The adjustment of curricula in veterinary faculties in sub-Saharan Africa.
A survey was conducted by questionnaire to assess the current undergraduate curricula in the veterinary faculties of sub-Saharan Africa. The survey also examined how such curricula are adjusted for crucial developments in the veterinary field, such as privatisation, decentralisation and globalisation, with the increasing risk of transboundary diseases. The results demonstrate that most of these faculties face serious shortages, both in their budgets and of qualified personnel. Most faculties do not have formal feedback systems to allow former graduates to contribute to periodic reviews of the curricula. Although some north-south and south-south collaboration exists among African veterinary faculties, more intensive regional collaboration at both undergraduate and postgraduate level would allow optimal use of the available funds and human resources. The creation of a regional veterinary council and a committee of deans would be an excellent step forward in ensuring internationalisation and harmonisation of veterinary education and establishing a regional accreditation system.


Curing lights for orthodontic bonding: a systematic review and meta-analysis.
Light cure of resin-based adhesives is the mainstay of orthodontic bonding. In recent years, alternatives to conventional halogen lights offering reduced curing time and the potential for lower attachment failure rates have emerged. The relative merits of curing lights in current use, including halogen-based lamps, light-emitting diodes (LEDs), and plasma arc lights, have not been analyzed systematically. In this study, we reviewed randomized controlled trials and controlled clinical trials to assess the risks of attachment failure and bonding time in orthodontic patients in whom brackets were cured with halogen lights, LEDs, or plasma arc systems. Multiple electronic database searches were undertaken, including MEDLINE, EMBASE, and the Cochrane Oral Health Group's Trials Register, CENTRAL. Language restrictions were not applied. Unpublished literature was searched on ClinicalTrials.gov, the National Research Register, Pro-Quest Dissertation Abstracts, and Thesis database. Search terms included randomized controlled trial, controlled clinical trial, random allocation, double blind method, single blind method, orthodontics, LED, halogen, bond, and bracket. Authors of primary studies were contacted as required, and reference lists of the included studies were screened. Randomized controlled trials and clinical controlled trials directly comparing conventional halogen lights, LEDs, or plasma arc systems involving patients with full arch, fixed, or bonded orthodontic appliances (not banded) with follow-up periods of a minimum of 6 months were included. Using predefined forms, 2 authors undertook independent extraction of articles; disagreements were resolved by discussion. The assessment of the risk of bias of the randomized controlled trials was based on the Cochrane Risk of Bias tool. Ten studies met the inclusion criteria; 2 were excluded because of high risk of bias. In the comparison of bond failure risk with halogen lights and plasma arc lights, 1851 brackets were included in both groups. Little statistical heterogeneity was observed in this analysis (I(2) = 4.8%; P = 0.379). There was no statistical difference in bond failure risk between the groups (OR, 0.92; 95% CI, 0.68-1.23; prediction intervals, 0.54, 1.56). Similarly, no statistical difference in bond failure risk was observed in the meta-analysis comparing halogen lights and LEDs (OR, 0.96; 95% CI, 0.64-1.44; prediction intervals, 0.07, 13.32). The pooled estimates from both comparisons were OR, 0.93; 95% CI, 0.74-1.17; and prediction intervals, 0.69, 1.17. There is no evidence to support the use of 1 light cure type over another based on risk of attachment failure.


Resolving a 150-year-old paternity case in Mormon history using DTC autosomal DNA testing of distant relatives.
Although autosomal DNA testing has been available for a number of years, its use to reconstruct genetic profiles of people that lived centuries in the past is relatively recent and there are no published cases where it was employed to verify a kinship relation, likely to be an alleged paternity, that occurred one and a half century ago. DNA testing has already been employed to study the ancestry and posterity of Joseph Smith Jr., founder of the Latter-day Saint (Mormon) movement. Thanks to information found on the paternally inherited Y chromosome, a number of alleged paternities have been disproved, but obviously this analysis is not effective for alleged daughters. Likewise, his reconstructed mitogenome sequence, reported here for the first time, provides information about his maternal ancestry, but is useless in any paternity questions due to the strict maternal inheritance. Among all the children attributed to Joseph Smith Jr., Josephine Lyon, born in 1844, is perhaps the most frequently mentioned. In the current study, 56 individuals, mostly direct descendants of Joseph Smith Jr. and Josephine Lyon, had their autosomal DNA tested to verify Josephine's biological paternity. Nearly 600,000 autosomal SNPs from each subject were typed and detailed genealogical data were compiled. The absence of shared DNA between Josephine's grandson and Joseph Smith Jr.'s five great-grandchildren together with various amounts of autosomal DNA shared by the same individual with four other relatives of Windsor Lyon is a clear indication that Josephine was not related to the Smith, but to the Lyon's family. These inferences were also verified using kinship analyses and likelihood ratio calculations.


Perchlorate production by photodecomposition of aqueous chlorine solutions.
Aqueous chlorine solutions (defined as chlorine solutions (Cl(2,T)) containing solely or a combination of molecular chlorine (Cl(2)), hypochlorous acid (HOCl), and hypochlorite (OCl(-))) are known to produce toxic inorganic disinfection byproduct (e.g., chlorate and chlorite) through photoactivated transformations. Recent reports of perchlorate (ClO(4)(-)) production-a well-known thyroid hormone disruptor- from stored bleach solutions indicates the presence of unexplored transformation pathway(s). The evaluation of this potential ClO(4)(-) source is important given the widespread use of aqueous chlorine as a disinfectant. In this study, we perform detailed rate analysis of ClO(4)(-) generation from aqueous chlorine under varying environmental conditions including ultraviolet (UV) light sources, intensity, solution pH, and Cl(2,T) concentrations. Our results show that ClO(4)(-) is produced upon UV exposure of aqueous chlorine solutions with yields ranging from 0.09 × 10(-3) to 9.2 × 10(-3)% for all experimental conditions. The amount of ClO(4)(-) produced depends on the starting concentrations of Cl(2,T) and ClO(3)(-), UV source wavelength, and solution pH, but it is independent of light intensity. We hypothesize a mechanistic pathway derived from known reactions of Cl(2,T) photodecomposition that involves the reaction of Cl radicals with ClO(3)(-) to produce ClO(4)(-) with calculated rate coefficient (k(ClO4-)) of (4-40) × 10(5) M(-1) s(-1) and (3-250) × 10(5) M(-1) s(-1) for UV-B/C and UV-A, respectively. The measured ClO(4)(-) concentrations for both UV-B and UV-C experiments agreed well with our model (R(2) = 0.88-0.99), except under UV-A light exposure (R(2) = 0.52-0.93), suggesting the possible involvement of additional pathways at higher wavelengths. Based on our results, phototransformation of aqueous chlorine solutions at concentrations relevant to drinking water treatment would result in ClO(4)(-) concentrations (~0.1 μg L(-1)) much below the proposed drinking water limits. The importance of the hypothesized mechanism is discussed in relation to natural ClO(4)(-) formation by atmospheric transformations.


Pathogenic species of the genus Haemophilus and Streptococcus pneumoniae produce immunoglobulin A1 protease.
Thirty-seven strains of the genus Haemophilus and five strains of Streptococcus pneumoniae were examined for their ability to produce extracellular enzyme that cleaves immunoglobulin molecules. All strains of H. influenzae, H. aegyptius, and S. pneumoniae elaborated enzyme that selectively cleaved human immunoglobulin A1 (IgA1) myeloma proteins but was inactive against a variety of other proteins including human IgA2, IgG, and IgM, porcine and bovine secretory IgA, human and bovine serum albumins, and ovalbumin. Although susceptible, human secretory IgA remained largely undigested. Two strains of H. pleuropneumoniae isolated from fatally infected pigs cleaved porcine secretory IgA, but had no effect on human IgA proteins. None of 16 strains that belonged to nonpathogenic Haemophilus species produced IgA protease. Analyses of the cleavage products of human IgA1 and secretory IgA proteins by immunochemical methods, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and analytical ultracentrifugation revealed that Fab and Fc fragments were produced. Since the production of IgA1 protease by Neisseria meningitidis has been reported previously, our finding that H. influenzae and S. pneumoniae produce an IgA1 protease indicates that this is a property of all three major etiological agents of bacterial meningitis. This suggests that IgA1 protease production may be an important factor in the pathogenesis of this disease.


A prospective study of serum C-reactive protein and colorectal cancer risk in men.
Chronic inflammation has been implicated in the etiology of colorectal cancer. C-reactive protein (CRP), a sensitive marker of inflammation, has been investigated with regard to colorectal cancer in only three previous studies, and the results from these investigations were inconsistent. We examined serum CRP levels in relation to colorectal cancer incidence in a nested case-control study within the Alpha Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study, a cohort of 29,133 Finnish males enrolled from 1985 to 1988 with follow-up through April 2002. Colorectal cancer cases were ascertained by the Finnish Cancer Registry; this analysis included 130 cases of colorectal cancer (with available blood), which occurred between 1990 and April 30, 2002, and 260 matched controls. Baseline median CRP levels were approximately 25% higher among colorectal cancer cases (3.4 mg/L) than controls (2.6 mg/L; P = 0.04). Relative to men in the lowest quartile of CRP concentration, men in the highest quartile had an odds ratio of 2.9 (95% confidence interval, 1.4-6.0) for developing colorectal cancer with a dose-response relationship supported (P(trend) = 0.006). The relation between CRP and incident colorectal cancer was modified by body mass index such that the association was stronger among lean individuals than in heavier individuals (P(interaction) = 0.018). These results support the notion that chronic low-grade inflammation is a marker for increased risk of colorectal cancer.


