Opening the policy blackbox: unravelling the process for changing national diagnostic and treatment guidelines for vivax malaria in seven countries.
The changing global health landscape has highlighted the need for more proactive, efficient and transparent health policy-making. After more than 60 years of limited development, novel tools for vivax malaria are finally available, but need to be integrated into national policies. This paper maps the malaria policy-making processes in seven endemic countries, to identify areas where it can be improved to align with best practices and optimal efficiency. Data were collected during a workshop, convened by the Asia Pacific Malaria Elimination Network's Vivax Working Group in 2019, and subsequent interviews with key stakeholders from Cambodia, Ethiopia, Indonesia, Pakistan, Papua New Guinea (PNG), Sri Lanka and Vietnam. Documentation of policy processes provided by respondents was reviewed. Data analysis was guided by an analytic framework focused on three a priori defined domains: "context," "actors" and "processes". The context of policy-making varied with available funding for malaria, population size, socio-economic status, and governance systems. There was limited documentation of the process itself or terms of reference for involved actors. In all countries, the NMP plays a critical role in initiating and informing policy change, but the involvement of other actors varied considerably. Available evidence was described as a key influencer of policy change; however, the importance of local evidence and the World Health Organization's endorsement of new treatments and diagnostics varied. The policy process itself and its complexity varied but was mostly semi-siloed from other disease specific policy processes in the wider Ministry of Health. Time taken to change and introduce a new policy guideline previously varied from 3 months to 3 years. In the medium to long term, a better alignment of anti-malarial policy-making processes with the overall health policy-making would strengthen health governance. In the immediate term, shortening the timelines for policy change will be pivotal to meet proposed malaria elimination milestones.


Synthesis and resolution of planar-chiral ruthenium-palladium complexes with ECE' pincer ligands.
Feel the pinch! Planar-chiral, cationic, ruthenium-palladium complexes based on eta(6),eta(1)-coordinated ECE' pincer ligands are synthesized as racemic mixtures by reacting ECE'-palladium complexes and [Ru(C(5)R(5))(MeCN)(3)](+) arenophiles (R=H or Me). Chiral resolution of the cationic complexes was achieved by using the chiral counterion [Delta-TRISPHAT](-), and solving the X-ray crystal structure of one diastereoisomer (shown here).


[Public financing of health research in five Latin American countries].
Describe the public subsystems of the national health research systems (SNIS) in five Latin American countries (Argentina, Bolivia, Chile, Paraguay, and Uruguay), emphasizing the types of institutional arrangements in place in each country to promote, develop, and sustain their SNIS, as well as explicit or implicit mechanisms for prioritizing health research projects. The bodies responsible for managing the public resources allocated to finance health research projects in the five countries studied were identified. The types of projects financed were then analyzed-using a matrix constructed by area and object of study-, certain characteristics of the principal investigators, and the sums allocated between 2002 and 2006. Only the countries with greater resources or better developed networks of investigators have formal structures for allocating funds with regular calls for proposals and fixed rules. None of them has explicit comprehensive mechanisms for prioritizing health research. Moreover, the health research priorities in the countries vary widely. In this regard, it is significant that problems such as "nutrition and the environment" or "violence and accidents" receive little attention in most countries. The same holds true for a number of public health issues in some countries. In contrast, the research in the "hard sciences" absorbs up to one-third of the total resources for research. Many questions arise about the ability of these countries to adapt and generate new knowledge, as well as the nearly nonexistent research on social, economic, and cultural determinants, or on health services and systems that have a high impact on groups with limited access to health care. Explicit priorities should be set with stakeholders for the health research agenda, and mechanisms should be adopted for monitoring and following up health research financing by subject and area of study.


