypti.
Two inbred (isofemale) Aedes aegypti mosquito lines were derived that manifested a resistant or susceptible phenotype following ingestion of yellow fever virus; lack of virus movement from the midgut defined the resistant phenotype. Other flaviviruses, including dengue 1-4, Uganda S, and Zika, viruses behaved in a similar fashion in the two mosquito lines. Crosses between the two lines produced progeny that were of intermediate susceptibility, indicating codominance; F2 backcrosses to the parents yielded results consistent with a major controlling genetic locus and provide evidence of a second locus capable of modulating the phenotype of the major gene. The rapid selection necessary to fix the susceptible and refractory phenotypes support the hypothesis of a single major controlling locus. Viral movement across the midgut is likely to be governed by a single major gene and modifying minor genes or a group of closely linked genes. These inbred mosquito lines will be useful in discovering the molecular basis for flavivirus resistance in Ae. aegypti.


Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content.
To assess the size of the lipid pool and the number of smooth muscle cells and monocyte/macrophages in human aortic plaques that were intact and to compare the results with those in aortic plaques undergoing ulceration and thrombosis. The lipid pool was measured as a percentage of the total cross sectional area of the plaque. Immunohistochemistry was used to identify cell types (monocytes/macrophages (M phi) by EBM11 and HAM56, smooth muscle cells by alpha actin). The area of the tissue occupied by each cell type was measured by quantitative microscopy in the peripheral (shoulder) area of the plaque and the plaque cap. Absolute counts of each cell type were expressed as the ratio of SMC:M phi. Aortas were obtained at necropsy from men aged less than 69 years who died suddenly (within 6 hours of the onset of symptoms) of ischaemic heart disease. 155 plaques from 13 aortas were studied. Four aortas showed intact plaques only (group A, n = 31). Nine aortas showed both intact plaques (group B, n = 79) and plaques that were undergoing thrombosis (group C, n = 45). In 41 (91.1%) of the 45 plaques undergoing thrombosis (group C) lipid pools occupied more than 40% of the cross sectional area of the plaque. Only 12 (10.9%) of the 110 intact plaques (groups A + B) had lipid pools of this size. The mean size of the lipid pool in plaques of groups A, B, and C was 12.7%, 27.3% and 56.7% respectively. Compared with intact plaques those undergoing thrombosis contained a smaller volume of smooth muscle cells (2.8% v 11.8%) and a larger volume of monocyte/macrophages (13.7% v 2.9%) in the plaque cap. The ratio of the number of smooth muscle cells to monocytes/macrophages was 7.8 in group A plaques, 4.1 in group B plaques, and 1.0 in group C plaques. This gradient was the result of an absolute increase in monocyte/macrophages and an absolute decrease in smooth muscle cells. In the aorta ulceration and thrombosis were characteristic of plaques with a high proportion of their volume occupied by extracellular lipid, and in which there was a shift toward a preponderance of monocyte/macrophages compared with smooth muscle cells in the cap.