Bifurcation in Blood Oscillatory Rhythms for Patients with Ischemic Stroke: A Small Scale Clinical Trial using Laser Doppler Flowmetry and Computational Modeling of Vasomotion.
We describe application of spectral analysis of laser Doppler flowmetry (LDF) signals to investigation of cerebrovascular haemodynamics in patients with post-acute ischemic stroke (AIS) and cerebrovascular insufficiency. LDF was performed from 3 to 7 days after the onset of AIS on forehead in the right and left supraorbital regions in patients. Analysis of LDF signals showed that perfusion in the microvasculature in AIS patients was lower than that in patients with cerebrovascular insufficiency. As a result of wavelet analysis of the LDF signals we obtained activation of the vasomotion in the frequency range of myogenic oscillation of 0.1 Hz and predominantly nutritive regime microcirculation after systemic thrombolytic therapy of the AIS patients. In case of significant stroke size, myogenic activity, and nutritive pattern microhaemodynamics were reduced, in some cases non-nutritive pattern and/or venular stasis was revealed. Wavelet analysis of the LDF signals also showed asymmetry in wavelet spectra of the LDF signals obtained in stroke-affected and unaffected hemispheres in the AIS patients. A mechanism underlying the observed asymmetry was analyzed by computational modeling of vasomotion developed in Arciero and Secomb (2012). We applied this model to describe relaxation oscillation of arteriole diameter which is forced by myogenic oscillation induced by synchronous calcium oscillation in vascular smooth muscle cells. Calculation showed that vasomotion frequency spectrum at the low-frequency range (0.01 Hz) is reciprocally modulated by myogenic oscillation (0.1 Hz) that correlates with experimental observation of inter-hemispheric variation in the LDF spectrum.


Impact of International Subarachnoid Aneurysm Trial results on treatment of ruptured intracranial aneurysms in the United States. Clinical article.
The utilization of endovascular treatment for ruptured intracranial aneurysms is expected to change since the publication of the International Subarachnoid Aneurysm Trial (ISAT) in 2002. The authors performed this analysis to determine the impact of ISAT results on treatment selection for ruptured intracranial aneurysms and associated in-hospital outcomes using nationally representative data. We determined the national estimates of treatments used for ruptured intracranial aneurysms and associated in-hospital outcomes, length of stay, mortality, and cost incurred using the Nationwide Inpatient Survey (NIS) data. The NIS is the largest all-payer inpatient care database in the US and contains data from 986 hospitals approximating a 20% stratified sample of US hospitals. All the variables pertaining to hospitalization were compared between 2000-2002 and 2004-2006, and in-hospital outcomes were analyzed using multivariate analysis. In the 3-year periods prior to and after the ISAT, there were 70,637 and 77,352 admissions for ruptured intracranial aneurysms, respectively. There was a significant increase in endovascular treatment after publication of the ISAT (trend test, p < 0.0001) The in-hospital mortality for ruptured intracranial aneurysm admissions decreased from 27% to 24% (odds ratio [OR] 0.89, 95% CI 0.83-0.96, p = 0.003) after the publication of the ISAT. The cost of hospitalization after adjusting for procedures practices was not significantly higher after the publication of the ISAT ($21,437 vs $22,817, p < 0.89), but cost of hospitalization was higher in the post-ISAT period for patients undergoing endovascular procedure. The results of the ISAT have been associated with a prominent change in practice patterns related to the treatment of ruptured aneurysms. The cost of hospitalization has increased and the mortality has decreased, presumably due to a larger proportion of patients receiving any treatment and endovascular treatment.


Single-Crystal 40Ar/39Ar Dating of the Eocene-Oligocene Transition in North America.
Explanations for the causes of climatic changes and associated faunal and floral extinctions at the close of the Eocene Epoch have long been controversial because of, in part, uncertainties in correlation and dating of global events. New single-crystal laser fusion (SCLF) (40)Ar/(39)Ar dates on tephra from key magnetostratigraphic and fossilbearing sections necessitate significant revision in North American late Paleogene chronology. The Chadronian-Orellan North American Land Mammal "Age" boundary, as a result, is shifted from 32.4 to 34.0 Ma (million years ago), the Orellan-Whitneyan boundary is shifted from 30.8 to 32.0 Ma, and the Whitneyan-Arikareean boundary is now approximately 29.0 Ma. The new dates shift the correlation of Chron C12R from the Chadronian to within the Orellan-Whitneyan interval, the Chadronian becomes late Eocene in age, and the North American Oligocene is restricted to the Orellan, Whitneyan, and early Arikareean. The Eocene-Oligocene boundary, and its associated climate change and extinction events, as a result, correlates with the Chadronian-Orellan boundary, not the Duchesnean-Chadronian boundary.


Dietary vitamin D and risk of non-Hodgkin lymphoma: the multiethnic cohort.
The present study explored the association between dietary vitamin D and non-Hodgkin's lymphoma (NHL) risk. The multiethnic cohort (MEC) includes more than 215 000 Caucasians, African Americans, Native Hawaiians, Japanese Americans and Latinos, aged 45-75. After 10 years of follow-up, 939 incident NHL cases were identified. Risk was estimated using proportional hazards' models adjusted for possible confounders. Vitamin D intake was not associated with NHL risk in the entire cohort (P(trend) = 0.72 for men and P(trend) = 0.83 for women), but significantly lowered disease risk in African American women (hazard ratio (HR) = 0.50, 95 % CI: 0.28, 0.90, P(trend) = 0.03) and was borderline protective in African American men (HR = 0.68; 95 % CI: 0.39, 1.19; P(trend) = 0.31) when the highest to the lowest tertile was compared. In NHL subtype analyses, a 19, 36 and 32 % lowered risk, although not significant, was observed for diffuse large B-cell lymphoma, follicular lymphoma and small lymphocytic lymphoma/chronic lymphocytic leukemia in women, respectively. High dietary intake of vitamin D did not show a protective effect against NHL within the MEC except among African Americans, possibly because vitamin D production due to sun exposure is limited in this population.


Structure of cellulose microfibrils in primary cell walls from collenchyma.
In the primary walls of growing plant cells, the glucose polymer cellulose is assembled into long microfibrils a few nanometers in diameter. The rigidity and orientation of these microfibrils control cell expansion; therefore, cellulose synthesis is a key factor in the growth and morphogenesis of plants. Celery (Apium graveolens) collenchyma is a useful model system for the study of primary wall microfibril structure because its microfibrils are oriented with unusual uniformity, facilitating spectroscopic and diffraction experiments. Using a combination of x-ray and neutron scattering methods with vibrational and nuclear magnetic resonance spectroscopy, we show that celery collenchyma microfibrils were 2.9 to 3.0 nm in mean diameter, with a most probable structure containing 24 chains in cross section, arranged in eight hydrogen-bonded sheets of three chains, with extensive disorder in lateral packing, conformation, and hydrogen bonding. A similar 18-chain structure, and 24-chain structures of different shape, fitted the data less well. Conformational disorder was largely restricted to the surface chains, but disorder in chain packing was not. That is, in position and orientation, the surface chains conformed to the disordered lattice constituting the core of each microfibril. There was evidence that adjacent microfibrils were noncovalently aggregated together over part of their length, suggesting that the need to disrupt these aggregates might be a constraining factor in growth and in the hydrolysis of cellulose for biofuel production.


Value of ultrasonography in assessment of recent injury of anterior talofibular ligament in children.
Sprained ankle is a very common injury in children. Proper treatment of ligament injuries enables full recovery. X-ray and US examinations are commonly available diagnostic methods. Two hundred and six children (113 girls and 93 boys, mean age 10.6) with recent ankle joint sprain (up to 7 days of injury) were subject to a retrospective analysis. All patients underwent an X-ray and US examination of the ankle joint within 7 days of injury. In 19 patients, anterior talofibular ligament reconstruction was conducted. X-ray failed to visualize a pathology in 129 children (63%); in 24 patients (12%), avulsion fracture of the lateral malleolus was found, and in 36 cases (17%), effusion in the talocrural joint was detected. Ultrasonography failed to visualize a pathology in 19 children (9%); in 60 patients (29%), it showed avulsion fracture of the lateral malleolus involving the attachment of the anterior talofibular ligament (ATFL); in 34 cases (17%), complete ATFL tear was detected, and in 51 patients (25%), partial ATFL injury was found. Other injuries constituted 19%. The surgeries conducted to repair the anterior talofibular ligament (19) confirmed the US/X-ray diagnoses in 100% of cases. Avulsion ATFL injury, i.e. the one that involves the ligament attachment site, is usually found in younger children (median: 8 years of age). Complete ATFL tears (not involving the attachment site) concern older children (median: 14 years of age). Since X-ray is of limited value in diagnosing ankle joint pathologies in recent sprain injuries in children, soft tissue imaging, i.e. ultrasonography, is the basic examination to assess the ligament complex. Avulsion fractures, which involve the ATFL attachment site and are usually found in younger children, are a consequence of the incomplete ossification and require urgent diagnosis and orthopedic consultation.


Eligibility requirements for advanced health informatics certification.
AMIA is leading the effort to strengthen the health informatics profession by creating an advanced health informatics certification (AHIC) for individuals whose informatics work directly impacts the practice of health care, public health, or personal health. The AMIA Board of Directors has endorsed a set of proposed AHIC eligibility requirements that will be presented to the future AHIC certifying entity for adoption. These requirements specifically establish who will be eligible to sit for the AHIC examination and more generally signal the depth and breadth of knowledge and experience expected from certified individuals. They also inform the development of the accreditation process and provide guidance to graduate health informatics programs as well as individuals interested in pursuing AHIC. AHIC eligibility will be determined by practice focus, education in primary field and health informatics, and significant health informatics experience.


Adductor longus activation during common hip exercises.
Hip-adductor strains are among the most common lower-extremity injuries sustained in athletics. Treatment of these injuries involves a variety of exercises used to target the hip adductors. To identify the varying activation levels of the adductor longus during common hip-adductor exercises. Descriptive study. Laboratory. 24 physically active, college-age students. None. Peak and average electromyographic (EMG) activity of the adductor longus muscle during the following 6 hip-adductor rehabilitation exercises: side-lying hip adduction, ball squeezes, rotational squats, sumo squats, standing hip adduction on a Swiss ball, and side lunges. The side-lying hip-adduction exercise produced more peak and average activation than any other exercise (P < .001). Ball squeezes produced more peak and average activation than rotational squats, sumo squats, and standing adduction on a Swiss ball (P < .001). Ball squeezes had more average activation than side lunges (P = .001). All other variables for peak activation during the exercises were not statistically significant (P > .08). These results allowed the authors to provide an overall ranking system (highest to lowest muscle activation): side-lying hip adduction, ball squeezes, side lunges, standing adduction on a Swiss ball, rotational squats, and sumo squats. The study provides a ranking system on the activation levels of the adductor longus muscle for 6 common hip-adductor rehabilitation exercises, with the side-lying hip-adduction and ball-squeeze exercises displaying the highest overall activation.