Transgenic overexpression of BMP4 increases astroglial and decreases oligodendroglial lineage commitment.
Bone morphogenetic proteins (BMPs) promote astrocytic differentiation of cultured subventricular zone stem cells. To determine whether BMPs regulate the astrocytic lineage in vivo, transgenic mice were constructed that overexpress BMP4 under control of the neuron-specific enolase (NSE) promoter. Overexpression of BMP4 was first detectable by Western analysis on embryonic day 16 and persisted into the adult. The overexpression of BMP4 resulted in a remarkable 40% increase in the density of astrocytes in multiple brain regions accompanied by a decrease in the density of oligodendrocytes ranging between 11 and 26%, depending on the brain region and the developmental stage. No changes in neuron numbers or the pattern of myelination were detected, and there were no gross structural abnormalities. Similar phenotypes were observed in three independently derived transgenic lines. Coculture of transgenic neurons with neural progenitor cells significantly enhanced astrocytic lineage commitment by the progenitors; this effect was blocked by the BMP inhibitor Noggin, indicating that the stimulation of astrogliogenesis was due to BMP4 release by the transgenic neurons. These observations suggest that BMP4 directs progenitor cells in vivo to commit to the astrocytic rather than the oligodendroglial lineage. Further, differentiation of radial glial cells into astrocytes was accelerated, suggesting that radial glia were a source of at least some of the supernumerary astrocytes. Therefore, BMPs are likely important mediators of astrocyte development in vivo.


Rho Guanine Nucleotide Exchange Factor ARHGEF17 Is a Risk Gene for Intracranial Aneurysms.
Intracranial aneurysm (IA) is usually a late-onset disease, affecting 1% to 3% of the general population and leading to life-threatening subarachnoid hemorrhage. Genetic susceptibility has been implicated in IAs, but the causative genes remain elusive. We performed next-generation sequencing in a discovery cohort of 20 Chinese IA patients. Bioinformatics filters were exploited to search for candidate deleterious variants with rare and low allele frequency. We further examined the candidate variants in a multiethnic sample collection of 86 whole exome sequenced unsolved familial IA cases from 3 previously published studies. We identified that the low-frequency variant c.4394C>A_p.Ala1465Asp (rs2298808) of ARHGEF17 was significantly associated with IA in our Chinese discovery cohort (P=7.3×10-4; odds ratio=7.34). It was subsequently replicated in Japanese familial IA patients (P=0.039; odds ratio=4.00; 95% confidence interval=0.832-14.8) and was associated with IA in the large Chinese sample collection comprising 832 sporadic IA-affected and 599 control individuals (P=0.041; odds ratio=1.51; 95% confidence interval=1.02-Inf). When combining the sequencing data of all familial IA patients from 4 different ethnicities (ie, Chinese, Japanese, European American, and French-Canadian), we identified a significantly increased mutation burden for ARHGEF17 (21/106 versus 11/306; P=8.1×10-7; odds ratio=6.6; 95% confidence interval=2.9-15.8) in cases as compared with controls. In zebrafish, arhgef17 was highly expressed in the brain blood vessel. arhgef17 knockdown caused blood extravasation in the brain region. Endothelial lesions were identified exclusively on cerebral blood vessels in the arhgef17-deficient zebrafish. Our results provide compelling evidence that ARHGEF17 is a risk gene for IA.


Low Disclosure of PrEP Nonadherence and HIV-Risk Behaviors Associated With Poor HIV PrEP Adherence in the HPTN 067/ADAPT Study.
We evaluated the relationship between 2 types of social relationships, ie, (1) external support for use of HIV pre-exposure prophylaxis (PrEP) and related study supplies and (2) participants' disclosure of PrEP use and condom use and HIV PrEP adherence among daily-dosing regimen participants in HIV Prevention Trials Network (HPTN) 067, an open-label trial of oral tenofovir (TFV) disoproxil fumarate (TDF) 300 mg/emtricitabine (FTC) 200 mg. Using HPTN 067 survey data, we developed scales examining (1) Low Perceived External Support for PrEP: low perceived support by others for PrEP use or perceived negative reactions to the pill case (scoring ranges from 0 to 2) and (2) Participant-Staff Disclosure Challenges Scale, which identifies challenges to sharing nonuse of PrEP or condoms to study staff (scoring ranges from 0 to 4); these scales are the primary independent variables. Adherence, the dependent variable, was determined using log-transformed plasma TFV concentrations. generalized estimating equation (GEE) linear regression was used to assess the association between both scales and adherence. Participants (n = 161) included HIV-uninfected women in South Africa, and men who have sex with men and transgender women, in Thailand and the United States. In multivariable analyses, higher scores in the Participant-Staff Disclosure Challenges Scale were significantly associated with lower PrEP adherence [exp(β) = 0.62, 95% CI: (0.46 to 0.84); P = 0.002] as were increased days since the last PrEP dose [exp(β) = 0.73, 95% CI: (0.65 to 0.83); P ≤ 0.001]. Given the association with adherence, study staff-participant interactions and participants' disclosure of PrEP challenges may be worthwhile intervention targets for improving PrEP adherence in confirmatory studies.


