Perceived versus objective breast cancer risk in diverse women.
Prior research suggests that women do not accurately estimate their risk for breast cancer. Estimating and informing women of their risk is essential for tailoring appropriate screening and risk reduction strategies. Data were collected for BreastCARE, a randomized controlled trial designed to evaluate a PC-tablet based intervention providing multiethnic women and their primary care physicians with tailored information about breast cancer risk. We included women ages 40-74 visiting general internal medicine primary care clinics at one academic practice and one safety net practice who spoke English, Spanish, or Cantonese, and had no personal history of breast cancer. We collected baseline information regarding risk perception and concern. Women were categorized as high risk (vs. average risk) if their family history met criteria for referral to genetic counseling or if they were in the top 5% of risk for their age based on the Gail or Breast Cancer Surveillance Consortium Model (BCSC) breast cancer risk model. Of 1,261 participants, 25% (N=314) were classified as high risk. More average risk than high risk women had correct risk perception (72% vs. 18%); 25% of both average and high risk women reported being very concerned about breast cancer. Average risk women with correct risk perception were less likely to be concerned about breast cancer (odds ratio [OR]=0.3; 95% confidence interval [CI]=0.2-0.4) while high risk women with correct risk perception were more likely to be concerned about breast cancer (OR=5.1; 95%CI=2.7-9.6). Many women did not accurately perceive their risk for breast cancer. Women with accurate risk perception had an appropriate level of concern about breast cancer. Improved methods of assessing and informing women of their breast cancer risk could motivate high risk women to apply appropriate prevention strategies and allay unnecessary concern among average risk women.


Double-leg isometric exercise training in older men.
Double-leg isometric training has been demonstrated to reduce resting blood pressure in young men when using electromyographic activity (EMG) to regulate exercise intensity. This study assessed this training method in healthy older (45-60 years.) men. Initially, 35 older men performed an incremental isometric exercise test to determine the linearity of the heart rate versus percentage peak EMG (%EMGpeak) and systolic blood pressure versus %EMGpeak relationship. Thereafter, 20 participants were allocated to a training or control group. The training group performed three double-leg isometric sessions per week for 8 weeks, at 85% of peak heart rate. The training resulted in a significant reduction in resting systolic (11 ± 8 mmHg, P < 0.05) and mean arterial (5 ± 7 mmHg, P < 0.05) blood pressure. There was no significant change in resting systolic blood pressure for the control group or diastolic blood pressure in either group (all P > 0.05). These findings show that this training method, used previously in young men, is also effective in reducing resting systolic and mean arterial blood pressure in older men.


[Risk factors for neonatal mortality among children with low birth weight].
To analyze the risk factors associated with neonatal deaths among children with low birth weight. A cohort study was carried out on live births weighing between 500 g and 2,499 g from single pregnancies without anencephaly in Recife (Northeastern Brazil) between 2001 and 2003. Data on 5,687 live births and 499 neonatal deaths obtained from the Live Birth Information System and the Mortality Information System were integrated through the linkage technique. Using a hierarchical model, variables from the distal level (socioeconomic factors), intermediate level (healthcare factors) and proximal level (biological factors) were subjected to univariate analysis and multivariate logistic regression. After adjusting the variables through multivariate logistic regression, the factors from the distal level that remained significantly associated with neonatal death were: cohabitation by the parents, number of live births and type of maternity hospital. At the intermediate level, the factors were: number of prenatal consultations, complexity of the maternity hospital and type of delivery. At the proximal level, the factors were: sex, gestational age, birth weight, Apgar score and presence of congenital malformation. The main factors associated with neonatal mortality among low weight live births are related to prenatal and postnatal care. Such factors are reducible through health sector actions.


Safety and efficacy of extending a previous endoscopic sphincterotomy for the treatment of retained or recurrent common bile duct stones.
The aim of the study was to evaluate the safety and efficacy of extending a previous endoscopic sphincterotomy (ES) in patients with retained or recurrent common bile duct (CBD) stones. Between 2001 and 2013, extension of a previous ES, for known or suspected CBD stones, was performed in 118 patients (m/f, 53/65) with a median age of 74 (range: 31-91) years (group A). During the same period, ES was performed in 1064 patients with suspected or known choledocholithiasis (group B). The efficacy and complications of the extension (group A) were analyzed and a comparison was made between groups regarding complications. Bile duct cannulation was straightforward in all patients in group A, while it was considered difficult in 49% of patients in group B. Complete clearance was achieved in 76/97 patients (78%) with CBD stones, after a mean of 1.18 attempts per patient. Mechanical lithotripsy was required in 10% of patients. After extension, immediate bleeding occurred in 24 patients (20%), which stopped spontaneously in 9 (37%) and endoscopic hemostasis was required in the remainder. Complications were more frequent in group B (5.3% vs. 0.8%, P=0.031), but there was no significant difference for any individual complication. Immediate bleeding was more common in group B (29% vs. 20%, P=0.035), but there was no difference in clinical bleeding. Extension of a previous ES seems to be a simple, effective and safe technique, allowing stone clearance in nearly 80% of patients; it is thus recommended in patients with CBD stones after ES.


Neohesperidin suppresses osteoclast differentiation, bone resorption and ovariectomised-induced osteoporosis in mice.
Excessive bone resorption by osteoclasts plays an important role in osteoporosis. Bone loss occurs in ovariectomised (OVX) mice in a similar manner to that in humans, so this model is suitable for evaluating potential new therapies for osteoporosis. Neohesperidin (NE) is a flavonoid compound isolated from citrus fruits. Its role in bone metabolism is unknown. In this study we found that neohesperidin inhibits osteoclast differentiation, bone resorption and the expression of osteoclast marker genes, tartrate-resistant acid phosphatase and cathepsin K. In addition, neohesperidin inhibited receptor activator of NF-κB ligand (RANKL)-induced activation of NF-κB, and the degradation of inhibitor of kappa B-alpha (IκBα). Furthermore, neohesperidin inhibited RANKL induction of nuclear factor of activated T-cells (NFAT) and calcium oscillations. In vivo treatment of ovariectomised mice with neohesperidin protected against bone loss in mice. The results suggest neohesperidin has anti-osteoclastic effects in vitro and in vivo and possesses therapeutic potential as a natural anti-catabolic treatment in osteoporosis.


Effects of nurse staffing and nurse education on patient deaths in hospitals with different nurse work environments.
Better hospital nurse staffing, more educated nurses, and improved nurse work environments have been shown to be associated with lower hospital mortality. Little is known about whether and under what conditions each type of investment works better to improve outcomes. To determine the conditions under which the impact of hospital nurse staffing, nurse education, and work environment are associated with patient outcomes. Outcomes of 665 hospitals in 4 large states were studied through linked data from hospital discharge abstracts for 1,262,120 general, orthopedic, and vascular surgery patients, a random sample of 39,038 hospital staff nurses, and American Hospital Association data. A 30-day inpatient mortality and failure-to-rescue. The effect of decreasing workloads by 1 patient/nurse on deaths and failure-to-rescue is virtually nil in hospitals with poor work environments, but decreases the odds on both deaths and failures in hospitals with average environments by 4%, and in hospitals with the best environments by 9% and 10%, respectively. The effect of 10% more Bachelors of Science in Nursing Degree nurses decreases the odds on both outcomes in all hospitals, regardless of their work environment, by roughly 4%. Although the positive effect of increasing percentages of Bachelors of Science in Nursing Degree nurses is consistent across all hospitals, lowering the patient-to-nurse ratios markedly improves patient outcomes in hospitals with good work environments, slightly improves them in hospitals with average environments, and has no effect in hospitals with poor environments.


MRI measures show significant cerebellar gray matter volume loss in multiple sclerosis and are associated with cerebellar dysfunction.
Regional atrophy measures may offer useful information about the causes of specific clinical deficits in multiple sclerosis (MS). To determine the magnitude of cerebellar gray and white matter (GM and WM) atrophy in patients with clinically isolated syndromes (CIS) and MS, and their role in clinical manifestations of cerebellar damage. T1-weighted volumetric magnetic resonance imaging (MRI) of 73 patients [29 CIS, 33 relapsing-remitting MS (RRMS), 11 secondary progressive MS (SPMS)] was compared with 25 controls. GM and WM regions were generated using SPM5 and cerebellar regions delineated. Linear regression was used to investigate differences in tissue-specific cerebellar volumes between groups and the association with clinical measures. Mean cerebellar GM volume (CGMV) was 100.1 cm(3) in controls, 96.4 cm(3) in CIS patients, 91.8 cm(3) in RRMS patients, and 88.8 cm(3) in SPMS patients. Mean cerebellar WM volumes (CWMV) were 21.3 cm(3), 20.4 cm(3), 19.9 cm(3), and 18.8 cm(3), respectively. CGMV was reduced by 4.8 cm(3) (P = 0.054) in RRMS patients, and 8.5 cm(3) (P = 0.012) in SPMS patients, relative to controls. Only patients with SPMS showed a borderline significant reduction in CWMV compared with controls (mean 2.1 cm(3), P = 0.053). CGMV was significantly smaller in patients assessed as having cerebellar dysfunction compared with patients who had normal cerebellar function. Significant associations of CGMV and CWMV with performance on the nine-hole peg test were also observed. Clinically relevant GM atrophy occurs in the cerebellum of MS patients and is more prominent than WM atrophy. As such, it may provide complementary data to other regional atrophy and intrinsic tissue measures.


Signal-quality indices for the electrocardiogram and photoplethysmogram: derivation and applications to wireless monitoring.
The identification of invalid data in recordings obtained using wearable sensors is of particular importance since data obtained from mobile patients is, in general, noisier than data obtained from nonmobile patients. In this paper, we present a signal quality index (SQI), which is intended to assess whether reliable heart rates (HRs) can be obtained from electrocardiogram (ECG) and photoplethysmogram (PPG) signals collected using wearable sensors. The algorithms were validated on manually labeled data. Sensitivities and specificities of 94% and 97% were achieved for the ECG and 91% and 95% for the PPG. Additionally, we propose two applications of the SQI. First, we demonstrate that, by using the SQI as a trigger for a power-saving strategy, it is possible to reduce the recording time by up to 94% for the ECG and 93% for the PPG with only minimal loss of valid vital-sign data. Second, we demonstrate how an SQI can be used to reduce the error in the estimation of respiratory rate (RR) from the PPG. The performance of the two applications was assessed on data collected from a clinical study on hospital patients who were able to walk unassisted.