Coalescence-time distributions in a serial founder model of human evolutionary history.
Simulation studies have demonstrated that a variety of patterns in worldwide genetic variation are compatible with the trends predicted by a serial founder model, in which populations expand outward from an initial source via a process in which new populations contain only subsets of the genetic diversity present in their parental populations. Here, we provide analytical results for key quantities under the serial founder model, deriving distributions of coalescence times for pairs of lineages sampled either from the same population or from different populations. We use these distributions to obtain expectations for coalescence times and for homozygosity and heterozygosity values. A predicted approximate linear decline in expected heterozygosity with increasing distance from the source population reproduces a pattern that has been observed both in human genetic data and in simulations. Our formulas predict that populations close to the source location have lower between-population gene identity than populations far from the source, also mirroring results obtained from data and simulations. We show that different models that produce similar declining patterns in heterozygosity generate quite distinct patterns in coalescence-time distributions and gene identity measures, thereby providing a basis for distinguishing these models. We interpret the theoretical results in relation to their implications for human population genetics.


Ecallantide: in acute hereditary angioedema.
Ecallantide, a recombinant protein that is a selective, highly potent and reversible inhibitor of human plasma kallikrein, is indicated for the treatment of acute attacks of hereditary angioedema (HAE) in patients aged >or=16 years. In the randomized, double-blind, placebo-controlled, multicentre, phase III trial EDEMA3, mean symptom response to treatment at 4 hours (assessed using the Treatment Outcome Score [TOS]; primary endpoint) was significantly greater with a single subcutaneous dose of ecallantide 30 mg than with placebo in patients with acute, moderate to severe attacks of HAE. In addition, the mean change from baseline in symptom severity at 4 hours (assessed using the Mean Symptom Complex Severity [MSCS] scale) was significantly greater with ecallantide than with placebo. At 4 hours in the similarly designed EDEMA4 trial, the mean change from baseline in MSCS score (primary endpoint) and mean TOS were both significantly greater in recipients of a single subcutaneous dose of ecallantide 30 mg than in placebo recipients. Subcutaneous ecallantide 30 mg was generally well tolerated in patients with acute attacks of HAE in the EDEMA3 and EDEMA4 trials. Adverse events were mostly of mild to moderate severity, and no event that was more common in ecallantide than placebo recipients occurred in >10% of patients.


Impact of a community-wide combination HIV prevention intervention on knowledge of HIV status among adolescents.
To determine the impact of a community-wide combination HIV-prevention package (PopART Intervention) that includes universal testing and treatment (UTT) on knowledge of HIV status, among adolescents aged 15--19 years. The HPTN 071 (PopART) for Youth (P-ART-Y) study was nested within HPTN 071 (PopART), a three-arm, cluster-randomized trial conducted from 2013 through 2018 in 21 communities in Zambia and South Africa. Communities were randomly assigned to arm A (combination prevention intervention with universal ART), arm B (prevention intervention with ART provided according to local guidelines), or arm C (standard-of-care). Knowledge of HIV status was measured using data collected during the third round of the PopART intervention in arms A and B (October 2016 to December 2017) and by conducting a cross-sectional survey (August to November 2017) in arm C communities to provide comparative data. The survey was conducted among ∼200 randomly selected adolescents in each community. We used linear regression of the 21 community-level values to make comparisons among trial arms. Knowledge of HIV status was 78.2% (23 544/30 089) in arm A and 76.0% (24 417/32 148) in arm B communities, compared with 32.9% (698/2120) in arm C communities. Knowledge of HIV status varied by country, triplet, sex, and age. The adjusted mean difference was 42.3% between arm A with arm C, 95% CI 28.1-56.6, P less than 0.001 and 40.4% between arm B with arm C, 95% CI 24.6-56.2, P < 0.001). Implementation of a community-wide combination HIV-prevention package that includes UTT substantially enhanced knowledge of HIV status among adolescents.


TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway.
TAZ is a WW domain containing a transcription coactivator that modulates mesenchymal differentiation and development of multiple organs. In this study, we show that TAZ is phosphorylated by the Lats tumor suppressor kinase, a key component of the Hippo pathway, whose alterations result in organ and tissue hypertrophy in Drosophila and contribute to tumorigenesis in humans. Lats phosphorylates TAZ on several serine residues in the conserved HXRXXS motif and creates 14-3-3 binding sites, leading to cytoplasmic retention and functional inactivation of TAZ. Ectopic expression of TAZ stimulates cell proliferation, reduces cell contact inhibition, and promotes epithelial-mesenchymal transition (EMT). Elimination of the Lats phosphorylation sites results in a constitutively active TAZ, enhancing the activity of TAZ in promoting cell proliferation and EMT. Our results elucidate a molecular mechanism for TAZ regulation and indicate a potential function of TAZ as an important target of the Hippo pathway in regulating cell proliferation tumorigenesis.


Predicting stochastic systems by noise sampling, and application to the El Niño-Southern Oscillation.
Interannual and interdecadal prediction are major challenges of climate dynamics. In this article we develop a prediction method for climate processes that exhibit low-frequency variability (LFV). The method constructs a nonlinear stochastic model from past observations and estimates a path of the "weather" noise that drives this model over previous finite-time windows. The method has two steps: (i) select noise samples--or "snippets"--from the past noise, which have forced the system during short-time intervals that resemble the LFV phase just preceding the currently observed state; and (ii) use these snippets to drive the system from the current state into the future. The method is placed in the framework of pathwise linear-response theory and is then applied to an El Niño-Southern Oscillation (ENSO) model derived by the empirical model reduction (EMR) methodology; this nonlinear model has 40 coupled, slow, and fast variables. The domain of validity of this forecasting procedure depends on the nature of the system's pathwise response; it is shown numerically that the ENSO model's response is linear on interannual time scales. As a result, the method's skill at a 6- to 16-month lead is highly competitive when compared with currently used dynamic and statistic prediction methods for the Niño-3 index and the global sea surface temperature field.


Multivariate meta-analysis: a robust approach based on the theory of U-statistic.
Meta-analysis is the methodology for combining findings from similar research studies asking the same question. When the question of interest involves multiple outcomes, multivariate meta-analysis is used to synthesize the outcomes simultaneously taking into account the correlation between the outcomes. Likelihood-based approaches, in particular restricted maximum likelihood (REML) method, are commonly utilized in this context. REML assumes a multivariate normal distribution for the random-effects model. This assumption is difficult to verify, especially for meta-analysis with small number of component studies. The use of REML also requires iterative estimation between parameters, needing moderately high computation time, especially when the dimension of outcomes is large. A multivariate method of moments (MMM) is available and is shown to perform equally well to REML. However, there is a lack of information on the performance of these two methods when the true data distribution is far from normality. In this paper, we propose a new nonparametric and non-iterative method for multivariate meta-analysis on the basis of the theory of U-statistic and compare the properties of these three procedures under both normal and skewed data through simulation studies. It is shown that the effect on estimates from REML because of non-normal data distribution is marginal and that the estimates from MMM and U-statistic-based approaches are very similar. Therefore, we conclude that for performing multivariate meta-analysis, the U-statistic estimation procedure is a viable alternative to REML and MMM. Easy implementation of all three methods are illustrated by their application to data from two published meta-analysis from the fields of hip fracture and periodontal disease. We discuss ideas for future research based on U-statistic for testing significance of between-study heterogeneity and for extending the work to meta-regression setting.


A novel sensor platform matching the improved version of IPMVP option C for measuring energy savings.
It is easy to measure energy consumption with a power meter. However, energy savings cannot be directly computed by the powers measured using existing power meter technologies, since the power consumption only reflects parts of the real energy flows. The International Performance Measurement and Verification Protocol (IPMVP) was proposed by the Efficiency Valuation Organization (EVO) to quantify energy savings using four different methodologies of A, B, C and D. Although energy savings can be estimated following the IPMVP, there are limitations on its practical implementation. Moreover, the data processing methods of the four IPMVP alternatives use multiple sensors (thermometer, hygrometer, Occupant information) and power meter readings to simulate all facilities, in order to determine an energy usage benchmark and the energy savings. This study proposes a simple sensor platform to measure energy savings. Using usually the Electronic Product Code (EPC) global standard, an architecture framework for an information system is constructed that integrates sensors data, power meter readings and occupancy conditions. The proposed sensor platform is used to monitor a building with a newly built vertical garden system (VGS). A VGS shields solar radiation and saves on energy that would be expended on air-conditioning. With this platform, the amount of energy saved in the whole facility is measured and reported in real-time. The data are compared with those obtained from detailed measurement and verification (M&V) processes. The discrepancy is less than 1.565%. Using measurements from the proposed sensor platform, the energy savings for the entire facility are quantified, with a resolution of ±1.2%. The VGS gives an 8.483% daily electricity saving for the building. Thus, the results show that the simple sensor platform proposed by this study is more widely applicable than the four complicated IPMVP alternatives and the VGS is an effective tool in reducing the carbon footprint of a building.


Family discussions about contraception and family planning: a qualitative exploration of black parent and adolescent perspectives.
Parent-adolescent communication is associated with increased adolescent contraceptive use. However, studies of this association are limited by their lack of examination of the communication process, reliance on cross-sectional designs and infrequent comparison of parent and adolescent perspectives. Examining communication in black families is particularly important, given the high pregnancy rate among black adolescents. Between December 2007 and March 2008, a total of 21 focus groups were conducted with 53 black families (68 parents and 57 adolescents) in Pennsylvania. Separate groups were held for males and females, and for parents and adolescents. The discussion guide explored family communication about sexual health topics, including contraception, family planning and abortion. Sessions were audio-recorded; data were transcribed and analyzed using a grounded theory approach to content analysis and the constant comparison method. Five key themes emerged among both parents and adolescents. First, discussions about contraception were indirect and framed in terms of the need to avoid negative consequences of sex. Second, contraceptive knowledge was low. Third, parents more often reported helping male adolescents get condoms than helping females get contraceptives. Fourth, discussions emphasized planning for the future over contraception. Finally, negative attitudes toward abortion were prevalent. Parent-adolescent communication interventions should improve contraceptive knowledge, help parents understand the harmful effects of gender biases in information dissemination, and provide mothers and fathers with communication skills tailored to enhance the role they play in their adolescents' sexual development.