Blood metal levels and third trimester maternal plasma matrix metalloproteinases (MMPs).
While it is known that in utero exposure to environmental toxicants, namely heavy metals, can adversely affect the neonate, there remains a significant paucity of information on maternal biological changes specific to metal exposures during pregnancy. This study aims at identifying associations between maternal metal exposures and matrix metalloproteinases (MMPs) that are known to be engaged in pregnancy process. Third trimester maternal plasma (n = 1533) from a pregnancy cohort (Maternal-Infant Research on Environmental Chemicals Study, MIREC) were analyzed for MMP-1,-2,-7,-9 and -10 by affinity-based multiplex protein array analyses. Maternal metal concentrations (mercury, cadmium, lead, arsenic and manganese) in 1st and 3rd trimesters exhibited strong correlations (p < 0.05). Multivariate regression models were used to estimate odds ratio (OR) for the association between metal concentrations in quartiles and high (90%) and low (10%) maternal MMP levels. Significant (p < 0.05) metal exposure-related effects were observed with the different MMP isoform responses. MMP profiles were specific to the trimester at which the maternal blood metals were analyzed. Our findings suggest that the profiles of these MMP isoforms vary with the type of metal exposure, blood metal concentrations and the trimester at which metal levels were determined. These new findings on maternal metal-MMP relationships can guide future explorations on toxicity mechanisms relevant to metal exposure-mediated adverse birth outcomes.


A physicochemical study of Al(+3) interactions with edible seaweed biomass in acidic waters.
In this article, a study of the Al(+3) interactions in acidic waters with biomass of different edible seaweeds: brown (Fucus vesiculosus, Saccorhiza polyschides), red (Mastocarpus stellatus, Gelidium sesquipedale, Chondrus crispus), and green (Ulva rigida, Codium tomentosum), has been performed. The influence of both, the initial concentration of metal and the solution pH, on the Al-uptake capacity of the biomass has been analyzed. From preliminary tests, species Fucus vesiculosus and Gelidium sesquipedale have been selected for a more exhaustive analysis. Sorption kinetic studies demonstrated that 60 min are enough to reach equilibrium. The intraparticle diffusion model has been used to describe kinetic data. Equilibrium studies have been carried out at pH values of 1, 2.5, and 4. Langmuir isotherms showed that the best uptake values, obtained at pH 4, were 33 mg/g for F. vesiculosus and 9.2 mg/g for G. sesquipedale. These edible seaweeds have been found particularly effective in binding aluminum metal ions for most of the conditions tested. Physicochemical data reported at these low pH values could be of interest, not only in modeling aluminum-containing antacids-food pharmacokinetic processes produced in the stomach (pH values 1 to 3) but in remediation studies in acidic waters. Aluminum is thought to be linked to neurological disruptions such as Alzheimer's disease. In this article, the adsorption ability of different types of edible seaweeds toward aluminum has been studied. The choice of low pH values is due to the fact that stomach region is acidic with a pH value between 1 and 3 as a consequence of hydrochloric secretion; so physicochemical data reported in this study could be of interest in modeling drug-food interactions, in particular those referring to aluminum-containing antacids-food pharmacokinetic processes produced in the gastrointestinal tract.