Long-term risk of cervical intraepithelial neoplasia grade 3 or worse according to high-risk human papillomavirus genotype and semi-quantitative viral load among 33,288 women with normal cervical cytology.
In this prospective cohort study, we estimated the long-term risk of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) by high-risk human papillomavirus (hrHPV) genotype and semi-quantitative viral load at baseline among 33,288 women aged 14-90 years with normal baseline cytology. During 2002-2005, residual liquid-based cervical cytology samples were collected from women screened for cervical cancer in Copenhagen, Denmark. Samples were HPV-tested with Hybrid Capture 2 (HC2) and genotyped with INNO-LiPA. Semi-quantitative viral load was measured by HC2 relative light units in women with single hrHPV infections. The cohort was followed in a nationwide pathology register for up to 11.5 years. In women aged ≥30 years at baseline, the 8-year absolute risk for CIN3+ following baseline detection of HPV16 was 21.8% (95% confidence interval [CI]: 18.0-25.6%). The corresponding risks for HPV18, HPV31, HPV33, and other hrHPV types, respectively, were 12.8% (95% CI: 7.6-18.0%), 11.3% (95% CI: 7.7-14.9%), 12.9% (95% CI: 7.0-18.8%) and 3.9% (95% CI: 2.7-5.2%). Similar absolute risk estimates were observed in women aged <30 years. Higher HPV16-viral load was associated with increased risk of CIN3+ (hazard ratio = 1.34, 95% CI: 1.10-1.64, per 10-fold increase in viral load). A similar trend, although statistically nonsignificant, was found for viral load of HPV18. The 8-year absolute risk of CIN3+ in women with HPV16-viral load ≥100.0 pg/ml was 30.2% (95% CI: 21.9-38.6%). Our results support that hrHPV genotyping during cervical cancer screening may help identify women at highest risk of CIN3+.


Active streets for children: The case of the Bogotá Ciclovía.
The Ciclovía is a worldwide program in which streets are temporarily closed to motorized transport to create a space for recreation and outdoor play among children and adults. The aim of this study was to assess the associations between physical activity (PA), sedentary time (SED), body mass index and Ciclovía participation among children aged 9 to 13 years. All students in the 4th and 5th grades from the selected schools were invited to participate in the study. The study included 923 children. PA and SED were measured using waist-worn accelerometers, and height and weight were measured using standardized procedures. Ciclovía participation was self-reported. The analyses included multilevel linear, generalized mixed and generalized additive models. The mean age of the sample was 10.1±0.7 years, and 49.5% were boys. In the last year, 46% of the children participated in the Ciclovía, and 34% reported participating frequently (at least once per month). No differences were found in the mean minutes of moderate-to-vigorous PA on weekdays between frequent Ciclovía users and sporadic and non-Ciclovía users (72 vs 69; p = 0.09). In contrast, frequent Ciclovía users had higher moderate-to-vigorous PA on Sundays than sporadic and non-Ciclovía users (65.6 vs 59.2; p = 0.01), specifically between the hours of 12:00 and 16:00. In addition, frequent Ciclovía users did not differ from the sporadic and non-Ciclovía users in SED (515.3 vs 521.3; p = 0.19). Frequent Ciclovía users had lower SED on Sundays than the sporadic and non-Ciclovía users (437.7 vs 456.5; p = 0.005). Additionally, frequent Ciclovía users were more likely to be overweight (28.3% vs 20.4% p = 0.01). We did not find differences in participation by sex, and low-to-middle income children were more likely to participate. The Ciclovías offer an innovative, inclusive recreational space and consequently provide opportunities to increase moderate-to-vigorous PA and reduce SED among children.


Shadow Detection in Remote Sensing Images Based on Spectral Radiance Separability Enhancement.
Shadow detection is a basic task of remote sensing image analysis, but it is often seriously disturbed by vegetation, water bodies, and black objects. It is observed that vegetation and dark objects often show a dark look in visible bands but brighter in the near-infrared (NIR), and is also noticed that the reflection of inland water bodies in the green band is stronger than that in the blue band. Taking advantage of these physical properties and combining them with the bluish and dark appearance of shadows, we propose a simple but effective shadow detection method for multispectral remote sensing images. These physical properties are used to create transformation models that suppress features such as vegetation, water bodies, etc., but at the same time enhance shadows. Then, we transform the shadow representation into a color space to generate candidate shadows using dominant color components. To separate shadows from the others, we propose two indexes, the normalized Color Difference Composite Index (CDCI) and Color Purity Index (CPI), and fuse them to achieve shadows and their confidence. The experimental results indicate that the proposed method can effectively detect the shadows in multispectral images and outperforms the state-of-the-art approaches.


A survey of provider experiences and perceptions of preferential access to cardiovascular care in Ontario, Canada.
The public health insurance system in Canada is predicated on equal access to care for persons in need. To determine the views and experiences of Ontario physicians and hospital administrators in providing patients with preferential access to specialized cardiovascular care on the basis of nonclinical factors. Survey with self-administered questionnaire. Ontario, Canada. All Ontario cardiologists (n = 268), cardiac surgeons (n = 68), and hospital chief executives (n = 218) and random samples of internists (n = 300) and family physicians (n = 300). Elicited responses (yes or no) to questions on whether and why preferential access occurred and whether the respondents had been personally involved in such a situation. After undeliverable surveys and respondents no longer involved with acute care were excluded, the eligible response rate was 71.3% (788 of 1105 respondents). More than 80% of physicians and 53% of hospital chief executives had been personally involved in managing a patient who had received preferential access on the basis of factors other than medical need. Patients deemed most likely to receive such treatment were those with personal ties to the treating physicians (93% [95% CI, 91% to 95%]), high-profile public figures (85% [CI, 82% to 87%]), and politicians (83% [CI, 80% to 86%]). Physicians were significantly more likely than chief executives to indicate that hospital board members (81% and 68%; P < 0.001) and donors to hospital foundations (63% and 42%; P < 0.001) would receive preferential access. Most respondents indicated that preferential access was more likely to be provided if patients or families were well informed, aggressive, or potentially litigious. The survey did not permit estimation of the frequency of episodes of preferential access. Although equality of access is a cornerstone principle of Canada's universal health care system, some access to specialized cardiovascular services occurs preferentially on the basis of factors other than clinical need. The actual magnitude and consequences of this phenomenon remain unknown.


Diagnostic algorithm for lower-risk myelodysplastic syndromes.
Rapid advances over the past decade have uncovered the heterogeneous genomic and immunologic landscape of myelodysplastic syndromes (MDS). This has led to notable improvements in the accuracy and timing of diagnosis and prognostication of MDS, as well as the identification of possible novel targets for therapeutic intervention. For the practicing clinician, however, this increase in genomic, epigenomic, and immunologic knowledge needs consideration in a "real-world" context to aid diagnostic specificity. Although the 2016 revision to the World Health Organization classification for MDS is comprehensive and timely, certain limitations still exist for day-to-day clinical practice. In this review, we describe an up-to-date diagnostic approach to patients with suspected lower-risk MDS, including hypoplastic MDS, and demonstrate the requirement for an "integrated" diagnostic approach. Moreover, in the era of rapid access to massive parallel sequencing platforms for mutational screening, we suggest which patients should undergo such analyses, when such screening should be performed, and how those data should be interpreted. This is particularly relevant given the recent findings describing age-related clonal hematopoiesis.


States With Prescription Drug Monitoring Mandates Saw A Reduction In Opioids Prescribed To Medicaid Enrollees.
Prescription drug monitoring programs are promising tools to use in addressing the prescription opioid epidemic, yet prescribers' participation in these state-run programs remained low as of 2014. Statutory mandates for prescribers to register with their state's program, use it, or both are believed to be effective tools to realize the programs' full potential. Our analysis of aggregate Medicaid drug utilization data indicates that state mandates for prescriber registration or use adopted in 2011-14 were associated with a reduction of 9-10 percent in population-adjusted numbers of Schedule II opioid prescriptions received by Medicaid enrollees and amounts of Medicaid spending on these prescriptions. This effect was largely associated with mandates of registration, which were comprehensive in all adopting states, and not with mandates of use, which were largely limited in scope or strength before 2015. Our findings support the use of mandates of registration in prescription drug monitoring programs as an effective and relatively low-cost policy. Future research should further assess the value of strong mandates of use to ensure safer and more appropriate prescribing of opioids.


Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis.
The E693Q mutation in the amyloid beta precursor protein (APP) leads to cerebral amyloid angiopathy (CAA), with recurrent cerebral hemorrhagic strokes and dementia. In contrast to Alzheimer disease (AD), the brains of those affected by hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) show few parenchymal amyloid plaques. We found that neuronal overexpression of human E693Q APP in mice (APPDutch mice) caused extensive CAA, smooth muscle cell degeneration, hemorrhages and neuroinflammation. In contrast, overexpression of human wild-type APP (APPwt mice) resulted in predominantly parenchymal amyloidosis, similar to that seen in AD. In APPDutch mice and HCHWA-D human brain, the ratio of the amyloid-beta40 peptide (Abeta40) to Abeta42 was significantly higher than that seen in APPwt mice or AD human brain. Genetically shifting the ratio of AbetaDutch40/AbetaDutch42 toward AbetaDutch42 by crossing APPDutch mice with transgenic mice producing mutated presenilin-1 redistributed the amyloid pathology from the vasculature to the parenchyma. The understanding that different Abeta species can drive amyloid pathology in different cerebral compartments has implications for current anti-amyloid therapeutic strategies. This HCHWA-D mouse model is the first to develop robust CAA in the absence of parenchymal amyloid, highlighting the key role of neuronally produced Abeta to vascular amyloid pathology and emphasizing the differing roles of Abeta40 and Abeta42 in vascular and parenchymal amyloid pathology.


Validation of Visual Caries Activity Assessment: A 2-yr Cohort Study.
We evaluated the predictive and construct validity of a caries activity assessment system associated with the International Caries Detection and Assessment System (ICDAS) in primary teeth. A total of 469 children were reexamined: participants of a caries survey performed 2 yr before (follow-up rate of 73.4%). At baseline, children (12-59 mo old) were examined with the ICDAS and a caries activity assessment system. The predictive validity was assessed by evaluating the risk of active caries lesion progression to more severe conditions in the follow-up, compared with inactive lesions. We also assessed if children with a higher number of active caries lesions were more likely to develop new lesions (construct validity). Noncavitated active caries lesions at occlusal surfaces presented higher risk of progression than inactive ones. Children with a higher number of active lesions and with higher caries experience presented higher risk of developing new lesions. In conclusion, the caries activity system associated with the ICDAS presents predictive and construct validity in primary teeth in the assessment of occlusal caries lesions, but predictive validity was not observed in smooth surfaces.