Outcomes of Automated Auditory Evoked Potential Performed in Different Settings and the Factors Associated with Referred Cases.
Introduction For the population with risk factors for hearing loss, the first option to assess the hearing status is the performance of the automated brainstem auditory evoked potential (BAEP) test because of its efficacy in identifying retrocochlear hearing loss. Objective To verify the outcomes of automated BAEP performed in different settings as well as the factors associated with the prevalence of hearing impairment. Methods Cross-sectional study conducted from October of 2014 to May of 2015. The sample consisted of 161 infants with at least one risk factor for hearing loss who underwent automated BAEP during the hospital stay or at the outpatient clinic. After 30 days, the altered cases were referred for BAEP diagnosis. Results One hundred and thirty-eight infants (86%) had a result of "pass" and 23 (14%) of "failure" in the automated BAEP. There was no statistically significant difference in the rate of "referred" results between examinations performed in different settings. The infants' ages did not influence the number of abnormal cases. All of the 23 infants who presented a "referred" result in the automated BAEP, unilateral or bilateral, were sent for BAEP diagnosis, and out of these, 9 (39%) remained with at least some degree of alteration. The average age of diagnosis was 2.7 months. Conclusion The results of the automated BAEP were similar when performed during hospitalization or after discharge. Neither the age at the examination nor the gender of the patient influenced the prevalence of hearing loss.


Measurement of fingertip blood flow using thermal clearance reflects anastomotic rather than nutrient blood flow.
A thermal clearance probe was used to measure fingertip blood flow. When flow was occluded the baseline value was reproducible (coefficient of variation 2% between subjects), whereas basal and maximum flow were poorly reproducible even within subjects. Synchronous changes in thermal clearance were seen when two probes were used on fingers and toes of different limbs (r = 0.77 - 0.97), in keeping with a central control mechanism. Fingertip blood flow, as measured by thermal clearance, correlated with Po2 of venous blood draining from the dorsum of the hand (r = 0.72 - 0.92). Contralateral hand cooling caused a sharp reduction of fingertip thermal clearance by 44.2 +/- 3.7%. Thermal clearance traces were damped in fingers with heavy keratinization, and improved when keratin was removed. Comparisons with venous occlusion plethysmography (VOP) and photoelectric plethysmography (PPG) showed that thermal clearance correlates with both methods (r = 0.60 - 0.92 for VOP and 0.64 - 0.93 for PPG) but with much integration of the signal and a 10 s lag. It is concluded that the probes used measure predominantly anastomotic flow and not nutrient skin blood flow alone.


neu/ERBB2 cooperates with p53-172H during mammary tumorigenesis in transgenic mice.
Thirty percent of human breast cancers have amplification of ERBB2, often in conjunction with mutations in p53. The most common p53 mutation in human breast cancers is an Arg-to-His mutation at codon 175, an allele that functions in a dominant oncogenic manner in tumorigenesis assays and is thus distinct from loss of p53. Transgenic mice expressing mouse mammary tumor virus-driven neu transgene (MMTV-neu) develop clonal mammary tumors with a latency of 234 days, suggesting that other events are necessary for tumor development. We have examined the role of mutations in p53 in tumor development in these mice. We have found that 37% of tumors arising in these mice have a missense mutations in p53. We have directly tested for cooperativity between neu and mutant p53 in mammary tumorigenesis by creating bitransgenic mice carrying MMTV-neu and 172Arg-to-His p53 mutant (p53-172H). In these bitransgenic mice, tumor latency is shortened to 154 days, indicating strong cooperativity. None of the nontransgenic mice or the p53-172H transgenic mice developed tumors within this time period. Tumors arising in the p53-172H/neu bitransgenic mice were anaplastic and aneuploid and exhibited increased apoptosis, in distinction to tumors arising in p53-null mice, in which apoptosis is diminished. Further experiments address potential mechanisms of cooperativity between the two transgenes. In these bitransgenic mice, we have recapitulated two common genetic lesions that occur in human breast cancer and have shown that p53 mutation is an important cooperating event in neu-mediated oncogenesis.


Gemcitabine versus the combination of cisplatin and etoposide in patients with inoperable non-small-cell lung cancer in a phase II randomized study.
A phase II randomized study was conducted to evaluate the efficacy and toxicity of gemcitabine (GEM) versus the combination of cisplatin and etoposide (EP) in Chinese patients with inoperable (stage III or IV) non-small-cell lung cancer (NSCLC). From March 1995 to February 1996, 53 patients were enrolled onto the study: 27 onto the GEM arm and 26 onto the EP arm. In the GEM arm, gemcitabine 1,250 mg/m2 was given as a 30-minute intravenous (i.v.) infusion on days 1, 8, and 15 of each 28-day cycle. In the EP arm, cisplatin 80 mg/m2 was given on day 1 and etoposide 80 mg/m2 was given on days 1, 2, and 3 of each 28-day cycle. Twenty-six patients are assessable for treatment response on the GEM arm and 24 on the EP arm. Five patients (19.2%) on the GEM arm and five patients (20.8%) on the EP arm achieved a partial response (PR). No complete responses were attained on either treatment arm. All patients enrolled onto the study were eligible for toxicity assessment. The main toxicities were myelosuppression and vomiting, which included World Health Organization (WHO) grade 3 or 4 leukopenia (3.7%), thrombocytopenia (7.4%), anemia (7.4%), and nausea/vomiting (3.7%) on the GEM arm, and WHO grade 3 or 4 leukopenia (30.8%), thrombocytopenia (7.7%), anemia (15.4%), and nausea/vomiting (34.6%) on the EP arm. The median survival time was 37 weeks on the GEM arm and 48 weeks on the EP arm. Gemcitabine is a well-tolerated chemotherapeutic agent for NSCLC. The antitumor activity was promising, with a 19.2% single-drug response rate, when compared with EP combination chemotherapy, which had a response rate of 20.8%. The safety profile is better than that of EP treatment.


Comparison of a subjective and an objective measure of physical activity in a population sample.
The aim of this study was to compare physical activity components in the long, self-administrated version of IPAQ with an accelerometer in a population sample. In total 980 subjects (18-65 years) wore an accelerometer (Actigraph) for 7 consecutive days and thereafter filled in the IPAQ. Measures of total physical activity, time spent in moderate and in vigorous activity as well as time spent sitting as assessed by the IPAQ and the Actigraph were compared. The results showed significant low to moderate correlations (Rs = 0.07-0.36) between the 2 instruments and significantly (P < .001) higher values for sitting and vigorous intensity physical activity from the IPAQ compared with the Actigraph. The higher the values reported by the IPAQ the bigger differences were seen between the instruments. Comparison between the tertiles of total physical activity by the 2 instruments showed significant overall association with consistent agreement in the low and the high tertiles. The long form of IPAQ is a valid measure of physical activity in population research. However, the IPAQ likely overestimates actual physical activity as shown by its limited ability to classify adults into low and high categories of physical activity based on accelerometer data.


Lipoic acid mitigates bisphenol A-induced testicular mitochondrial toxicity in rats.
Bisphenol A (BPA) is one of the highest volume chemicals produced worldwide. BPA is used in the production of polycarbonate plastics and epoxy resins used in manufacturing plastic baby bottles and lining of food cans. In this study, we investigated the BPA-induced testicular oxidative stress and perturbation of mitochondrial marker enzymes in male albino rats and its amelioration by α-lipoic acid (LA). Rats were administered a dose of BPA (10 mg/kg body weight) orally for 14 days. This resulted in decreased testes weight, total testicular protein content, testicular enzymes such as acid phosphatase, alkaline phosphatase and lactate dehydrogenase and decline in activities of marker mitochondrial enzymes such as succinate dehydrogenase, malate dehydrogenase, isocitrate dehydrogenase, monoamine oxidase and NADH dehydrogenase. The serum testosterone and total antioxidant status were reduced. Besides, it also affected the activities of testicular antioxidant enzymes such as glutathione reductase, glutathione peroxidase, superoxide dismutase and catalase. BPA also caused lipid peroxidation and decrease in reduced glutathione content of mitochondria. The co-administration of LA (20 mg/kg body weight; orally for 14 days) together with BPA resulted in restoration of the mitochondrial marker enzyme activities and increasing enzymatic and non-enzymatic antioxidants of mitochondria. The obtained results demonstrated that LA has a potential role in mitigating BPA-induced mitochondrial toxicity through antioxidant mechanism or by direct free radical scavenging activity.


Performance of an annular resonator with a polarizer in the annular leg.
Experiments were performed on a CO(2) laser with an annular resonator. The objective of these experiments was to control the polarization in an annular laser and to verify computer code predictions. A Mylar pellicle was placed in the annular leg, and its angular orientation with respect to the optical axis was varied. The pellicle had different transmittances for horizontal and vertical polarizations and also had stress-induced birefringence. At small angles of incidence in the pellicle, the birefringence dominated, and the output had a complicated nature. However, at large angles of incidence, the transmittance difference forced the laser into a well-defined mode for which the near field was horizontally polarized at the top and bottom and the two sides and vertically polarized at intermediate locations. The experimental results were in good agreement with the computer code calculations.


Sector-wide analysis of early childhood development and education in emergencies in Colombia and considerations to strengthen systems globally.
There is an urgent need to strengthen early childhood development and education in emergencies (ECDEiE) globally. Colombia has faced protracted and acute crises for decades. Also, the country has applied a unique approach to holistic and integrated ECDE policy formulation. We argue that these characteristics offer a valuable country-case to identify barriers and levers to the operationalization of ECDEiE. We applied a sector-wide analysis protocol that harmonized components of the Humanitarian Programme Cycle by the Inter-Agency Standing Committee and of a framework to characterize the governance of ECDE systems. The study outlines how the policy and program characteristics identified may represent levers or barriers to the effective operationalization of ECDEiE in Colombia. We discuss how these attributes could be considered in the trans-sectoral dialogue between ECDE and humanitarian actors with the aim of strengthening ECDEiE systems globally.


To meat or not to meat? New perspectives on Neanderthal ecology.
Neanderthals have been commonly depicted as top predators who met their nutritional needs by focusing entirely on meat. This information mostly derives from faunal assemblage analyses and stable isotope studies: methods that tend to underestimate plant consumption and overestimate the intake of animal proteins. Several studies in fact demonstrate that there is a physiological limit to the amount of animal proteins that can be consumed: exceeding these values causes protein toxicity that can be particularly dangerous to pregnant women and newborns. Consequently, to avoid food poisoning from meat-based diets, Neanderthals must have incorporated alternative food sources in their daily diets, including plant materials as well.