Long-Term Oxygen Therapy in COPD Patients Who Do Not Meet the Actual Recommendations.
Chronic respiratory failure due to chronic obstructive pulmonary disease (COPD) is an increasing problem worldwide. Many patients with severe COPD develop hypoxemic respiratory failure during the natural progression of disease. Long-term oxygen therapy (LTOT) is a well-established supportive treatment for COPD and has been shown to improve survival in patients who develop chronic hypoxemic respiratory failure. The degree of hypoxemia is severe when partial pressure of oxygen in arterial blood (PaO2) is ≤55 mmHg and moderate if PaO2 is between 56 and 69 mmHg. Although current guidelines consider LTOT only in patients with severe resting hypoxemia, many COPD patients with moderate to severe disease experience moderate hypoxemia at rest or during special circumstances, such as while sleeping or exercising. The efficacy of LTOT in these patients who do not meet the actual recommendations is still a matter of debate, and extensive research is still ongoing to understand the possible benefits of LTOT for survival and/or functional outcomes such as the sensation of dyspnea, exacerbation frequency, hospitalizations, exercise capacity, and quality of life. Despite its frequent use, the administration of "palliative" oxygen does not seem to improve dyspnea except for delivery with high-flow humidified oxygen. This narrative review will focus on current evidence for the effects of LTOT in the presence of moderate hypoxemia at rest, during sleep, or during exercise in COPD.


Accuracy of prehospital triage of trauma patients by emergency physicians: a retrospective study in western Switzerland.
Accurate identification of major trauma patients in the prehospital setting positively affects survival and resource utilization. Triage algorithms using predictive criteria of injury severity have been identified in paramedic-based prehospital systems. Our rescue system is based on prehospital paramedics and emergency physicians. The aim of this study was to evaluate the accuracy of the prehospital triage performed by physicians and to identify the predictive factors leading to errors of triage. Retrospective study of trauma patients triaged by physicians. Prehospital triage was analyzed using criteria defining major trauma victims (MTVs, Injury Severity Score >15, admission to ICU, need for immediate surgery and death within 48 h). Adequate triage was defined as MTVs oriented to the trauma centre or non-MTV (NMTV) oriented to regional hospitals. One thousand six hundred and eighty-five patients (blunt trauma 96%) were included (558 MTV and 1127 NMTV). Triage was adequate in 1455 patients (86.4%). Overtriage occurred in 171 cases (10.1%) and undertriage in 59 cases (3.5%). Sensitivity and specificity was 90 and 85%, respectively, whereas positive predictive value and negative predictive value were 75 and 94%, respectively. Using logistic regression analysis, significant (P<0.05) predictors of undertriage were head or thorax injuries (odds ratio >2.5). Predictors of overtriage were paediatric age group, pedestrian or 2 wheel-vehicle road traffic accidents (odds ratio >2.0). Physicians using clinical judgement provide effective prehospital triage of trauma patients. Only a few factors predicting errors in triage process were identified in this study.


Proximate Context of HIV-Related Stigma and Women's Use of Skilled Childbirth Services in Uganda.
HIV-related stigma compromises both HIV prevention and treatment and has recently been described as a barrier to utilization of skilled childbirth services in sub-Saharan Africa. This study uses the 2011 Uganda Demographic Health Survey to estimate the associations between HIV-related stigma, measured both at the individual and community level, and use of facility delivery among women. Consistent with theoretical predictions, higher levels of stigma are associated with reduced likelihood of facility delivery. The negative relationship between stigma and facility delivery is especially pronounced when stigma is measured at the community level, highlighting the importance of understanding the proximate context of HIV-related stigma and its potential effects on behavior. Reducing the stigma of HIV will be critical to achieving the twin goals of reducing overall maternal mortality and preventing mother-to-child HIV transmission.