A biochemical framework for eIF4E-dependent mRNA export and nuclear recycling of the export machinery.
The eukaryotic translation initiation factor eIF4E acts in the nuclear export and translation of a subset of mRNAs. Both of these functions contribute to its oncogenic potential. While the biochemical mechanisms that underlie translation are relatively well understood, the molecular basis for eIF4E's role in mRNA export remains largely unexplored. To date, over 3000 transcripts, many encoding oncoproteins, were identified as potential nuclear eIF4E export targets. These target RNAs typically contain a ∼50-nucleotide eIF4E sensitivity element (4ESE) in the 3' UTR and a 7-methylguanosine cap on the 5' end. While eIF4E associates with the cap, an unknown factor recognizes the 4ESE element. We previously identified cofactors that functionally interacted with eIF4E in mammalian cell nuclei including the leucine-rich pentatricopeptide repeat protein LRPPRC and the export receptor CRM1/XPO1. LRPPRC simultaneously interacts with both eIF4E bound to the 5' mRNA cap and the 4ESE element in the 3' UTR. In this way, LRPPRC serves as a specificity factor to recruit 4ESE-containing RNAs within the nucleus. Further, we show that CRM1 directly binds LRPPRC likely acting as the export receptor for the LRPPRC-eIF4E-4ESE RNA complex. We also found that Importin 8, the nuclear importer for cap-free eIF4E, imports RNA-free LRPPRC, potentially providing both coordinated nuclear recycling of the export machinery and an important surveillance mechanism to prevent futile export cycles. Our studies provide the first biochemical framework for the eIF4E-dependent mRNA export pathway.


Uncus and amiygdala lesions: effects on social behavior in the free-ranging rhesus monkey.
The eflect of uncinectomny on the social behavior of free-ranging rhesus monkeys was observed on Cayo Santiago Island. Operated subjects showed social indifjerence, failed to display appropriate aggressive and submissive gestures. were expelled from their social group, and evenitlually died. Two juvenile subjects with the lesion restricted to amygdala survived and have rejoinied their social group. Size of lesion and age at operation were major factors in determniting the degree of behavioral change.


Uncertainty in perception and the Hierarchical Gaussian Filter.
In its full sense, perception rests on an agent's model of how its sensory input comes about and the inferences it draws based on this model. These inferences are necessarily uncertain. Here, we illustrate how the Hierarchical Gaussian Filter (HGF) offers a principled and generic way to deal with the several forms that uncertainty in perception takes. The HGF is a recent derivation of one-step update equations from Bayesian principles that rests on a hierarchical generative model of the environment and its (in)stability. It is computationally highly efficient, allows for online estimates of hidden states, and has found numerous applications to experimental data from human subjects. In this paper, we generalize previous descriptions of the HGF and its account of perceptual uncertainty. First, we explicitly formulate the extension of the HGF's hierarchy to any number of levels; second, we discuss how various forms of uncertainty are accommodated by the minimization of variational free energy as encoded in the update equations; third, we combine the HGF with decision models and demonstrate the inversion of this combination; finally, we report a simulation study that compared four optimization methods for inverting the HGF/decision model combination at different noise levels. These four methods (Nelder-Mead simplex algorithm, Gaussian process-based global optimization, variational Bayes and Markov chain Monte Carlo sampling) all performed well even under considerable noise, with variational Bayes offering the best combination of efficiency and informativeness of inference. Our results demonstrate that the HGF provides a principled, flexible, and efficient-but at the same time intuitive-framework for the resolution of perceptual uncertainty in behaving agents.


Characteristics and Health-care Utilization History of Patients With Bronchiectasis in US Medicare Enrollees With Prescription Drug Plans, 2006 to 2014.
Bronchiectasis is an increasingly common chronic inflammatory airway disease. There is an urgent need to understand the epidemiology of bronchiectasis in older adults. We describe the prevalence and characteristics of patients with bronchiectasis within the US Medicare population. Among the 40% of Medicare enrollees with prescription drug plans from 2006 to 2014, we identified patients ≥ 65 years of age with bronchiectasis by International Classification of Diseases, Ninth Revision, Clinical Modification claims (494.0 or 494.1) from a pulmonologist and no claim for cystic fibrosis. We calculated the prevalence from 2012 to 2014. Incident or newly diagnosed patients were those enrolled in Medicare at least 12 months prior to the first bronchiectasis diagnosis. We described clinical and health-care utilization characteristics for this cohort during the prior 12-month (baseline) period, and explored differences between those with and without a COPD diagnosis. We identified 252,362 patients with bronchiectasis meeting all eligibility criteria. The average annual prevalence from 2012 to 2014 was 701 per 100,000 persons. Newly diagnosed patients were a mean age of 76 years, predominately women (65%), and predominately white, non-Hispanic (84%). During the baseline period, 12% were hospitalized for respiratory infections. Fifty-one percent had a dual diagnosis of COPD. Newly diagnosed patients with bronchiectasis and COPD had significantly different characteristics and utilization, for example were more likely hospitalized for respiratory infections during the baseline period (16% vs 7%) and to have a smoking history (46% vs 17%) compared with those without a dual COPD diagnosis, respectively. We confirmed a high prevalence of bronchiectasis in the United States and significant heterogeneity in patients with bronchiectasis with and without COPD that should be further explored.


Exclusive Transduction of Human CD4+ T Cells upon Systemic Delivery of CD4-Targeted Lentiviral Vectors.
Playing a central role in both innate and adaptive immunity, CD4(+) T cells are a key target for genetic modifications in basic research and immunotherapy. In this article, we describe novel lentiviral vectors (CD4-LV) that have been rendered selective for human or simian CD4(+) cells by surface engineering. When applied to PBMCs, CD4-LV transduced CD4(+) but not CD4(-) cells. Notably, also unstimulated T cells were stably genetically modified. Upon systemic or intrasplenic administration into mice reconstituted with human PBMCs or hematopoietic stem cells, reporter gene expression was predominantly detected in lymphoid organs. Evaluation of GFP expression in organ-derived cells and blood by flow cytometry demonstrated exclusive gene transfer into CD4(+) human lymphocytes. In bone marrow and spleen, memory T cells were preferentially hit. Toward therapeutic applications, we also show that CD4-LV can be used for HIV gene therapy, as well as for tumor therapy, by delivering chimeric Ag receptors. The potential for in vivo delivery of the FOXP3 gene was also demonstrated, making CD4-LV a powerful tool for inducible regulatory T cell generation. In summary, our work demonstrates the exclusive gene transfer into a T cell subset upon systemic vector administration opening an avenue toward novel strategies in immunotherapy.


Effect of surface interactions on adhesion of electrospun meshes on substrates.
Despite the importance of adhesion between electrospun meshes and substrates, the knowledge on adhesion mechanism and the method to improve the adhesion remain limited. Here, we precisely design the model system based on electrospun poly(ethylene oxide) (PEO) meshes and the substrate of styrene-b-(ethylene-co-butylene)-b-styrene elastomer (SEBS), and quantitatively measure the adhesion with a weight method. The surfaces of SEBS with different roughness are obtained by casting SEBS solution on the smooth and rough glass slides, respectively. Then, the surfaces of casted SEBS are respectively grafted with PEG oligomers and long PEG chains much larger than the entanglement molecular weight by surface-initiated atom transfer radical polymerization (SI-ATRP) of poly(ethylene glycol) methyl ether methacrylate (PEGMA). The detached surfaces of SEBS and electrospun fibers after adhesion measurements are analyzed by scanning electron microscopy (SEM). The adhesive force and adhesion energy are found to lie in the range from 68 to 220 mN and from 12 to 46 mJ/m(2), respectively, which are slightly affected by surface roughness of substrate but mainly determined by surface interactions. Just as the chemical cross-linking induces the strong adhesion, the chain entanglements on the interface lead to the higher adhesion than those generated by hydrophilic-hydrophobic interactions and hydrophilic interactions. The long grafted chains and the enhanced temperature facilitate the chain entanglements, resulting in the strong adhesive force. This work sheds new light on the adhesion mechanism at molecular level, which may be helpful to improve the adhesion between the electrospun fibers and substrates in an environmentally friendly manner.


Effects of a new isoquinolinone derivative on induction of action potential bursts in central snail neuron.
The effects of 7-bromo-1,4-dihydro-2-phenyl-4,4-bis(4-pyridinylmethyl)2H-isoquinolin-3-one dihydrochloride (BDPBI) on induction of action potential bursts were studied pharmacologically on the RP4 central neuron of the giant African snail (Achatina fulica Ferussac). The effects of m-3M3FBS, a phospholipase activator and HTMT, a histamine (H1) receptor agonist, on the neuron were also tested. The RP4 neuron showed spontaneous firing of action potential. Extracellular application of BDPBI (150 micromol/l) reversibly elicited bursts of potential (BoP) on the neuron. m-3M3FBS and HTMT also elicited BoP on the RP4 neuron. The BoP elicited by BDPBI were blocked by U73122 (6 micromol/l), a compound commonly used as a phospholipase C (PLC) inhibitor. Neomycin (3.5 mmol/l), a high-magnesium solution (30 mmol/l), replacing the physiological sodium ion with lithium ion or adding diphenhydramine, chloropheniramine decreased the BoP elicited by BDPBI. The BoP elicited by BDPBI were not inhibited after administration with (1) prazosin, propranolol, atropine, d-tubocurarine, hexamethonium, haloperidol, cimetidine, (2) calcium-free solution, (3) high-potassium (12 mmol/l) solution, and (4) pretreatment with KT-5720. The BoP elicited by HTMT was not inhibited after administration of diphenhydramine or chloropheniramine. Voltage-clamped studies revealed that BDPBI decreased the amplitudes of calcium and steady-state outward currents while it did not alter the amplitude of the fast inward current. No negative slope relationship of the steady-state current voltage relationship was found in BDPBI-treated neurons. It is concluded that BDPBI reversibly elicited BoP in the central snail neuron. The effect was not due to (1) the extracellular calcium ion fluxes, or (2) the activation of cholinergic, adrenergic or histamine receptors. The BDPBI-elicited BoP were dependent on the phospholipase activity in the neuron.