Modulation of A-type potassium channels by a family of calcium sensors.
In the brain and heart, rapidly inactivating (A-type) voltage-gated potassium (Kv) currents operate at subthreshold membrane potentials to control the excitability of neurons and cardiac myocytes. Although pore-forming alpha-subunits of the Kv4, or Shal-related, channel family form A-type currents in heterologous cells, these differ significantly from native A-type currents. Here we describe three Kv channel-interacting proteins (KChIPs) that bind to the cytoplasmic amino termini of Kv4 alpha-subunits. We find that expression of KChIP and Kv4 together reconstitutes several features of native A-type currents by modulating the density, inactivation kinetics and rate of recovery from inactivation of Kv4 channels in heterologous cells. All three KChIPs co-localize and co-immunoprecipitate with brain Kv4 alpha-subunits, and are thus integral components of native Kv4 channel complexes. The KChIPs have four EF-hand-like domains and bind calcium ions. As the activity and density of neuronal A-type currents tightly control responses to excitatory synaptic inputs, these KChIPs may regulate A-type currents, and hence neuronal excitability, in response to changes in intracellular calcium.


Genetic analysis of geraniol metabolism during fermentation.
Geraniol produced by grape is the main precursor of terpenols which play a key role in the floral aroma of white wines. We investigated the fate of geraniol during wine fermentation by Saccharomyces cerevisiae. The volatile compounds produced during fermentation of a medium enriched with geraniol were extracted by Stir-bar sorptive extraction and analysed by GC-MS. We were able to detect and quantify geranyl acetate but also citronellyl- and neryl-acetate. The presence of these compounds partly explains the disparition of geraniol. The amounts of terpenyl esters are strain dependant. We demonstrated both by gene overexpression and gene-deletion the involvement of ATF1 enzyme but not ATF2 in the acetylation of terpenols. The affinity of ATF1 enzyme for several terpenols and for isoamyl alcohol was compared. We also demonstrated that OYE2 is the enzyme involved in geraniol to citronellol reduction. Fermenting strain deleted from OYE2 gene produces far less citronellol than wild type strain. Moreover lab strain over-expressing OYE2 allows 87% geraniol to citronellol reduction in bioconversion experiment compared to about 50% conversion with control strain.


High-fidelity Database-free Deep Learning Reconstruction for Real-time Cine Cardiac MRI.
Real-time cine cardiac MRI provides an ECG-free free-breathing alternative to clinical gold-standard ECG-gated breath-hold segmented cine MRI for evaluation of heart function. Real-time cine MRI data acquisition during free breathing snapshot imaging enables imaging of patient cohorts that cannot be imaged with segmented or breath-hold acquisitions, but requires rapid imaging to achieve sufficient spatial-temporal resolutions. However, at high acceleration rates, conventional reconstruction techniques suffer from residual aliasing and temporal blurring, including advanced methods such as compressed sensing with radial trajectories. Recently, deep learning (DL) reconstruction has emerged as a powerful tool in MRI. However, its utility for free-breathing real-time cine MRI has been limited, as database-learning of spatio-temporal correlations with varying breathing and cardiac motion patterns across subjects has been challenging. Zero-shot self-supervised physics-guided deep learning (PG-DL) reconstruction has been proposed to overcome such challenges of database training by enabling subject-specific training. In this work, we adapt zero-shot PG-DL for real-time cine MRI with a spatio-temporal regularization. We compare our method to TGRAPPA, locally low-rank (LLR) regularized reconstruction and database-trained PG-DL reconstruction, both for retrospectively and prospectively accelerated datasets. Results on highly accelerated real-time Cartesian cine MRI show that the proposed method outperforms other reconstruction methods, both visibly in terms of noise and aliasing, and quantitatively.


Incidence and risk of intestinal and extra-intestinal complications in Medicaid patients with inflammatory bowel disease: a 5-year population-based study.
Intestinal and extra-intestinal complications are associated with inflammatory bowel disease (IBD) but their exact incidence is not well known. In order to improve our understanding of their incidence and impact, we assessed the complications associated with ulcerative colitis (UC) and Crohn's disease (CD) in a population-based study in Medicaid patients. We utilized a retrospective cohort design and identified cases of UC and CD using Medi-Cal, the Medicaid program for the State of California. The disease cohort was age- and gender-matched to four controls each and the intestinal and extra-intestinal complications of CD and UC (analyzed separately) were studied over a period of 5 years following the initial diagnosis. For UC, the total number of intestinal complications, per 100 cases, was 92 observed compared to 21 expected; the total number of extra-intestinal complications was 42 observed compared to 30 expected. For CD, the number of intestinal complications was 81 observed compared to 20 expected and for extra-intestinal complications, 37 observed compared to 26 expected (all p < 0.001). For both UC and CD, bleeding was the most frequently seen intestinal complication, while the most common extra-intestinal complication was osteoporosis. IBD is associated with several intestinal and extra-intestinal complications of variable incidence and risk. Success of therapeutic regimens should be measured by decreases in incidence, risks, and costs of these complications, in addition to the usual impact on disease activity.


Diethylstilbesterol has gender-specific effects on weight gain and bone development in mice.
Neonatal exposure to diethylstilbesterol (DES) in female mice programs estrogen-sensitive tissues, resulting in greater body weight gain and positive effects on bone architecture at adulthood. Using the CD-1 mouse model, the objective of the present study was to examine how short-term neonatal exposure to DES modulates weight gain as well as bone mineral density (BMD), bone strength, and bone microarchitecture in both males and females at adulthood. Male and female offspring (n = 8-12 pups/treatment/gender) were randomized to DES (2 mg/kg bw/d) or control (corn oil) from postnatal day 1 to 5 (subcutaneous injection, once daily) and sacrificed at 4 mo of age. Body weight was measured weekly, while bone mineral, strength, and microarchitecture were measured at 4 mo of age. DES treatment resulted in significantly higher body weight in females but lower weight in males at 4 mo of age. In DES-treated females, markedly higher BMD of lumbar vertebrae (LV1-LV3) was translated into significantly stronger LV2 that was more resistant to fracture; similar effects were observed at the femur midpoint. At the spine, males had a markedly lower BMD and peak load, suggesting an adverse effect. Microstructural analyses demonstrated that functional changes in femurs, i.e., peak load, were primarily due to modulation of cortical bone. In conclusion, neonatal exposure to DES exerted gender-specific effects on body weight gain and bone health.


Acute lymphoblastic leukemia.
The inaugural NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for acute lymphoblastic leukemia (ALL) were developed as a result of meetings convened by a multi-disciplinary panel of experts in 2011. These NCCN Guidelines provide recommendations on the diagnostic evaluation and workup for ALL, risk assessment, risk-stratified treatment approaches based on the Philadelphia chromosome status and age (adults vs. adolescents/young adults), assessment of minimal residual disease, and supportive care considerations. It is recommended that patients be treated at specialized centers with expertise in the management of ALL.


The effect of antilymphocyte induction therapy on renal allograft survival. A meta-analysis of individual patient-level data. Anti-Lymphocyte Antibody Induction Therapy Study Group.
Randomized, controlled trials have not shown that the perioperative use of antilymphocyte antibodies (induction therapy) improves survival of cadaveric kidney allografts. This study combined individual patient-level data from published trials to examine the effect of induction therapy on allograft survival. Randomized, controlled trials identified from MEDLINE. Published trials that compared adult recipients of cadaveric renal allografts who did and did not receive antilymphocyte antibodies in the perioperative period were selected if individual patient-level data were available. Individual patient-level data were collected for each of 628 study patients. Multivariable Cox proportional hazards regression was used to estimate the effect of induction therapy on allograft survival. The adjusted rate ratio for allograft failure with induction therapy compared with conventional therapy was 0.62 (95% CI, 0.43 to 0.90) (P = 0.012) over 2 years and 0.82 (CI, 0.62 to 1.09) (P = 0.17) over 5 years. The effect of induction therapy on allograft survival diminished over time; no benefit overall was seen after 2 years after transplantation (rate ratio, 1.13 [CI, 0.72 to 1.78]) (P > 0.2). Greater HLA-DR mismatch, delayed allograft function, diabetes mellitus in the recipient, African-American ethnicity of the recipient, and presensitization (panel-reactive antibody levels > or = 20%) were significantly associated with allograft failure at 5 years. Among high-risk patients, only those who were presensitized benefited from induction therapy at 2 years (rate ratio, 0.12 [CI, 0.03 to 0.44]) (P = 0.001). Results were similar at 5 years. Using individual-level data, this study showed a benefit of induction therapy at 2 years, particularly among presensitized patients. Although the benefit of this therapy subsequently waned, presensitized patients continued to have benefit at 5 years.


A Comprehensive Measure of Lifeyears Lost due to COVID-19 in 2020: A Comparison across Countries and with Past Disasters.
Typically, disaster damages are measured separately in four dimensions: fatalities, injuries, dislocations, and the financial damage that they wreak. Noy (2016) developed a lifeyears index of disaster damage which aggregates these disparate measures. Here, we use this lifeyears index to assess the costs of the COVID-19 pandemic across countries and compare these costs to the average annual costs of all other disasters that have occurred in all countries in the past 20 years. We find that the costs of the pandemic, measured for 2020, far outweigh the annual costs associated with other disasters in the past two decades. It is the economic loss that dominates this impact. The human and social implications of this economic loss are plausibly much greater than the direct toll in mortality and morbidity in almost all countries. Finally, it is small countries like the Maldives and Guyana that have experienced the most dramatic and painful crisis, largely under the radar of the world's attention. Our conclusion from these findings is not that governments' policy reactions were unwarranted. If anything, we find that the loss of lifeyears is correlated positively across the three dimensions we examine. Countries that experienced a deeper health crisis also experienced a deeper economic one.


A novel role for ATM in regulating proteasome-mediated protein degradation through suppression of the ISG15 conjugation pathway.
Ataxia Telangiectasia (A-T) is an inherited immunodeficiency disorder wherein mutation of the ATM kinase is responsible for the A-T pathogenesis. Although the precise role of ATM in A-T pathogenesis is still unclear, its function in responding to DNA damage has been well established. Here we demonstrate that in addition to its role in DNA repair, ATM also regulates proteasome-mediated protein turnover through suppression of the ISG15 pathway. This conclusion is based on three major pieces of evidence: First, we demonstrate that proteasome-mediated protein degradation is impaired in A-T cells. Second, we show that the reduced protein turnover is causally linked to the elevated expression of the ubiquitin-like protein ISG15 in A-T cells. Third, we show that expression of the ISG15 is elevated in A-T cells derived from various A-T patients, as well as in brain tissues derived from the ATM knockout mice and A-T patients, suggesting that ATM negatively regulates the ISG15 pathway. Our current findings suggest for the first time that proteasome-mediated protein degradation is impaired in A-T cells due to elevated expression of the ISG15 conjugation pathway, which could contribute to progressive neurodegeneration in A-T patients.