Socio-demographic and clinical determinants of late presentation among patients newly diagnosed with HIV in the Eastern Cape, South Africa.
South Africa recently implemented the 'test and treat' strategy for all HIV-infected individuals receiving diagnosis at the health facility level. However, the impact of this programme in terms of the prevention of HIV transmission, morbidity and mortality associated with HIV can only be maximized if patients are diagnosed early. This study determines the prevalence of late presentation among newly diagnosed HIV-infected individuals and also examines the socio-demographic and clinical determinants for late presentation in health facilities in the Eastern Cape Province, South Africa.In this cross-sectional study, a total of 335 newly diagnosed patients were recruited consecutively between August 2016 and July 2017. Late presenter for HIV care was defined in accordance with the European Late Presenter Consensus working group as a patient who reports for care when the CD4 count is below 350 cells/μL and/or when there is an established AIDS-defining clinical condition, irrespective of CD4 count. Adjusted and unadjusted logistic regression analysis was used to examine the determinants of late HIV diagnosis.Participants' mean age was 33.6 (SD: 10.6). Almost 96% of the participants believed their route of HIV infection was heterosexual sex. Most newly diagnosed HIV-infected patients (60%) were late presenters (CD4+ count ≤350 cells/μL and/or having an AIDS-defining illness in World Health Organisation (WHO)-defined stage III/IV), with 35% presenting with Acquired Immune Deficiency Syndrome (AIDS)-related complications. In the adjusted model, only male sex (AOR: 2.81; CI: 1.51-5.23), no formal education (AOR: 5.63; CI: 1.68-18.85), and overweight body mass category (AOR: 2.45; CI: 1.04-5.75) were independently associated with late HIV diagnosis.The majority of newly diagnosed HIV-infected individuals were late presenters. To maximize the impact of the 'test and treat' policy aimed at reducing new HIV transmissions and preventing the morbidity and mortality associated with HIV, there is a need for programmes to improve early detection of HIV in the study settings. This programme should target males and individuals with no formal education for maximum impact.


Alternate and incidental diagnoses on noncontrast-enhanced spiral computed tomography for acute flank pain.
Our aim was to determine the incidence and spectrum of significant alternate or incidental diagnoses established or suggested on spiral computed tomography (CT) in a large series of patients with suspected renal colic. Records of all patients that had undergone spiral CT (5-mm to 7-mm slice thickness) for acute flank pain during a 5-year period were reviewed. The radiological diagnoses of urinary calculi and obstruction as well as clinical entities not suspected otherwise were analyzed. A total of 4000 CTs had been performed in the evaluation of acute flank pain. Urinary calculi had been identified in 3120 patients (78.0%). There were 398 patients (9.9%) who had an alternate cause of flank pain or an incidentally detected condition on CT. Of these patients, 102 (25.6%) had more than one additional finding. A total of 153 clinical conditions had been identified mimicking flank pain secondary to calculus and obstruction. In 47 patients (1.2%), incidental solid masses had been detected. Spiral CT is a valuable technique in the evaluation of acute flank pain with uncertain clinical diagnosis. A wide spectrum of alternate and additional diagnoses including abdominal solid organ tumors and other significant abdominal conditions such as pancreatitis can be established or suggested on spiral CT performed for suspected acute urinary colic.


Comprehensive case management in the private sector for patients with severe mental illness.
Intensive case management for severely psychiatrically ill patients is a relatively new phenomenon in the private sector. The authors describe a comprehensive case management program designed at Blue Cross Blue Shield of Massachusetts to meet the needs of the most severely ill psychiatric patients in a private managed care environment. The case management program emphasizes involvement of patients in creating comprehensive treatment plans; development of a relationship between case managers, patients and their families, and providers; and clinical coordination between the public and private sectors to create individualized treatment plans. The program's case managers are able to flex the benefit limitations of a managed care or indemnity plan to integrate public and private services and can enlist providers outside a managed care network. The paper describes service utilization by the first 33 patients who participated in the program for one year.


Core competencies for disaster medicine and public health.
Effective preparedness, response, and recovery from disasters require a well-planned, integrated effort with experienced professionals who can apply specialized knowledge and skills in critical situations. While some professionals are trained for this, others may lack the critical knowledge and experience needed to effectively perform under stressful disaster conditions. A set of clear, concise, and precise training standards that may be used to ensure workforce competency in such situations has been developed. The competency set has been defined by a broad and diverse set of leaders in the field and like-minded professionals through a series of Web-based surveys and expert working group meetings. The results may provide a useful starting point for delineating expected competency levels of health professionals in disaster medicine and public health.