The impact of the National Institute for Health Research Health Technology Assessment programme, 2003-13: a multimethod evaluation.
The National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme supports research tailored to the needs of NHS decision-makers, patients and clinicians. This study reviewed the impact of the programme, from 2003 to 2013, on health, clinical practice, health policy, the economy and academia. It also considered how HTA could maintain and increase its impact. Interviews (n = 20): senior stakeholders from academia, policy-making organisations and the HTA programme. Bibliometric analysis: citation analysis of publications arising from HTA programme-funded research. Researchfish survey: electronic survey of all HTA grant holders. Payback case studies (n = 12): in-depth case studies of HTA programme-funded research. We make the following observations about the impact, and routes to impact, of the HTA programme: it has had an impact on patients, primarily through changes in guidelines, but also directly (e.g. changing clinical practice); it has had an impact on UK health policy, through providing high-quality scientific evidence - its close relationships with the National Institute for Health and Care Excellence (NICE) and the National Screening Committee (NSC) contributed to the observed impact on health policy, although in some instances other organisations may better facilitate impact; HTA research is used outside the UK by other HTA organisations and systematic reviewers - the programme has an impact on HTA practice internationally as a leader in HTA research methods and the funding of HTA research; the work of the programme is of high academic quality - the Health Technology Assessment journal ensures that the vast majority of HTA programme-funded research is published in full, while the HTA programme still encourages publication in other peer-reviewed journals; academics agree that the programme has played an important role in building and retaining HTA research capacity in the UK; the HTA programme has played a role in increasing the focus on effectiveness and cost-effectiveness in medicine - it has also contributed to increasingly positive attitudes towards HTA research both within the research community and the NHS; and the HTA focuses resources on research that is of value to patients and the UK NHS, which would not otherwise be funded (e.g. where there is no commercial incentive to undertake research). The programme should consider the following to maintain and increase its impact: providing targeted support for dissemination, focusing resources when important results are unlikely to be implemented by other stakeholders, particularly when findings challenge vested interests; maintaining close relationships with NICE and the NSC, but also considering other potential users of HTA research; maintaining flexibility and good relationships with researchers, giving particular consideration to the Technology Assessment Report (TAR) programme and the potential for learning between TAR centres; maintaining the academic quality of the work and the focus on NHS need; considering funding research on the short-term costs of the implementation of new health technologies; improving the monitoring and evaluation of whether or not patient and public involvement influences research; improve the transparency of the priority-setting process; and continuing to monitor the impact and value of the programme to inform its future scientific and administrative development.


MYB rearrangement and clinicopathologic characteristics in head and neck adenoid cystic carcinoma.
Salivary gland adenoid cystic carcinoma (ACC) is rare, aggressive, and challenging to treat. Many ACCs have a t(6;9) chromosomal translocation resulting in a MYB-NFIB fusion gene, but the clinical significance is unclear. The purposes of this study were to describe the clinicopathologic factors impacting survival and to determine the prevalence and clinical significance of MYB-NFIB fusion. Case series. Medical records of patients treated for ACC of the head and neck from 1974 to 2011 were reviewed and clinicopathologic data recorded. Fluorescence in situ hybridization (FISH) was used to detect MYB rearrangement in archival tumor tissue as a marker of MYB-NFIB fusion. One hundred fifty-eight patients were included, with median follow-up 75.1 months. Median overall survival was 171.5 months (95% confidence interval [CI] = 131.9-191.6), and median disease-free survival was 112.0 months (95% CI = 88.7-180.4). Advanced stage was associated with decreased overall survival (adjusted ptrend < 0.001), and positive margins were associated with decreased disease-free survival (adjusted hazard ratio [aHR] = 8.80, 95% CI = 1.25-62.12, P = 0.029). Ninety-one tumors were evaluable using FISH, and 59 (65%) had evidence of a MYB-NFIB fusion. MYB-NFIB positive tumors were more likely than MYB-NFIB negative tumors to originate in minor salivary glands (adjusted prevalence ratios = 1.51, 95% CI = 1.07-2.12, P = 0.019). MYB-NFIB tumor status was not significantly associated with disease-free or overall survival (hazard ratio [HR] = 1.53, 95% CI = 0.77-3.02, P = 0.22 and HR = 0.91, 95% CI = 0.46-1.83, P = 0.80, respectively, for MYB-NFIB positive compared with MYB-NFIB negative tumors). Stage and margin status were important prognostic factors for ACC. Tumors with evidence of MYB-NFIB fusion were more likely to originate in minor salivary glands, but MYB-NFIB tumor status was not significantly associated with prognosis. 4.


Safety of reduced antibiotic prescribing for self limiting respiratory tract infections in primary care: cohort study using electronic health records.
To determine whether the incidence of pneumonia, peritonsillar abscess, mastoiditis, empyema, meningitis, intracranial abscess, and Lemierre's syndrome is higher in general practices that prescribe fewer antibiotics for self limiting respiratory tract infections (RTIs). Cohort study. 610 UK general practices from the UK Clinical Practice Research Datalink. Registered patients with 45.5 million person years of follow-up from 2005 to 2014. Standardised proportion of RTI consultations with antibiotics prescribed for each general practice, and rate of antibiotic prescriptions for RTIs per 1000 registered patients. Incidence of pneumonia, peritonsillar abscess, mastoiditis, empyema, meningitis, intracranial abscess, and Lemierre's syndrome, adjusting for age group, sex, region, deprivation fifth, RTI consultation rate, and general practice. From 2005 to 2014 the proportion of RTI consultations with antibiotics prescribed decreased from 53.9% to 50.5% in men and from 54.5% to 51.5% in women. From 2005 to 2014, new episodes of meningitis, mastoiditis, and peritonsillar abscess decreased annually by 5.3%, 4.6%, and 1.0%, respectively, whereas new episodes of pneumonia increased by 0.4%. Age and sex standardised incidences for pneumonia and peritonsillar abscess were higher for practices in the lowest fourth of antibiotic prescribing compared with the highest fourth. The adjusted relative risk increases for a 10% reduction in antibiotic prescribing were 12.8% (95% confidence interval 7.8% to 17.5%, P<0.001) for pneumonia and 9.9% (5.6% to 14.0%, P<0.001) for peritonsillar abscess. If a general practice with an average list size of 7000 patients reduces the proportion of RTI consultations with antibiotics prescribed by 10%, then it might observe 1.1 (95% confidence interval 0.6 to 1.5) more cases of pneumonia each year and 0.9 (0.5 to 1.3) more cases of peritonsillar abscess each decade. Mastoiditis, empyema, meningitis, intracranial abscess, and Lemierre's syndrome were similar in frequency at low prescribing and high prescribing practices. General practices that adopt a policy to reduce antibiotic prescribing for RTIs might expect a slight increase in the incidence of treatable pneumonia and peritonsillar abscess. No increase is likely in mastoiditis, empyema, bacterial meningitis, intracranial abscess, or Lemierre's syndrome. Even a substantial reduction in antibiotic prescribing was predicted to be associated with only a small increase in numbers of cases observed overall, but caution might be required in subgroups at higher risk of pneumonia.


Task specialization in two social spiders, Stegodyphus sarasinorum (Eresidae) and Anelosimus eximius (Theridiidae).
Understanding the social organization of group-living organisms is crucial for the comprehension of the underlying selective mechanisms involved in the evolution of cooperation. Division of labour and caste formation is restricted to eusocial organisms, but behavioural asymmetries and reproductive skew is common in other group-living animals. Permanently, social spiders form highly related groups with reproductive skew and communal brood care. We investigated task differentiation in nonreproductive tasks in two permanently and independently derived social spider species asking the following questions: Do individual spiders vary consistently in their propensity to engage in prey attack? Are individual spiders' propensities to engage in web maintenance behaviour influenced by their previous engagement in prey attack? Interestingly, we found that both species showed some degree of task specialization, but in distinctly different ways: Stegodyphus sarasinorum showed behavioural asymmetries at the individual level, that is, individual spiders that had attacked prey once were more likely to attack prey again, independent of their body size or hunger level. In contrast, Anelosimus eximius showed no individual specialization, but showed differentiation according to instar, where adult and subadult females were more likely to engage in prey attack than were juveniles. We found no evidence for division of labour between prey attack and web maintenance. Different solutions to achieve task differentiation in prey attack for the two species studied here suggest an adaptive value of task specialization in foraging for social spiders.


Poverty concentration and determinants in China's urban low-income neighbourhoods and social groups.
Based on a large-scale household survey conducted in 2007, this article reports on poverty concentration and determinants in China's low-income neighbourhoods and social groups. Three types of neighbourhood are recognized: dilapidated inner-city neighbourhoods, declining workers' villages and urban villages. Respondents are grouped into four categories: working, laid-off/unemployed and retired urban residents, together with rural migrants. We first measure poverty concentration across different types of neighbourhood and different groups. The highest concentrations are found in dilapidated inner-city neighbourhoods and among the laid-off/unemployed. Mismatches are found between actual hardships, sense of deprivation and distribution of social welfare provision. Second, we examine poverty determinants. Variations in institutional protection and market remuneration are becoming equally important in predicting poverty generation, but are differently associated with it in the different neighbourhoods and groups. As China's urban economy is increasingly shaped by markets, the mechanism of market remuneration is becoming a more important determinant of poverty patterns, especially for people who are excluded from state institutions, notably laid-off workers and rural migrants.


Dietary patterns and risk of colorectal adenoma: a systematic review and meta-analysis of observational studies.
Current evidence suggests that dietary patterns may play an important role in colorectal cancer risk. The present study aimed to perform a systematic review and meta-analysis of observational studies exploring the association between dietary patterns and colorectal adenomas (a precancerous condition). Pubmed and EMBASE electronic databases were systematically searched to retrieve eligible studies. Only studies exploring the risk or association with colorectal adenomas for the highest versus lowest category of exposure to a posteriori dietary patterns were included in the quantitative analysis. Random-effects models were applied to calculate relative risks (RRs) of colorectal adenomas for high adherence to healthy or unhealthy dietary patterns. Statistical heterogeneity and publication bias were explored. Twelve studies were reviewed. Three studies explored a priori dietary patterns using scores identifying adherence to the Mediterranean, Paleolithic and Dietary Approaches to Stop Hypertension (DASH) diet and reported an association with decreased colorectal adenoma risk. Two studies tested the association with colorectal adenomas between a posteriori dietary patterns showing lower odds of disease related to plant-based compared to meat-based dietary patterns. Seven studies identified 23 a posteriori dietary patterns and the analysis revealed that higher adherence to healthy and unhealthy dietary patterns was significantly associated risk of colorectal adenomas (RR = 0.81, 95% confidence interval = 0.71, 0.94 and RR = 1.24, 95% confidence interval = 1.13, 1.35, respectively) with no evidence of heterogeneity or publication bias. The results of this systematic review and meta-analysis indicate that dietary patterns may be associated with the risk of colorectal adenomas.