Pharmacokinetics of digoxin in the rat.
Previous studies on the pharmacokinetics of 3H-digoxin in the rat have been based on total radioactivity in the plasma, even though the drug is extensively metabolized in this species. A comparison of total radioactivity vs. unchanged drug in rat plasma after administration of 3H-digoxin clearly showed the need to separate digoxin from its metabolites. The pharmacokinetics of digoxin were therefore examined using solvent extraction and thin-layer chromatography to isolate unchanged drug. Digoxin levels after a 1 mg/kg iv dose were measured in the plasma and urine of adult male rats in which the bile duct or the ureters had been ligated, as well as in sham-operated controls. In all cases, digoxin concentrations were best described by a two-compartment open model. Digoxin was rapidly eliminated from the plasma of controls, with a half-life of 2.5 hr, a volume of distribution of 3.6 liter/kg, and a renal clearance somewhat lower than the glomerular filtration rate. No significant change in these parameters was observed in rats with bile duct ligation. The total body clearance of 5.77 ml/min in the controls was reduced by only 10% in the bile duct-ligated rats. In animals with bilateral ureter ligation, the body clearance was reduced by 30% and the plasma half-life of digoxin was increased to 4 hr, although no significant change in the apparent volume of distribution was noted. Approximately 60% of the total body clearance was unaffected by bile duct and ureter ligations, and was assumed to be due to biotransformation. Biliary excretion was found to be important for digoxigenin bisdigitoxoside, inasmuch as rats with bile duct ligation showed elevated metabolite levels in the plasma as well as a 3-fold increase in renal excretion of the bisglycoside.


An improved serodiagnostic procedure for visceral leishmaniasis.
The enzyme-linked immunosorbent assay (ELISA) is a sensitive and specific serodiagnostic method for leishmaniasis. In this report, we describe how this versatile assay can be improved by the use of protein A or protein G conjugates for the specific detection of Leishmania antibody in the sera of patients with visceral leishmaniasis. In direct comparisons with anti-immunoglobulin conjugate, enzyme-linked protein A gave significantly higher absorbance values for positive sera without a corresponding increase in absorbance values for sera from normal individuals or from patients with other diseases known to cross-react with leishmaniasis. The effect was to increase the distance between positive and negative values, which aided in the interpretation of the results. This also permitted visual distinction between positive sera and negative or weakly reactive sera. The assay was effective using either blood or serum as the source of primary antibody. A further advantage of protein A over anti-Ig conjugate was its ability to detect specific antibody in dog as well as human sera. Finally, we demonstrated the usefulness of the protein A ELISA with a recombinant leishmania antigen, gp63.


Development of glaucoma after phacoemulsification for removal of cataracts in dogs: 22 cases (1987-1997).
To determine factors contributing to glaucoma after lens extraction via phacoemulsification in dogs. Retrospective study. 22 dogs (29 eyes) with glaucoma and 21 dogs (30 eyes) without glaucoma after phacoemulsification. Medical record review. Eyes at increased risk for glaucoma included those of Boston Terriers, those with uveal or retinal abnormalities before surgery, and those with intraoperative intraocular hemorrhage. Significant differences between groups were not detected for incidence of preoperative lens-induced uveitis, presence of an intraocular lens, or frequency of an acute postoperative increase in intraocular pressure. Glaucoma developed (mean +/- SD) 12.8+/-14.1 months (median, 10 months; range, 0.25 to 55 months) after surgery. Eighteen of 29 (62%) eyes with potential for vision after onset of glaucoma retained vision for a mean of 16.5+/-12.8 months (median, 10.8 months; range, 1.5 to 37 months) after glaucoma was diagnosed. Most of these eyes still had vision at the conclusion of the study period. Risk factors identified by this study will aid in preoperative counseling of clients and refining selection criteria for candidates for phacoemulsification. Careful follow-up for the remainder of the dog's life after surgery may improve long-term success rates by permitting early intervention before intraocular pressure increases substantially and vision is irreversibly lost. Surgery for cataracts may still be worthwhile in dogs with increased risk of glaucoma, especially if elderly, because of the lengthy period to onset of glaucoma after surgery and the beneficial effects of treatment after glaucoma develops.


Ensemble Deep Learning for Cervix Image Selection toward Improving Reliability in Automated Cervical Precancer Screening.
Automated Visual Examination (AVE) is a deep learning algorithm that aims to improve the effectiveness of cervical precancer screening, particularly in low- and medium-resource regions. It was trained on data from a large longitudinal study conducted by the National Cancer Institute (NCI) and has been shown to accurately identify cervices with early stages of cervical neoplasia for clinical evaluation and treatment. The algorithm processes images of the uterine cervix taken with a digital camera and alerts the user if the woman is a candidate for further evaluation. This requires that the algorithm be presented with images of the cervix, which is the object of interest, of acceptable quality, i.e., in sharp focus, with good illumination, without shadows or other occlusions, and showing the entire squamo-columnar transformation zone. Our prior work has addressed some of these constraints to help discard images that do not meet these criteria. In this work, we present a novel algorithm that determines that the image contains the cervix to a sufficient extent. Non-cervix or other inadequate images could lead to suboptimal or wrong results. Manual removal of such images is labor intensive and time-consuming, particularly in working with large retrospective collections acquired with inadequate quality control. In this work, we present a novel ensemble deep learning method to identify cervix images and non-cervix images in a smartphone-acquired cervical image dataset. The ensemble method combined the assessment of three deep learning architectures, RetinaNet, Deep SVDD, and a customized CNN (Convolutional Neural Network), each using a different strategy to arrive at its decision, i.e., object detection, one-class classification, and binary classification. We examined the performance of each individual architecture and an ensemble of all three architectures. An average accuracy and F-1 score of 91.6% and 0.890, respectively, were achieved on a separate test dataset consisting of more than 30,000 smartphone-captured images.


Forskolin stimulates prostaglandin synthesis in rabbit heart by a mechanism that requires calcium and is independent of cyclic AMP.
Infusion of forskolin, an adenylate cyclase activator, in concentrations (2 microM) that do not alter basal prostaglandin (PG) synthesis inhibit synthesis of PG elicited by isoproterenol in rabbit heart. This inhibitory action of forskolin appears to be dependent on cyclic AMP (cAMP). Bolus injection of forskolin (75 nmol), however, was found to stimulate PG synthesis in rabbit heart. The purpose of this study was to elucidate the mechanism of the stimulatory action of forskolin on PG synthesis (prostaglandin I2 measured as 6-ketoprostaglandin F1 alpha [6-keto-PGF1 alpha]) in isolated perfused rabbit heart. Forskolin enhanced PG production in a dose-dependent manner. 1,9-Dideoxyforskolin, a forskolin analogue devoid of adenylate cyclase-stimulating activity, also enhanced PG synthesis. The cAMP analogue chlorophenylthio-cAMP failed to stimulate output of 6-keto-PGF1 alpha, although this agent produced dose-related changes in mechanical function in rabbit heart. Furthermore, the adenylate cyclase inhibitor (-)-N6-(R-phenylisopropyl)adenosine potentiated, whereas the phosphodiesterase inhibitor cilostamide attenuated, forskolin-stimulated PG production. (-)-N6-(R-Phenylisopropyl)adenosine and cilostamide had no effect on the mechanical actions of chlorophenylthio-cAMP, suggesting selectivity of these agents for adenylate cyclase and phosphodiesterase, respectively. 6-Keto-PGF1 alpha output elicited by forskolin was abolished by reduction of calcium in the perfusion fluid as well as by the calcium channel blocker diltiazem. The intracellular calcium antagonists TMB-8 and ryanodine also abolished forskolin-stimulated PG synthesis in rabbit heart. PG synthesis stimulated by 1,9-dideoxyforskolin was also prevented by reduced extracellular calcium, diltiazem, and ryanodine. The calmodulin antagonists trifluoperazine, W-7, and calmidazolium failed to significantly alter PG production in response to forskolin. These results indicate that forskolin-stimulated PG synthesis in rabbit heart is independent of cAMP and requires calcium from both extracellular and intracellular sources.


Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. Incidence rates are increasing in the United States. Monitoring incidence, survival, and mortality rates within at-risk populations can facilitate control efforts. Age-adjusted incidence trends for HCC were examined in the Surveillance, Epidemiology, and End Results (SEER) registries from 1975 to 2005. Age-specific rates were examined for birth cohorts born between 1900 and 1959. Age-adjusted incidence and cause-specific survival rates from 1992 to 2005 were examined in the SEER 13 registries by race/ethnicity, stage, and treatment. United States liver cancer mortality rates were also examined. Age-adjusted HCC incidence rates tripled between 1975 and 2005. Incidence rates increased in each 10-year birth cohort from 1900 through the 1950s. Asians/Pacific Islanders had higher incidence and mortality rates than other racial/ethnic groups, but experienced a significant decrease in mortality rates over time. From 2000 to 2005, marked increases in incidence rates occurred among Hispanic, black, and white middle-aged men. Between 1992 and 2004, 2- to 4-year HCC survival rates doubled, as more patients were diagnosed with localized and regional HCC and prognosis improved, particularly for patients with reported treatment. Recent 1-year survival rates remained, however, less than 50%. HCC incidence and mortality rates continue to increase, particularly among middle-aged black, Hispanic, and white men. Screening of at-risk groups and treatment of localized-stage tumors may contribute to increasing HCC survival rates in the United States. More progress is needed.


Evidence from Finland and Sweden on the relationship between early-life diseases and lifetime childlessness in men and women.
The percentage of people without children over their lifetime is approximately 25% in men and 20% in women. Individual diseases have been linked to childlessness, mostly in women, yet we lack a comprehensive picture of the effect of early-life diseases on lifetime childlessness. We examined all individuals born in 1956-1968 (men) and 1956-1973 (women) in Finland (n = 1,035,928) and Sweden (n = 1,509,092) to the completion of their reproductive lifespan in 2018. Leveraging nationwide registers, we associated sociodemographic and reproductive information with 414 diseases across 16 categories, using a population and matched-pair case-control design of siblings discordant for childlessness (71,524 full sisters and 77,622 full brothers). The strongest associations were mental-behavioural disorders (particularly among men), congenital anomalies and endocrine-nutritional-metabolic disorders (strongest among women). We identified new associations for inflammatory and autoimmune diseases. Associations were dependent on age at onset and mediated by singlehood and education. This evidence can be used to understand how disease contributes to involuntary childlessness.