Guidelines for the clinical and economic evaluation of health care technologies.
The health care system is routinely confronted with promising new technologies. In the past, most new technologies have been integrated into clinical practice without a rigorous demonstration of their effectiveness or efficiency. In order to provide a more rational approach to the adoption and utilization of health technology a comprehensive set of guidelines for both clinical and economic evaluation is proposed. While conceived of as an ideal that is unlikely to be universally met in practice, it is argued that decision making can be improved by striving towards this goal. The clinical guidelines stress the advantages of subjecting major new technologies to randomized controlled trials and insisting upon a demonstration of patient benefit in the application of diagnostic technologies. The economic guidelines stress comparisons with relevant alternative uses of the resources and the assessment of the impact on the quality of life. While application of the guidelines will produce rigorous and useful evidence, the final decisions concerning the allocation of health care resources must rest fundamentally on social value judgements and not solely, or even primarily, on informed expert opinion.


Working Memory Load Modulates Neuronal Coupling.
There is a severe limitation in the number of items that can be held in working memory. However, the neurophysiological limits remain unknown. We asked whether the capacity limit might be explained by differences in neuronal coupling. We developed a theoretical model based on Predictive Coding and used it to analyze Cross Spectral Density data from the prefrontal cortex (PFC), frontal eye fields (FEF), and lateral intraparietal area (LIP). Monkeys performed a change detection task. The number of objects that had to be remembered (memory load) was varied (1-3 objects in the same visual hemifield). Changes in memory load changed the connectivity in the PFC-FEF-LIP network. Feedback (top-down) coupling broke down when the number of objects exceeded cognitive capacity. Thus, impaired behavioral performance coincided with a break-down of Prediction signals. This provides new insights into the neuronal underpinnings of cognitive capacity and how coupling in a distributed working memory network is affected by memory load.


Surface area overestimation within three-dimensional digital images and its consequence for skeletal dosimetry.
The most recent methods for trabecular bone dosimetry are based on Monte Carlo transport simulations within three-dimensional (3D) images of real human bone samples. Nuclear magnetic resonance and micro-computed tomography have been commonly used as imaging tools for studying trabecular microstructure. In order to evaluate the accuracy of these techniques for radiation dosimetry, a previous study was conducted that showed an overestimate in the absorbed fraction of energy for low-energy electrons emitted within the marrow space and irradiating the bone trabeculae. This problem was found to be related to an overestimate of the surface area of the true bone-marrow interface within the 3D digital images, and was identified as the surface-area effect. The goal of the present study is to better understand how this surface-area effect occurs in the case of single spheres representing individual marrow cavities within trabecular bone. First, a theoretical study was conducted which showed that voxelization of the spherical marrow cavity results in a 50% overestimation of the spherical surface area. Moreover, this overestimation cannot be reduced through a reduction in the voxel size (e.g., improved image resolution). Second, a series of single-sphere marrow cavity models was created with electron sources simulated within the sphere (marrow source) and outside the sphere (bone trabeculae source). The series of single-sphere models was then voxelized to represent 3D digital images of varying resolution. Transport calculations were made for both marrow and bone electron sources within these simulated images. The study showed that for low-energy electrons (<100 keV), the 50% overestimate of the bone-marrow interface surface area can lead to a 50% overestimate of the cross-absorbed fraction. It is concluded that while improved resolution will not reduce the surface area effects found within 3D image-based transport models, a tenfold improvement in current image resolution would compensate the associated errors in cross-region absorbed fractions for low-energy electron sources. Alternatively, other methods of defining the bone-marrow interface, such as with a polygonal isosurface, would provide improvements in dosimetry without the need for drastic reductions in image voxel size.


Long-range hot-carrier transport in hybrid perovskites visualized by ultrafast microscopy.
The Shockley-Queisser limit for solar cell efficiency can be overcome if hot carriers can be harvested before they thermalize. Recently, carrier cooling time up to 100 picoseconds was observed in hybrid perovskites, but it is unclear whether these long-lived hot carriers can migrate long distance for efficient collection. We report direct visualization of hot-carrier migration in methylammonium lead iodide (CH3NH3PbI3) thin films by ultrafast transient absorption microscopy, demonstrating three distinct transport regimes. Quasiballistic transport was observed to correlate with excess kinetic energy, resulting in up to 230 nanometers transport distance that could overcome grain boundaries. The nonequilibrium transport persisted over tens of picoseconds and ~600 nanometers before reaching the diffusive transport limit. These results suggest potential applications of hot-carrier devices based on hybrid perovskites.