Why not the best? Social anxiety symptoms and perfectionism among Israeli Jews and Arabs: a comparative Study.
Social Anxiety Disorder (SAD) has been repeatedly shown to be very prevalent in the Western society and is characterized by low self-esteem, pessimism, procrastination and also perfectionism. Very few studies on SAD have been done in the Middle East or in Arab countries, and no study tackled the relationship between social anxiety symptoms and perfectionism in non-Western samples. We examined social anxiety symptoms and perfectionism in a group of 132 Israeli Jewish (IJ) and Israeli Arab (IA) students. Subjects completed the Liebowitz Social Anxiety Scale (LSAS), the Multidimensional Perfectionism Scale (MPS), the Negative Automatic Thoughts Questionnaire (ATQ-N), the Positive Automatic Thoughts Questionnaire (ATQ-P) and a socio-demographic questionnaire. The rate of SAD in our sample according to a LSAS score of 60 or more was 17.2% (IJ=13.8%, IA=19%, ns). The correlation between perfectionism and the LSAS was high in both groups, and in particular in the IJ group. The IA group had higher scores of social avoidance, of ATQ-P and of two of the MPS subscales: parental expectations and parental criticism. Concern over mistakes and negative automatic thoughts positively predicted social fear in the IJ group, whereas in the IA group being female, religious and less educated positively predicted social fear. Negative automatic thoughts and age positively predicted social avoidance in the IJ group. In general, the IJ and IA subjects showed higher social anxiety, higher ATQ-N scores and lower parental expectations as compared with non-clinical US samples. Social anxiety symptoms and perfectionism are prevalent in Arab and Jewish students in Israel and seem to be closely related. Further studies among non-western minority groups may detect cultural influences on social anxiety and might add to the growing body of knowledge on this intriguing condition.


Computer simulation of glioma growth and morphology.
Despite major advances in the study of glioma, the quantitative links between intra-tumor molecular/cellular properties, clinically observable properties such as morphology, and critical tumor behaviors such as growth and invasiveness remain unclear, hampering more effective coupling of tumor physical characteristics with implications for prognosis and therapy. Although molecular biology, histopathology, and radiological imaging are employed in this endeavor, studies are severely challenged by the multitude of different physical scales involved in tumor growth, i.e., from molecular nanoscale to cell microscale and finally to tissue centimeter scale. Consequently, it is often difficult to determine the underlying dynamics across dimensions. New techniques are needed to tackle these issues. Here, we address this multi-scalar problem by employing a novel predictive three-dimensional mathematical and computational model based on first-principle equations (conservation laws of physics) that describe mathematically the diffusion of cell substrates and other processes determining tumor mass growth and invasion. The model uses conserved variables to represent known determinants of glioma behavior, e.g., cell density and oxygen concentration, as well as biological functional relationships and parameters linking phenomena at different scales whose specific forms and values are hypothesized and calculated based on in vitro and in vivo experiments and from histopathology of tissue specimens from human gliomas. This model enables correlation of glioma morphology to tumor growth by quantifying interdependence of tumor mass on the microenvironment (e.g., hypoxia, tissue disruption) and on the cellular phenotypes (e.g., mitosis and apoptosis rates, cell adhesion strength). Once functional relationships between variables and associated parameter values have been informed, e.g., from histopathology or intra-operative analysis, this model can be used for disease diagnosis/prognosis, hypothesis testing, and to guide surgery and therapy. In particular, this tool identifies and quantifies the effects of vascularization and other cell-scale glioma morphological characteristics as predictors of tumor-scale growth and invasion.


An experimental study of pathologist's navigation patterns in virtual microscopy.
In virtual microscopy, a sequential process of captures of microscopical fields, allows to construct a virtual slide which is visualized using a specialized software, called the virtual microscopy viewer. This tool allows useful exploration of images, composed of thousands of microscopical fields of view at different levels of magnification, emulating an actual microscopical examination. The aim of this study was to establish the main pathologist's navigation patterns when exploring virtual microscopy slides, using a graphical user interface, adapted to the pathologist's workflow. Four pathologists with a similar level of experience, graduated from the same pathology program, navigated six virtual slides. Different issues were evaluated, namely, the percentage of common visited image regions, the time spent at each and its coincidence level, that is to say, the region of interest location. In addition, navigation patterns were also assessed, i.e., mouse movement velocities and linearity of the diagnostic paths. Results suggest that regions of interest are determined by a complex combination of the visited area, the time spent at each visit and the coincidence level among pathologists. Additionally, linear trajectories and particular velocity patterns were found for the registered diagnostic paths.


Role in tumor growth of a glycogen debranching enzyme lost in glycogen storage disease.
Bladder cancer is the most common malignancy of the urinary system, yet our molecular understanding of this disease is incomplete, hampering therapeutic advances. Here we used a genome-wide functional short-hairpin RNA (shRNA) screen to identify suppressors of in vivo bladder tumor xenograft growth (n = 50) using bladder cancer UMUC3 cells. Next-generation sequencing was used to identify the most frequently occurring shRNAs in tumors. Genes so identified were studied in 561 patients with bladder cancer for their association with stratification of clinical outcome by Kaplan-Meier analysis. The best prognostic marker was studied to determine its mechanism in tumor suppression using anchorage-dependent and -independent growth, xenograft (n = 20), and metabolomic assays. Statistical significance was determined using two-sided Student t test and repeated-measures statistical analysis. We identified the glycogen debranching enzyme AGL as a prognostic indicator of patient survival (P = .04) and as a novel regulator of bladder cancer anchorage-dependent (P < .001), anchorage-independent (mean ± standard deviation, 180 ± 23.1 colonies vs 20±9.5 in control, P < .001), and xenograft growth (P < .001). Rescue experiments using catalytically dead AGL variants revealed that this effect is independent of AGL enzymatic functions. We demonstrated that reduced AGL enhances tumor growth by increasing glycine synthesis through increased expression of serine hydroxymethyltransferase 2. Using an in vivo RNA interference screen, we discovered that AGL, a glycogen debranching enzyme, has a biologically and statistically significant role in suppressing human cancer growth.


Governing the resilience of neoliberalism through biopolitics.
Neoliberalism is widely regarded as the main culprit for the 2007/2008 global financial crisis. However, despite this abysmal failure, neoliberalism has not merely survived the crisis, but actually 'thrived'. How is it possible to account for the resilience of neoliberalism? Existing scholarship has answered this question either by focusing on the distinctive qualities of neoliberalism (such as adaptability, internal coherence and capacity to incorporate dissent) or on the biopolitical capacity of neoliberalism to produce resilient subjects. This article adopts a different perspective. Drawing on and partially challenging the perspective of Michel Foucault, I argue that neoliberalism and biopolitics should be considered two complementary governmental rationalities, and that biopolitical rationalities contribute to governing the uncertainties and risks stemming from the neoliberalization of life. Biopolitics, in other words, plays a key role in governing the resilience of neoliberalism. Through this conceptual lens, the article explores how biopolitical rationalities of care have been deployed to govern the neoliberal crisis of the Greek sovereign debt, which threatened the stability of the European banking system and, I shall argue, the neoliberal life, wealth and well-being of the European population. The article discusses how biopolitical racism is an essential component of the biopolitical governance of neoliberalism. Biopolitical racism displaces the sources of risk, dispossession and inequality from the neoliberal regime to 'inferior' populations, whose lack of compliance with neoliberal dictates is converted into a threat to our neoliberal survival. This threat deserves punishment and authorizes further dynamics of neoliberal dispossession.


Temporomandibular joint and muscle disorder-type pain and comorbid pains in a national US sample.
To compare prevalences of self-reported comorbid headache, neck, back, and joint pains in respondents with temporomandibular joint and muscle disorder (TMJMD)-type pain in the 2000-2005 US National Health Interview Survey (NHIS), and to analyze these self-reported pains by gender and age for Non-Hispanic (NH) Whites (Caucasians), Hispanics, and NH Blacks (African Americans). Data from the 2000-2005 NHIS included information on gender, age, race, ethnicity, education, different common types of pain (specifically TMJMD-type, severe headache/migraine, neck, and low back pains), changes in health status, and health care utilization. Estimates and test statistics (ie, Pearson correlations, regressions, and logistic models) were conducted using SAS survey analysis and SUDAAN software that take into account the complex sample design. A total of 189,977 people (52% female and 48% males, 73% NH Whites, 12% Hispanic, 11% NH Blacks, and 4% "Other") were included. A total of 4.6% reported TMJMD-type pain, and only 0.77% overall reported it without any comorbid headache/migraine, neck, or low back pains; also 59% of the TMJMD-type pain (n = 8,964) reported ⋝ two comorbid pains. Females reported more comorbid pain than males (odds ratio [OR] = 1.41, P < .001); Hispanic and NH Blacks reported more than NH Whites (OR = 1.56, P <.001; OR= 1.38, P <.001, respectively). In addition, 53% of those with TMJMD-type pain had severe headache/migraines, 54% had neck pain, 64% low back pain, and 62% joint pain. Differences in gender and race by age patterns were detected. For females, headache/migraine pain with TMJMD-type pain peaked around age 40 and decreased thereafter regardless of race/ethnicity. Neck pain continued to increase up to about age 60, with a higher prevalence for Hispanic women at younger ages, and more pronounced in males, being the highest in the non-Whites. Low back pain was higher in Black and Hispanic females across the age span, and higher among non-White males after age 60. Joint pain demonstrated similar patterns by race/ethnicity, with higher rates for Black females, and increased with age regardless of gender. TMJMD-type pain was most often associated with other common pains, and seldom existed alone. Two or more comorbid pains were common. Gender, race, and age patterns for pains with TMJMD-type pain resembled the specific underlying comorbid pain.