Tumor suppressor ras association domain family 5 (RASSF5/NORE1) mediates death receptor ligand-induced apoptosis.
Epigenetic silencing of RASSF (Ras association domain family) genes RASSF1 and RASSF5 (also called NORE1) by CpG hypermethylation is found frequently in many cancers. Although the physiological roles of RASSF1 have been studied in some detail, the exact functions of RASSF5 are not well understood. Here, we show that RASSF5 plays an important role in mediating apoptosis in response to death receptor ligands, TNF-α and TNF-related apoptosis-inducing ligand. Depletion of RASSF5 by siRNA significantly reduced TNF-α-mediated apoptosis, likely through its interaction with proapoptotic kinase MST1, a mammalian homolog of Hippo. Consistent with this, siRNA knockdown of MST1 also resulted in resistance to TNF-α-induced apoptosis. To further study the role of Rassf5 in vivo, we generated Rassf5-deficient mouse. Inactivation of Rassf5 in mouse embryonic fibroblasts (MEFs) resulted in resistance to TNF-α- and TNF-related apoptosis-inducing ligand-mediated apoptosis. Importantly, Rassf5-null mice were significantly more resistant to TNF-α-induced apoptosis and failed to activate Mst1. Loss of Rassf5 also resulted in spontaneous immortalization of MEFs at earlier passages than the control MEFs, and Rassf5-null immortalized MEFs, but not the immortalized wild type MEFs, were fully transformed by K-RasG12V. Together, our results demonstrate a direct role for RASSF5 in death receptor ligand-mediated apoptosis and provide further evidence for RASSF5 as a tumor suppressor.


Efficacy of Polyunsaturated Fatty Acids on Inflammatory Markers in Patients Undergoing Dialysis: A Systematic Review with Network Meta-Analysis of Randomized Clinical Trials.
The effects of polyunsaturated fatty acids (PUFAs) on inflammatory markers among patients receiving dialysis have been discussed for a long time, but previous syntheses made controversial conclusion because of highly conceptual heterogeneity in their synthesis. Thus, to further understanding of this topic, we comprehensively gathered relevant randomized clinical trials (RCTs) before April 2019, and two authors independently extracted data of C-reactive protein (CRP), high-sensitivity C-reactive protein (hs-CRP), and interleukin-6 (IL-6) for conducting network meta-analysis. Eighteen eligible RCTs with 962 patients undergoing dialysis were included in our study. The result showed that with placebo as the reference, PUFAs was the only treatment showing significantly lower CRP (weighted mean difference (WMD): -0.37, 95% confidence interval (CI): -0.07 to -0.68), but the CRP in PUFAs group was not significantly lower than vitamin E, PUFAs plus vitamin E, or medium-chain triglyceride. Although no significant changes were noted for hs-CRP and IL-6 levels, PUFAs showed the best ranking among treatments according to surface under the cumulative ranking. Therefore, PUFAs could be a protective option for patients receiving dialysis in clinical practice.


The effects of sleep debt on risk perception, risk attraction and betting behavior during a blackjack style gambling task.
Gamblers often gamble while experiencing fatigue due to sleep deprivation or cumulative sleep debt. Such fatigue has been shown to make decision makers behave more riskily. The present study aimed to test the role of two cognitive processes, risk perception and risk attraction, in this effect. Two hundred and two participants played twelve hands of a black-jack style card game while either fatigued or reasonably alert. Findings showed that both fatigued and alert participants rated higher risk bets as more risky than lower risk bets, suggesting risk perception was unaffected by fatigue. However, fatigued participants did not rate higher risk bets as less attractive than lower risk bets, and reduced the size of their wager to a lesser extent when objective risk increased. These findings are discussed in relation to the effects of fatigue on motivated tasks and the need for gamblers to be aware of the effects of fatigue.


Myelomatous Pleural Effusion: A Rare Involvement in Myeloma.
Extramedullary disease (EMD) incidence is between 7% and 18% in multiple myeloma. Overall survival of patients who develop EMD is significantly shorter than that of patients without EMD. Malignant myelomatous pleural effusions (MPEs) are rarely observed, occurring in less than 1% of cases. The diagnosis of MPE was confirmed by the detection of myeloma cells in the pleural fluid using flow cytometric analyses. We present a case of a 67-year-old male patient with IgG-kappa myelom. After a few line treatment regimens, he was admitted to hospital with back pain and blurred consciousness, and pleural effusion was detected. Pleural fluid analysis showed malignant plasma cells. It is a rare presentation of multiple myeloma, but important in diagnosis.


A Novel Mouse Model of Enteric Vibrio parahaemolyticus Infection Reveals that the Type III Secretion System 2 Effector VopC Plays a Key Role in Tissue Invasion and Gastroenteritis.
The Gram-negative marine bacterium Vibrio parahaemolyticus is a common cause of infectious gastroenteritis due to the ingestion of contaminated seafood. Most virulent V. parahaemolyticus strains encode two type III secretion systems (T3SS1 and T3SS2); however, the roles they and their translocated effectors play in causing intestinal disease remain unclear. While studies have identified T3SS1 effectors as responsible for killing epithelial cells in culture, the T3SS2 effectors caused massive epithelial cell disruption in a rabbit ileal loop model. Additional models are thus needed to clarify the pathogen-host interactions that drive V. parahaemolyticus-associated gastroenteritis. Germfree mice were infected with a pathogenic clinical isolate of V. parahaemolyticus, RIMD2210633 (RIMD). The pathogen was found to adhere to as well as invade the cecal mucosa, accompanied by severe inflammation and dramatic mucosal damage, including widespread sloughing of infected epithelial cells. Mice infected with a V. parahaemolyticus strain lacking the T3SS1 (POR2) also developed severe pathology, similar to that seen with RIMD. In contrast, the ΔT3SS2 strain (POR3) appeared unable to invade the intestinal mucosa or cause any mucosal pathology. Confirming a role for TS332 effectors, a strain expressing the T3SS2 but lacking VopC (POR2ΔvopC), a T3SS2 effector implicated in epithelial cell invasion in culture, was strongly attenuated in invading the intestinal mucosa and in causing gastroenteritis, although infection with this mutant resulted in more pathology than the ΔT3SS2 strain. We thus present an experimental system that enables further characterization of T3SS effectors as well as the corresponding host inflammatory response involved in the gastroenteritis caused by invasive V. parahaemolyticusIMPORTANCEVibrio parahaemolyticus causes severe gastroenteritis following consumption of contaminated seafood. Global warming has allowed this pathogen to spread worldwide, contributing to recent outbreaks. Clinical isolates are known to harbor an array of virulence factors, including T3SS1 and T3SS2; however, the precise role these systems play in intestinal disease remains unclear. There is an urgent need to improve our understanding of how V. parahaemolyticus infects hosts and causes disease. We present a novel mouse model for this facultative intracellular pathogen and observe that the T3SS2 is essential to pathogenicity. Moreover, we show that the T3SS2 effector VopC, previously shown to be a Rac and Cdc42 deamidase that facilitates bacterial uptake by nonphagocytic cells, also plays a key role in the ability of V. parahaemolyticus to invade the intestinal mucosa and cause gastroenteritis. This experimental model thus provides a valuable tool for future elucidation of virulence mechanisms used by this facultative intracellular pathogen during in vivo infection.


The algorithmic complexity of neural spike trains increases during focal seizures.
The interspike interval spike trains of spontaneously active cortical neurons can display nonrandom internal structure. The degree of nonrandom structure can be quantified and was found to decrease during focal epileptic seizures. Greater statistical discrimination between the two physiological conditions (normal vs seizure) was obtained with measurements of context-free grammar complexity than by measures of the distribution of the interspike intervals such as the mean interval, its standard deviation, skewness, or kurtosis. An examination of fixed epoch data sets showed that two factors contribute to the complexity: the firing rate and the internal structure of the spike train. However, calculations with randomly shuffled surrogates of the original data sets showed that the complexity is not completely determined by the firing rate. The sequence-sensitive structure of the spike train is a significant contributor. By combining complexity measurements with statistically related surrogate data sets, it is possible to classify neurons according to the dynamical structure of their spike trains. This classification could not have been made on the basis of conventional distribution-determined measures. Computations with more sophisticated kinds of surrogate data show that the structure observed using complexity measures cannot be attributed to linearly correlated noise or to linearly correlated noise transformed by a static monotonic nonlinearity. The patterns in spike trains appear to reflect genuine nonlinear structure. The limitations of these results are also discussed. The results presented in this article do not, of themselves, establish the presence of a fine-structure encoding of neural information.


Inequalities in lung cancer care of elderly patients with schizophrenia: an observational cohort study.
Cancer mortality is higher in individuals with schizophrenia, a finding that may be due, in part, to inequalities in care. We evaluated gaps in lung cancer diagnosis, treatment, and survival among elderly individuals with schizophrenia. The Surveillance, Epidemiology, and End Results database linked to Medicare records was used to identify patients 66 years or older with primary non-small cell lung cancer. Lung cancer stage, diagnostic evaluation, and rates of stage-appropriate treatment were compared among patients with and without schizophrenia using unadjusted and multiple regression analyses. Survival was compared among groups using Kaplan-Meier methods. Of the 96,702 patients with non-small cell lung cancer in the Surveillance, Epidemiology, and End Results database, 1303 (1.3%) had schizophrenia. In comparison with the general population, patients with schizophrenia were less likely to present with late-stage disease after controlling for age, sex, marital status, race/ethnicity, income, histology, and comorbidities (odds ratio = 0.82, 95% confidence interval = 0.73-0.93) and were less likely to undergo appropriate evaluation (p < .050 for all comparisons). Adjusting for similar factors, patients with schizophrenia were also less likely to receive stage-appropriate treatment (odds ratio = 0.50, 95% confidence interval = 0.43-0.58). Survival was decreased among patients with schizophrenia (mean survival = 22.3 versus 26.3 months, p = .002); however, no differences were observed after controlling for treatment received (p = .40). Elderly patients with schizophrenia present with earlier stages of lung cancer but are less likely to undergo diagnostic evaluation or to receive stage-appropriate treatment, resulting in poorer outcomes. Efforts to increase treatment rates for elderly patients with schizophrenia may lead to improved survival in this group.