Phylogenetic analyses of behavior support existence of culture among wild chimpanzees.
Culture has long been considered to be not only unique to humans, but also responsible for making us qualitatively different from all other forms of life. In recent years, however, researchers studying chimpanzees (Pan troglodytes) have challenged this idea. Natural populations of chimpanzees have been found to vary greatly in their behavior. Because many of these interpopulation differences cannot be readily explained by ecological factors, it has been argued that they result from social learning and, therefore, can be regarded as cultural variations. Recent studies showing social transmission in captive chimpanzee populations suggest that this hypothesis is plausible. However, the culture hypothesis has been questioned on the grounds that the behavioral variation may be explained at a proximate level by genetic differences between subspecies. Here we use cladistic analyses of the major cross-site behavioral data set to test the hypothesis that the behavioral differences among the best-documented chimpanzee populations are genetically determined. If behavioral diversity is primarily the product of genetic differences between subspecies, then population data should show less phylogenetic structure when data from a single subspecies (P. t. schweinfurthii) are compared with data from two subspecies (P. t. verus and P. t. schweinfurthii) analyzed together. Our findings are inconsistent with the hypothesis that the observed behavioral patterns of wild chimpanzee populations can be explained primarily by genetic differences between subspecies. Instead, our results support the suggestion that the behavioral patterns are the product of social learning and, therefore, can be considered cultural.


Epidemiological surveillance of Toxoplasma gondii in small ruminants in southern Spain.
Toxoplasmosis, caused by the protozoan Toxoplasma gondii, is a worldwide zoonotic disease, which affects most warm-blooded species. Besides the zoonotic relevance, toxoplasmosis is one of the major causes of reproductive disorders in small ruminants. A cross-sectional study was carried out to determine the seroprevalence, spatial distribution and risk factors associated with T. gondii infection in sheep and goats in southern Spain. During 2015-2017, a total of 1,943 small ruminants (998 sheep and 945 goats) from 127 flocks were tested for antibodies against T. gondii using the modified agglutination test (MAT, cut-off 1:25). Antibodies against T. gondii were detected in 464 of the 998 sheep (46.5 %; CI95 %: 43.4-49.6%) and 362 of the 945 goats (38.3 %; CI95 %: 35.2-41.4%) tested. The farm prevalence was 98.4 % (CI95 %: 95.4-100%) for sheep and 93.7 % (CI95 %: 87.6-99.7%) for goats. The generalized estimating equation analysis showed that presence of cats and existence of previous reproductive disorders were risk factors potentially associated with T. gondii seropositivity in small ruminants. Two statistically significant spatial clusters (P < 0.001) were identified. The seroprevalence observed in the present study indicates a widespread exposure to T. gondii in sheep and goats in southern Spain, which might have important implications for animal and public health. Management measures should be implemented in small ruminant farms in this region in order to reduce the risk of T. gondii infections, particularly in those areas identified in the spatial analysis.


Probing unnatural amino acid integration into enhanced green fluorescent protein by genetic code expansion with a high-throughput screening platform.
Genetic code expansion has developed into an elegant tool to incorporate unnatural amino acids (uAA) at predefined sites in the protein backbone in response to an amber codon. However, recombinant production and yield of uAA comprising proteins are challenged due to the additional translation machinery required for uAA incorporation. We developed a microtiter plate-based high-throughput monitoring system (HTMS) to study and optimize uAA integration in the model protein enhanced green fluorescence protein (eGFP). Two uAA, propargyl-L-lysine (Plk) and (S)-2-amino-6-((2-azidoethoxy) carbonylamino) hexanoic acid (Alk), were incorporated at the same site into eGFP co-expressing the native PylRS/tRNAPylCUA pair originating from Methanosarcina barkeri in E. coli. The site-specific uAA functionalization was confirmed by LC-MS/MS analysis. uAA-eGFP production and biomass growth in parallelized E. coli cultivations was correlated to (i) uAA concentration and the (ii) time of uAA addition to the expression medium as well as to induction parameters including the (iii) time and (iv) amount of IPTG supplementation. The online measurements of the HTMS were consolidated by end point-detection using standard enzyme-linked immunosorbent procedures. The developed HTMS is powerful tool for parallelized and rapid screening. In light of uAA integration, future applications may include parallelized screening of different PylRS/tRNAPylCUA pairs as well as further optimization of culture conditions.


The genomic landscape of human cellular circadian variation points to a novel role for the signalosome.
The importance of natural gene expression variation for human behavior is undisputed, but its impact on circadian physiology remains mostly unexplored. Using umbilical cord fibroblasts, we have determined by genome-wide association how common genetic variation impacts upon cellular circadian function. Gene set enrichment points to differences in protein catabolism as one major source of clock variation in humans. The two most significant alleles regulated expression of COPS7B, a subunit of the COP9 signalosome. We further show that the signalosome complex is imported into the nucleus in timed fashion to stabilize the essential circadian protein BMAL1, a novel mechanism to oppose its proteasome-mediated degradation. Thus, circadian clock properties depend in part upon a genetically-encoded competition between stabilizing and destabilizing forces, and genetic alterations in these mechanisms provide one explanation for human chronotype.


Measurement of the heme affinity for yeast dap1p, and its importance in cellular function.
Current studies on the Saccharomyces cerevisiae protein Dap1p have demonstrated a heme-related function within the ergosterol biosynthetic pathway. Here we present data to further the understanding of the role of heme in the proper biological functioning of Dap1p in cellular processes. First, we examined the role of Dap1p in stabilizing the P450 enzyme, Erg11p, a key regulatory protein in ergosterol biosynthesis. Our data indicate that the absence of Dap1p does not affect Erg11p mRNA, protein expression levels, or the protein degradation rates in S. Cerevisaie. Second, in order to probe the role of heme in the biological functioning of Dap1p, we measured ferric and ferrous heme binding affinities for Dap1p and the mutant Dap1pY138F, as well as equilibrium midpoint reduction potentials of the Fe(III)/Fe(II) couples. Our results show that both wild-type and mutant proteins bind heme in a 1:1 fashion, possessing tight ferric heme affinities, KD values of 400 pM and 200 nM, respectively, but exhibiting weak ferrous affinities, 2 and 10 microM, respectively. Additionally, the measured reduction potential of Dap1p, which was found to be -307 mV, is similar to that of other monotyrosinate hemoproteins. Although previous reports show the weaker affinity of Dap1pY138F for ferric heme lowers the production of ergosterol with respect to wild-type Dap1p in S. pombe, we find that Dap1pY138F expression is still sufficient to rescue the growth sensitivity of dap1Delta to fluconazole and methyl methanesulfonate in S. cerevisiae. Various interpretations of these results are discussed with respect to Dap1p function in the cell.


Graphene in a photonic metamaterial.
We demonstrate a photonic metamaterial that shows extraordinary sensitivity to the presence of a single atomic layer of graphene on its surface. Metamaterial's optical transmission increases multi-fold at the resonance frequency linked to the Fano-type plasmonic mode supported by the periodic metallic nanostructure. The experiments were performed with chemical vapor deposited (CVD) graphene covering a number of size-scaled metamaterial samples with plasmonic modes at different frequencies ranging from 167 to 187 Thz.


Pharmacologic profile of OC000459, a potent, selective, and orally active D prostanoid receptor 2 antagonist that inhibits mast cell-dependent activation of T helper 2 lymphocytes and eosinophils.
D prostanoid receptor 2 (DP₂) [also known as chemoattractant receptor-homologous molecule expressed on T helper 2 (Th2) cells (CRTH2)] is selectively expressed by Th2 lymphocytes, eosinophils, and basophils and mediates recruitment and activation of these cell types in response to prostaglandin D₂ (PGD₂). (5-Fluoro-2-methyl-3-quinolin-2-ylmethylindo-1-yl)-acetic acid (OC000459) is an indole-acetic acid derivative that potently displaces [³H]PGD₂ from human recombinant DP₂ (K(i) = 0.013 μM), rat recombinant DP₂ (K(i) = 0.003 μM), and human native DP₂ (Th2 cell membranes; K(i) = 0.004 μM) but does not interfere with the ligand binding properties or functional activities of other prostanoid receptors (prostaglandin E₁₋₄ receptors, D prostanoid receptor 1, thromboxane receptor, prostacyclin receptor, and prostaglandin F receptor). OC000459 inhibited chemotaxis (IC₅₀ = 0.028 μM) of human Th2 lymphocytes and cytokine production (IC₅₀ = 0.019 μM) by human Th2 lymphocytes. OC000459 competitively antagonized eosinophil shape change responses induced by PGD₂ in both isolated human leukocytes (pK(B) = 7.9) and human whole blood (pK(B) = 7.5) but did not inhibit responses to eotaxin, 5-oxo-eicosatetraenoic acid, or complement component C5a. OC000459 also inhibited the activation of Th2 cells and eosinophils in response to supernatants from IgE/anti-IgE-activated human mast cells. OC000459 had no significant inhibitory activity on a battery of 69 receptors and 19 enzymes including cyclooxygenase 1 (COX1) and COX2. OC000459 was found to be orally bioavailable in rats and effective in inhibiting blood eosinophilia induced by 13,14-dihydro-15-keto-PGD₂ (DK-PGD₂) in this species (ED₅₀ = 0.04 mg/kg p.o.) and airway eosinophilia in response to an aerosol of DK-PGD₂ in guinea pigs (ED₅₀ = 0.01 mg/kg p.o.). These data indicate that OC000459 is a potent, selective, and orally active DP₂ antagonist that retains activity in human whole blood and inhibits mast cell-dependent activation of both human Th2 lymphocytes and eosinophils.


Hyperosmolarity induced by high glucose promotes senescence in human glomerular mesangial cells.
Hyperglycemia is involved in the diabetic complication of different organs and can elevate serum osmolarity. Here, we tested whether hyperosmolarity promoted by high glucose levels induces cellular senescence in renal cells. We treated Wistar rats with streptozotocin to induce diabetes or with consecutive daily injections of mannitol to increase serum osmolarity and analyzed p53 and p16 genes in renal cortex by immunohistochemistry. Both diabetic and mannitol treated rats showed a significant increase in serum osmolarity, without significant signs of renal dysfunction, but associated with increased staining for p53 and p16 in the renal cortex. An increase in p53 and p16 expression was also found in renal cortex slices and glomeruli isolated from healthy rats, which were later treated with 30 mM glucose or mannitol. Intracellular mechanisms involved were analyzed in cultured human glomerular mesangial cells treated with 30 mM glucose or mannitol. After treatments, cells showed increased p53, p21 and p16 expression and elevated senescence-associated β-galactosidase activity. Senescence was prevented when myo-inositol was added before treatment. High glucose or mannitol induced constitutive activation of Ras and ERK pathways which, in turn, were activated by oxidative stress. In summary, hyperosmolarity induced renal senescence, particularly in glomerular mesangial cells, increasing oxidative stress, which constitutively activated Ras-ERK 1/2 pathway. Cellular senescence could contribute to the organ dysfunction associated with diabetes.