Pharmacokinetics of ertapenem in critically ill patients receiving continuous venovenous hemodialysis or hemodiafiltration.
This study characterizes the pharmacokinetics of ertapenem, a carbapenem antibiotic, in critically ill adult subjects receiving continuous renal replacement therapy (CRRT). Eight critically ill patients with suspected/known Gram-negative infections receiving continuous venovenous hemodialysis (CVVHD) or continuous venovenous hemodiafiltration (CVVHDF) and ertapenem were enrolled. One gram of ertapenem was infused over 30 min. Predialyzer blood samples were drawn with the first dose of ertapenem from the hemodialysis tubing at time zero, 30 min, and 1, 2, 4, 8, 12, 18, and 24 h after the start of the ertapenem infusion. Effluent was collected at the same time points. Ertapenem total serum, unbound serum, and effluent concentrations from all eight subjects were used simultaneously to perform a population compartmental pharmacokinetic modeling procedure using NONMEM. Monte Carlo simulations were performed to evaluate the ability of several ertapenem dosing regimens (500 mg once daily, 750 mg once daily, 500 mg twice daily, and 1,000 mg once daily) to obtain effective unbound serum concentrations above 0.5, 1, and 2 μg/ml. For our simulated patients, all regimens produced unbound ertapenem concentrations above 2 μg/ml for 40% of the dosing interval for at least 96% of simulated patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00877370.).


Mitotic kinesin inhibitors induce mitotic arrest and cell death in Taxol-resistant and -sensitive cancer cells.
Taxanes are powerful chemotherapy agents that target the microtubule cytoskeleton, leading to mitotic arrest and cell death; however, their clinical efficacy has been hampered due to the development of drug resistance. Therefore, other proteins involved in spindle assembly are being examined as potential targets for anticancer therapy. The mitotic kinesin, Eg5 is critical for proper spindle assembly; as such, inhibition of Eg5 leads to mitotic arrest making it a potential anticancer target. We wanted to validate Eg5 as a therapeutic target and determine if Eg5 inhibitors retain activity in Taxol-resistant cells. Using affinity chromatography we first show that the compound HR22C16 is an Eg5 inhibitor and does not interact with other microtubule motor proteins tested. Furthermore, HR22C16 along with its analogs, inhibit cell survival in both Taxol-sensitive and -resistant ovarian cancer cells with at least 15-fold greater efficacy than monastrol, the first generation Eg5 inhibitor. Further analysis with HR22C16-A1, the most potent HR22C16 analog, showed that it retains efficacy in PgP-overexpressing cells, suggesting that it is not a PgP substrate. We further show that HR22C16-A1 induces cell death following mitotic arrest via the intrinsic apoptotic pathway. Interestingly, the combination of HR22C16-A1 with Taxol results in an antagonistic antiproliferative and antimitotic effect, possibly due to the abrogation of Taxol-induced mitotic spindles by HR22C16-A1. Taken together, our results show that Eg5 inhibitors have promising anticancer activity and can be potentially used to overcome Taxol resistance in the clinical setting.


The Dnmt3a PWWP domain reads histone 3 lysine 36 trimethylation and guides DNA methylation.
The Dnmt3a DNA methyltransferase contains in its N-terminal part a PWWP domain that is involved in chromatin targeting. Here, we have investigated the interaction of the PWWP domain with modified histone tails using peptide arrays and show that it specifically recognizes the histone 3 lysine 36 trimethylation mark. H3K36me3 is known to be a repressive modification correlated with DNA methylation in mammals and heterochromatin in Schizosaccharomyces pombe. These results were confirmed by equilibrium peptide binding studies and pulldown experiments with native histones and purified native nucleosomes. The PWWP-H3K36me3 interaction is important for the subnuclear localization of enhanced yellow fluorescent protein-fused Dnmt3a. Furthermore, the PWWP-H3K36me3 interaction increases the activity of Dnmt3a for methylation of nucleosomal DNA as observed using native nucleosomes isolated from human cells after demethylation of the DNA with 5-aza-2'-deoxycytidine as substrate for methylation with Dnmt3a. These data suggest that the interaction of the PWWP domain with H3K36me3 is involved in targeting of Dnmt3a to chromatin carrying that mark, a model that is in agreement with several studies on the genome-wide distribution of DNA methylation and H3K36me3.


Update on the pattern electroretinogram in glaucoma.
To review the efficacy of the pattern electroretinogram (PERG) in early diagnosis of glaucoma. Stimulation parameters of check size and temporal frequency are considered. Analyses of various peaks (P50, N95, the N95/P50) and Fourier steady-state are considered. The relation to visual field defects is explored. The PERG is markedly alterated in glaucoma. It shows amplitude reductions in (still) normal areas of the visual field. Optical imaging on the retina needs to be optimal. Higher temporal frequency (>10 reversals/s) improves the sensitivity to detect glaucoma compared with transient stimulation. The ratio between the amplitudes to 0.8 degrees checks and to 16 degrees checks, "PERG ratio," exploits a check size-specific reduction in early glaucoma and reduces variability. Longitudinal studies suggest that the PERG can indicate incipient glaucoma damage before evidence from the visual field. The PERG is a demanding electrophysiological technique that can serve as a sensitive biomarker for retinal ganglion cell function. With appropriate paradigms, PERG assists in identifying those patients with elevated interocular pressure in whom glaucoma damage is incipient before visual field changes occur.


16S-23S rDNA intergenic sequences indicate that Leuconostoc oenos is phylogenetically homogeneous.
The study of the intra-specific phylogenetic structure of Leuconostoc oenos is essential to understand the participation of several strains in malo-lactic fermentation (MLF). RFLP of the PCR-amplified 16S-23S rDNA intergenic spacer region (ISR) was performed in Leuc. oenos and other related species. The RFLP patterns with seven endonucleases were identical for the 37 Leuc. oenos strains, but differed from those obtained for all other species tested. This method could provide an invaluable insight for molecular identification of the wine leuconostocs. The RFLP relationships of members of the genera Leuconostoc and Weissella were highly similar to those previously reported by 16S and 23S rRNA sequencing studies. The 16S-23S rDNA ISR was sequenced in five strains of Leuc. oenos. A single tRNA(Ala) was detected. The ISR sequence seems to be identical in the two rRNA (rrn) operons found in Leuc. oenos and no significant sequence variation was observed between strains that revealed relative differences as previously shown by PFGE. Results from the present study demonstrated that Leuc. oenos is phylogenetically a very homogeneous species (according to DNA-DNA hybridization studies) and sustain that this species is different from the genus Leuconostoc. The extremely conserved ISR of these organisms suggests that Leus. oenos strains currently isolated and characterized must have spread with the transfer of viticulture rather than coming from indigenous populations.


Spatial updating in virtual reality: the sufficiency of visual information.
Robust and effortless spatial orientation critically relies on "automatic and obligatory spatial updating", a largely automatized and reflex-like process that transforms our mental egocentric representation of the immediate surroundings during ego-motions. A rapid pointing paradigm was used to assess automatic/obligatory spatial updating after visually displayed upright rotations with or without concomitant physical rotations using a motion platform. Visual stimuli displaying a natural, subject-known scene proved sufficient for enabling automatic and obligatory spatial updating, irrespective of concurrent physical motions. This challenges the prevailing notion that visual cues alone are insufficient for enabling such spatial updating of rotations, and that vestibular/proprioceptive cues are both required and sufficient. Displaying optic flow devoid of landmarks during the motion and pointing phase was insufficient for enabling automatic spatial updating, but could not be entirely ignored either. Interestingly, additional physical motion cues hardly improved performance, and were insufficient for affording automatic spatial updating. The results are discussed in the context of the mental transformation hypothesis and the sensorimotor interference hypothesis, which associates difficulties in imagined perspective switches to interference between the sensorimotor and cognitive (to-be-imagined) perspective.


Pulmonary Complications of Opioid Overdose Treated With Naloxone.
We aim to determine whether administration of higher doses of naloxone for the treatment of opioid overdose is associated with increased pulmonary complications. This was a retrospective, observational, cross-sectional study of 1,831 patients treated with naloxone by the City of Pittsburgh Bureau of Emergency Medical Services. Emergency medical services and hospital records were abstracted for data in regard to naloxone dosing, route of administration, and clinical outcomes, including the development of complications such as pulmonary edema, aspiration pneumonia, and aspiration pneumonitis. For the purposes of this investigation, we defined high-dose naloxone as total administration exceeding 4.4 mg. Multivariable analysis was used to attempt to account for confounders such as route of administration and pretreatment morbidity. Patients receiving out-of-hospital naloxone in doses exceeding 4.4 mg were 62% more likely to have a pulmonary complication after opioid overdose (42% versus 26% absolute risk; odds ratio 2.14; 95% confidence interval 1.44 to 3.18). This association remained statistically significant after multivariable analysis with logistic regression (odds ratio 1.85; 95% confidence interval 1.12 to 3.04). A secondary analysis showed an increased risk of 27% versus 13% (odds ratio 2.57; 95% confidence interval 1.45 to 4.54) when initial naloxone dosing exceeded 0.4 mg. Pulmonary edema occurred in 1.1% of patients. Higher doses of naloxone in the out-of-hospital treatment of opioid overdose are associated with a higher rate of pulmonary complications. Furthermore, prospective study is needed to determine the causality of this relationship.


FRETboard: Semisupervised classification of FRET traces.
Förster resonance energy transfer (FRET) is a useful phenomenon in biomolecular investigations, as it can be leveraged for nanoscale measurements. The optical signals produced by such experiments can be analyzed by fitting a statistical model. Several software tools exist to fit such models in an unsupervised manner but lack the flexibility to adapt to different experimental setups and require local installations. Here, we propose to fit models to optical signals more intuitively by adopting a semisupervised approach, in which the user interactively guides the model to fit a given data set, and introduce FRETboard, a web tool that allows users to provide such guidance. We show that our approach is able to closely reproduce ground truth FRET statistics in a wide range of simulated single-molecule scenarios and correctly estimate parameters for up to 11 states. On in vitro data, we retrieve parameters identical to those obtained by laborious manual classification in a fraction of the required time. Moreover, we designed FRETboard to be easily extendable to other models, allowing it to adapt to future developments in FRET measurement and analysis.