Within-host modeling of blood-stage malaria.
Malaria infection continues to be a major health problem worldwide and drug resistance in the major human parasite species, Plasmodium falciparum, is increasing in South East Asia. Control measures including novel drugs and vaccines are in development, and contributions to the rational design and optimal usage of these interventions are urgently needed. Infection involves the complex interaction of parasite dynamics, host immunity, and drug effects. The long life cycle (48 hours in the common human species) and synchronized replication cycle of the parasite population present significant challenges to modeling the dynamics of Plasmodium infection. Coupled with these, variation in immune recognition and drug action at different life cycle stages leads to further complexity. We review the development and progress of "within-host" models of Plasmodium infection, and how these have been applied to understanding and interpreting human infection and animal models of infection.


Identification of glycoproteins containing specific glycans using a lectin-chemical method.
Glycosylation is one of the most common protein modifications. Each glycoprotein can be glycosylated at multiple glycosites, and each glycosites can be modified by different glycans. Due to this heterogeneity of glycosylation, it has proven difficult to study the structure-function relationship of specific glycans and their affected glycoproteins. Here, we report a novel method for rapid and quantitative identification of glycoproteins containing specific glycans. Lectin affinity isolations are followed by chemical immobilization of the captured glycopeptides, allowing the identification of glycoproteins containing specific glycans by subsequent mass spectrometry. The application of the method should be useful to facilitate our understanding of how changes in glycan associate with diseases, and to discover novel glycoproteins with certain glycans that could serve as biomarkers or therapeutic targets.


Rapid surveillance for health events following a mass meningococcal B vaccine program in a university setting: A Canadian Immunization Research Network study.
An outbreak of Neisseria meningitidis serotype B infection occurred at a small residential university; public health announced an organizational vaccination program with the 4-component Meningococcal B (4CMenB) vaccine (Bexsero(TM), Novartis/GlaxoSmithKline Inc.) several days later. Since there were limited published data on reactogenicity of 4CMenB in persons over 17years of age, this study sought to conduct rapid surveillance of health events in vaccinees and controls using an online survey. Vaccine uptake was 84.7% for dose 1 (2967/3500) and 70% (2456/3500) for dose 2; the survey response rates were 33.0% (987/2967) and 18.7% (459/2456) in dose 1 and dose 1 recipients respectively, and 12% in unvaccinated individuals (63/533). Most students were 20-29years of age (vaccinees, 64.0%; controls, 74.0). A new health problem or worsening of an existing health problem was reported by 30.0% and 30.3% of vaccine recipients after doses 1 and 2 respectively; and by 15.9% of controls. These health problems interfered with the ability to perform normal activities in most vaccinees reporting these events (74.7% post dose 1; 62.6% post dose 2), and in 60% of controls. The health problems led to a health care provider visit (including emergency room) in 12.8% and 14.4% of vaccinees post doses 1 and 2, respectively and in 40% of controls. The most common reactions in vaccinees were injection site reactions (20.6% post dose 1, 16.1% post dose 20 and non-specific systemic complaints (22.6% post dose 1, 17.6% post dose 2). No hospitalizations were reported. An online surveillance program during an emergency meningococcal B vaccine program was successfully implemented, and detected higher rates of health events in vaccinees compared to controls, and high rates of both vaccinees and controls seeking medical attention. The types of adverse events reported by young adult vaccinees were consistent with those previously.


Clinical presentation and outcomes in light chain amyloidosis patients with non-evaluable serum free light chains.
Hematologic response criteria in light chain (AL) amyloidosis require the difference in involved and uninvolved free light chains (dFLC) to be at least 5 mg/dl. We describe the clinical presentation and outcomes of newly diagnosed amyloidosis patients with dFLC <5 mg/dl (non-evaluable dFLC; 14%, n=165) compared with patients with dFLC ⩾5 mg/dl (evaluable dFLC; 86%, n=975). Patients with non-evaluable dFLC had less cardiac involvement (40% vs 80%, P<0.001), less liver involvement (11% vs 17%, P=0.04) and a trend toward less gastrointestinal involvement (18% vs 25%, P=0.08). However, significantly higher renal involvement (72% vs 56%, P=0.0002) was observed in the non-evaluable dFLC cohort. Differences in treatment patterns were observed, with 51% of treated patients undergoing upfront stem cell transplantation in the non-evaluable cohort compared with 28% in the evaluable dFLC group (P<0.001). Progression-free survival (61 vs 13 months, P<0.001) and overall survival (OS; 101 vs 29 months, P<0.001) were significantly longer in the non-evaluable dFLC cohort. Normalization of involved light chain levels and decrease in dFLC <1 mg/dl (baseline at least 2 mg/dl) were predictive of OS and associated with better dialysis-free survival and may be used for response assessment in patients with non-evaluable FLC levels.


Investigation by the Method of INNO-LiPA of Primary Resistance to Lamivudine in Patients with Chronic Hepatitis B Who Have Not Used Antiviral Therapy.
Two billion people around the world are exposed to the hepatitis B virus (HBV) and about 350 million are infected with chronic HBV. The infection can be acquired early (neonatal) and becomes chronic in 90%; this rate reduces to 30% between ages one and five years. There is a 25% risk of chronicity in adults. Nowadays, immunomodulatory and antiviral pegylated-interferons or oral antiviral agents are used in the treatment of chronic hepatitis B. Lamivudine is an effective oral antiviral agent which inhibits the replication of HVB by blocking reverse transcriptase enzyme. The study aims to detect the resistance of HBV to lamivudine in the community and evaluate the effectiveness and suitability of early treatment with lamivudine. One hundred patients who presented to our Faculty of Medicine Hospital Infectious Diseases and Clinical Microbiology Department and had not received any antiviral treatment were recruited. The INNO-LiPA method was applied to investigate primary lamivudine resistance in patients. Seventy-eight patients were HBeAg-negative and 22 patients were HBeAg-positive. A statistically significant correlation was found between HBeAg positivity, alanine aminotransferase (ALT) elevation and HBV DNA (p < 0.05). The rtM204V and L180M mutation motif was found in one patient with HBeAg positivity. Hepatitis B virus in our region is not a lamivudine-resistant strain and early treatment with lamivudine is an effective and convenient method.


Facilitation of visual search at new positions: a behavioral and ERP study of new object capture.
Visual search was studied in two consecutive displays. Display 1 items changed identity whilst retaining their positions when the additional items appeared in Display 2. In the New condition, the target appeared at one of the new positions, whereas in the Old condition, the target appeared at one of the old positions. Responses were faster and accuracy increased in the New condition. Event-related brain potentials revealed an Old-New difference 400 ms after Display 2 onset for the smaller set size, suggesting that subjects had a holistic impression that the target was absent at a new position. A posteriorly distributed processing difference between both conditions was manifest at around 1200 ms, suggesting a bias for search at new positions.


Apoptosis in cancer: from pathogenesis to treatment.
Apoptosis is an ordered and orchestrated cellular process that occurs in physiological and pathological conditions. It is also one of the most studied topics among cell biologists. An understanding of the underlying mechanism of apoptosis is important as it plays a pivotal role in the pathogenesis of many diseases. In some, the problem is due to too much apoptosis, such as in the case of degenerative diseases while in others, too little apoptosis is the culprit. Cancer is one of the scenarios where too little apoptosis occurs, resulting in malignant cells that will not die. The mechanism of apoptosis is complex and involves many pathways. Defects can occur at any point along these pathways, leading to malignant transformation of the affected cells, tumour metastasis and resistance to anticancer drugs. Despite being the cause of problem, apoptosis plays an important role in the treatment of cancer as it is a popular target of many treatment strategies. The abundance of literature suggests that targeting apoptosis in cancer is feasible. However, many troubling questions arise with the use of new drugs or treatment strategies that are designed to enhance apoptosis and critical tests must be passed before they can be used safely in human subjects.


Exon definition complexes contain the tri-snRNP and can be directly converted into B-like precatalytic splicing complexes.
The first step in splicing of pre-mRNAs with long introns is exon definition, where U1 and U2 snRNPs bind at opposite ends of an exon. After exon definition, these snRNPs must form a complex across the upstream intron to allow splicing catalysis. Exon definition and conversion of cross-exon to cross-intron spliceosomal complexes are poorly understood. Here we demonstrate that, in addition to U1 and U2 snRNPs, cross-exon complexes contain U4, U5, and U6 (which form the tri-snRNP). Tri-snRNP docking involves the formation of U2/U6 helix II. This interaction is stabilized by a 5' splice site (SS)-containing oligonucleotide, which can bind the tri-snRNP and convert the cross-exon complex into a cross-intron, B-like complex. Our data suggest that the switch from cross-exon to cross-intron complexes can occur directly when an exon-bound tri-snRNP interacts with an upstream 5'SS, without prior formation of a cross-intron A complex, revealing an alternative spliceosome assembly pathway.


Involvement of multimeric protein complexes in mediating the capacitation-dependent binding of human spermatozoa to homologous zonae pellucidae.
The recognition and binding of a free-swimming spermatozoon to an ovulated oocyte is one of the most important cellular interactions in biology. While traditionally viewed as a simple lock and key mechanism, emerging evidence suggests that this event may require the concerted action of several sperm proteins. In this study we examine the hypothesis that the activity of such proteins may be coordinated by their assembly into multimeric recognition complexes on the sperm surface. Through the novel application of blue native polyacrylamide gel electrophoresis (BN-PAGE), we tender the first direct evidence that human spermatozoa do indeed express a number of high molecular weight protein complexes on their surface. Furthermore, we demonstrate that a subset of these complexes displays affinity for homologous zonae pellucidae. Proteomic analysis of two such complexes using electrospray ionization mass spectrometry identified several of the components of the multimeric 20S proteasome and chaperonin-containing TCP-1 (CCT) complexes. The latter complex was also shown to harbor at least one putative zona pellucida binding protein, ZPBP2. Consistent with a role in the mediation of sperm-zona pellucida interaction we demonstrated that antibodies directed against individual subunits of these complexes were able to inhibit sperm binding to zona-intact oocytes. Similarly, these results were able to be recapitulated using native sperm lysates, the zona affinity of which was dramatically reduced by antibody labeling of the complex receptors, or in the case of the 20S proteasome the ubiquitinated zonae ligands. Overall, the strategies employed in this study have provided novel, causal insights into the molecular mechanisms that govern sperm-egg interaction.


Gene therapy restores dopamine transporter expression and ameliorates pathology in iPSC and mouse models of infantile parkinsonism.
Most inherited neurodegenerative disorders are incurable, and often only palliative treatment is available. Precision medicine has great potential to address this unmet clinical need. We explored this paradigm in dopamine transporter deficiency syndrome (DTDS), caused by biallelic loss-of-function mutations in SLC6A3, encoding the dopamine transporter (DAT). Patients present with early infantile hyperkinesia, severe progressive childhood parkinsonism, and raised cerebrospinal fluid dopamine metabolites. The absence of effective treatments and relentless disease course frequently leads to death in childhood. Using patient-derived induced pluripotent stem cells (iPSCs), we generated a midbrain dopaminergic (mDA) neuron model of DTDS that exhibited marked impairment of DAT activity, apoptotic neurodegeneration associated with TNFα-mediated inflammation, and dopamine toxicity. Partial restoration of DAT activity by the pharmacochaperone pifithrin-μ was mutation-specific. In contrast, lentiviral gene transfer of wild-type human SLC6A3 complementary DNA restored DAT activity and prevented neurodegeneration in all patient-derived mDA lines. To progress toward clinical translation, we used the knockout mouse model of DTDS that recapitulates human disease, exhibiting parkinsonism features, including tremor, bradykinesia, and premature death. Neonatal intracerebroventricular injection of human SLC6A3 using an adeno-associated virus (AAV) vector provided neuronal expression of human DAT, which ameliorated motor phenotype, life span, and neuronal survival in the substantia nigra and striatum, although off-target neurotoxic effects were seen at higher dosage. These were avoided with stereotactic delivery of AAV2.SLC6A3 gene therapy targeted to the midbrain of adult knockout mice, which rescued both motor phenotype and neurodegeneration, suggesting that targeted AAV gene therapy might be effective for patients with DTDS.


Cardio-haemodynamic assessment and venous lactate in severe dengue: Relationship with recurrent shock and respiratory distress.
Dengue can cause plasma leakage that may lead to dengue shock syndrome (DSS). In approximately 30% of DSS cases, recurrent episodes of shock occur. These patients have a higher risk of fluid overload, respiratory distress and poor outcomes. We investigated the association of echocardiographically-derived cardiac function and intravascular volume parameters plus lactate levels, with the outcomes of recurrent shock and respiratory distress in severe dengue. We performed a prospective observational study in Paediatric and adult ICU, at the Hospital for Tropical Diseases (HTD), Ho Chi Minh City, Vietnam. Patients with dengue were enrolled within 12 hours of admission to paediatric or adult ICU. A haemodynamic assessment and portable echocardiograms were carried out daily for 5 days from enrolment and all interventions recorded. 102 patients were enrolled; 22 patients did not develop DSS, 48 had a single episode of shock and 32 had recurrent shock. Patients with recurrent shock had a higher enrolment pulse than those with 1 episode or no shock (median: 114 vs. 100 vs. 100 b/min, P = 0.002), significantly lower Stroke Volume Index (SVI), (median: 21.6 vs. 22.8 vs. 26.8mls/m2, P<0.001) and higher lactate levels (4.2 vs. 2.9 vs. 2.2 mmol/l, P = 0.001). Higher SVI and worse left ventricular function (higher Left Myocardial Performance Index) on study days 3-5 was associated with the secondary endpoint of respiratory distress. There was an association between the total IV fluid administered during the ICU admission and respiratory distress (OR: 1.03, 95% CI 1.01-1.06, P = 0.001). Admission lactate levels predicted patients who subsequently developed recurrent shock (P = 0.004), and correlated positively with the total IV fluid volume received (rho: 0.323, P = 0.001) and also with admission ALT (rho: 0.764, P<0.001) and AST (rho: 0.773, P<0.001). Echo-derived intravascular volume assessment and venous lactate levels can help identify dengue patients at high risk of recurrent shock and respiratory distress in ICU. These findings may serve to, not only assist in the management of DSS patients, but also these haemodynamic endpoints could be used in future dengue fluid intervention trials.


Understanding surgical knot security: a proposal to standardize the literature.
There is very little published data concerning the knot handling properties of suture materials. The few studies that are available on this subject contain discrepancies in nomenclature, testing methods, and in the type of data reported. To date, there has been no effort to present what is currently known concerning knot security in a unified format. A review of the literature was conducted to determine what is currently known concerning surgical knots, the efficiency of these knots, testing techniques, and nomenclature. The structures of common surgical knots were analyzed and their relationships determined. The results of the various studies were analyzed and a summary of existing data was prepared. Based on current literature and a thorough analysis of surgical knots, a standard method for testing knot efficiency and a standard nomenclature were proposed. Suture security has been shown to be strongly influenced by the type of knot used. Knots in which the second throw contains two turns are most efficient. Existing studies have demonstrated a strong variation in the efficiency of different surgical knots. Standards for testing and nomenclature have been presented. Effort now needs to be directed in three areas: simulating in vivo conditions, testing knots under these conditions, and determining the factors that make some suture materials more efficient in knot holding than others.


Two separate regions in the genome of the tobacco etch virus contain determinants of the wilting response of Tabasco pepper.
Infection of Tabasco pepper by the tobacco etch virus (TEV) typically causes wilting associated with root necrosis. However, a strain of TEV, designated TEV nonwilting (TEV NW), is able to infect Tabasco pepper plants but does not cause wilting. In order to locate the genetic determinants responsible for the wilting response, a full-length cDNA clone of TEV NW from which infectious transcripts can be derived was made. A number of chimeric constructs were prepared by substituting cDNA fragments between TEV HAT (which causes wilting) and TEV NW clones. This approach was used to identify two wilting determinants in TEV HAT: one encompasses the 3' one-third of the P3 encoding region; the other spans the 3' end of the CI, the 6-kDa protein, and the 5' end of the VPg-NIa coding regions. Substitutions of both these TEV NW fragments into TEV HAT resulted in infection but not wilting of Tabasco pepper, while the replacement of either of the fragments alone did not alter the wilting response. This indicates that both TEV NW regions contain determinants necessary but not sufficient to alter the wilting response and that both must be present in order to avoid the wilting response. There was no difference between the in vitro transcription-translation products derived from constructs containing these regions from TEV HAT and TEV NW.


Transplantation of subalpine wood-pasture turfs along a natural climatic gradient reveals lower resistance of unwooded pastures to climate change compared to wooded ones.
Climate change could impact strongly on cold-adapted mountain ecosystems, but little is known about its interaction with traditional land-use practices. We used an altitudinal gradient to simulate a year-round warmer and drier climate for semi-natural subalpine grasslands across a landscape of contrasting land-use management. Turf mesocosms from three pasture-woodland land-use types-unwooded pasture, sparsely wooded pasture, and densely wooded pasture-spanning a gradient from high to low management intensity were transplanted downslope to test their resistance to two intensities of climate change. We found strong overall effects of intensive (+4 K) experimental climate change (i.e., warming and reduced precipitation) on plant community structure and function, while moderate (+2 K) climate change did not substantially affect the studied land-use types, thus indicating an ecosystem response threshold to moderate climate perturbation. The individual land-use types were affected differently under the +4 K scenario, with a 60% decrease in aboveground biomass (AGB) in unwooded pasture turfs, a 40% decrease in sparsely wooded pasture turfs, and none in densely wooded ones. Similarly, unwooded pasture turfs experienced a 30% loss of species, advanced (by 30 days) phenological development, and a mid-season senescence due to drought stress, while no such effects were recorded for the other land-use types. The observed contrasting effects of climate change across the pasture-woodland landscape have important implications for future decades. The reduced impact of climate change on wooded pastures as compared to unwooded ones should promote the sustainable land use of wooded pastures by maintaining low management intensity and a sparse forest canopy, which buffer the immediate impacts of climate change on herbaceous vegetation.


Peptide modified gold-coated polyurethanes as thrombin scavenging surfaces.
Thin layers of gold were deposited on polyurethane film and chemisorbed with three peptides having an N-terminal cysteine: Cys-Pro-Arg, Cys-(L)Phe-Pro-Arg, and Cys-(D)Phe-Pro-Arg. The ability of these surfaces to act as thrombin scavengers was evaluated. The peptides are related to the known thrombin inhibitor Phe-Pro-Arg chloromethyl ketone and were shown to have significant thrombin inhibitory activity in solution. Attachment of the peptides to gold was confirmed by water contact angle and X-ray photoelectron spectroscopy measurements. Thrombin adsorption from a buffer and plasma was investigated, and chromogenic substrate assays were carried out for thrombin activity on the surfaces and in the supernatant following adsorption. The data suggest that the peptide-modified surfaces are able to adsorb thrombin with high affinity from a buffer and that thrombin is taken up selectively from plasma. The Cys-(D)Phe-Pro-Arg modified surfaces showed particularly high affinity for thrombin. It was also found that the activity of thrombin adsorbed on the peptide surfaces was inhibited, and inhibition was greatest on the Cys-(D)Phe-Pro-Arg surface. We concluded that the peptide surfaces may have potential as antithrombogenic materials via their ability to scavenge and inhibit thrombin generated as a result of blood-material contact.


A linear programming model for allocating HIV prevention funds with state agencies: a pilot study.
Given the initiatives to improve resource allocation decisions for HIV prevention activities, a linear programming model was designed specifically for use by state and local decision-makers. A pilot study using information from the state of Florida was conducted and studied under a series of scenarios depicting the impact of common resource allocation constraints. Improvements over the past allocation strategy in the number of potential infections averted were observed in all scenarios with a maximal improvement of 73%. When allocating limited resources, policymakers must balance efficiency and equity. In this pilot study, the optimal allocation (i.e., most-efficient strategy) would not distribute resources in an equitable manner. Instead, only 12% of at-risk people would receive prevention funds. We find that less efficient strategies, where 58% fewer infections are averted, result in significantly more equitable allocations. This tool serves as a guide for allocating funds for prevention activities.


Assessment of congestive heart failure in chest radiographs. Observer performance with two common film-screen systems.
The effect of observer variations and film-screen quality on the diagnosis of congestive heart failure based on chest radiographs was studied in 27 patients. For each patient, two films were exposed, one with the Kodak Lanex Medium system and one with the Agfa MR 400 system. The films were presented to three observers who assessed the presence of congestive heart failure on a three-graded scale. The results showed no significant difference between the two systems but large systematic differences between the observers. There were also differences between the two ratings by the same observer that could not be explained by the film-screen factor. It is concluded that the choice between these two systems is of little importance in view of the interobserver and intraobserver variability that can exist within the same department.