Reliability of phenotypic tests for identification of Acinetobacter species.
A numerical approach was used for identification of 198 Acinetobacter strains assigned to DNA groups according to the classification of Tjernberg and Ursing (I. Tjernberg and J. Ursing, APMIS 97:595-605, 1989). The matrix used was constructed from data published by Bouvet and Grimont (P.J.M. Bouvet and P.A.D. Grimont, Int. J. Syst. Bacteriol. 36:228-240, 1986) and Bouvet and Jeanjean (P.J.M. Bouvet and S. Jeanjean, Res. Microbiol. 140:291-299, 1989). The tests chosen were those of the simplified identification scheme for Acinetobacter species devised by Bouvet and Grimont (P.J.M. Bouvet and P.A.D. Grimont, Ann. Inst. Pasteur/Microbiol. 138:569-578, 1987), namely, growth at 37, 41, and 44 degrees C, oxidation of glucose, gelatin hydrolysis, and assimilation of 14 carbon sources. Of the strains tested, 181 represented 12 DNA groups in the matrix; at a probability level of greater than or equal to 0.95, 78% of them were correctly identified, 2.2% were misidentified, and 19.8% were not identified. Seventeen strains represented two DNA groups not included in the matrix; nine of them were incorrectly assigned to a DNA group by these phenotypic tests. Because of problems of separating strains belonging to DNA groups 1, 2, 3, and 13 by using the phenotypic tests proposed by Bouvet and Grimont (Ann. Inst. Pasteur/Microbiol.), we suggest that these groups should be referred to as the Acinetobacter calcoaceticus-A. baumannii complex.


Modifying ligand-induced and constitutive signaling of the human 5-HT4 receptor.
G protein-coupled receptors (GPCRs) signal through a limited number of G-protein pathways and play crucial roles in many biological processes. Studies of their in vivo functions have been hampered by the molecular and functional diversity of GPCRs and the paucity of ligands with specific signaling effects. To better compare the effects of activating different G-protein signaling pathways through ligand-induced or constitutive signaling, we developed a new series of RASSLs (receptors activated solely by synthetic ligands) that activate different G-protein signaling pathways. These RASSLs are based on the human 5-HT(4b) receptor, a GPCR with high constitutive G(s) signaling and strong ligand-induced G-protein activation of the G(s) and G(s/q) pathways. The first receptor in this series, 5-HT(4)-D(100)A or Rs1 (RASSL serotonin 1), is not activated by its endogenous agonist, serotonin, but is selectively activated by the small synthetic molecules GR113808, GR125487, and RO110-0235. All agonists potently induced G(s) signaling, but only a few (e.g., zacopride) also induced signaling via the G(q) pathway. Zacopride-induced G(q) signaling was enhanced by replacing the C-terminus of Rs1 with the C-terminus of the human 5-HT(2C) receptor. Additional point mutations (D(66)A and D(66)N) blocked constitutive G(s) signaling and lowered ligand-induced G(q) signaling. Replacing the third intracellular loop of Rs1 with that of human 5-HT(1A) conferred ligand-mediated G(i) signaling. This G(i)-coupled RASSL, Rs1.3, exhibited no measurable signaling to the G(s) or G(q) pathway. These findings show that the signaling repertoire of Rs1 can be expanded and controlled by receptor engineering and drug selection.


Orthogonal coding methods for increasing the number of multiplexed channels in coherent beam combining.
We introduce orthogonally coded modulations for active coherent beam combining (CBC), and show how using Walsh codes enables the increase of the number of combined channels. Analytical, numerical, and experimental results are presented and compared to the standard multifrequency dithering technique, demonstrating that at least 5 times more fibers can be combined using the same modulation frequency. The modulation format excluded, no particular changes in the system need to be introduced and the benefits of active coherent beam combing, such as atmospheric turbulence compensation capability, are kept unchanged. Finally, we point out that this approach can be applied in partially CBC.


Maintaining power: women's experiences from labour onset before admittance to maternity ward.
In Sweden pregnant women are encouraged to remain at home until the active phase of labour. Recommendation is based on evidence, that women who seek care and are admitted in the latent phase of labour are subjected to more obstetric interventions and suffer more complications than women who remain at home until the active phase of labour. The aim of this study was to obtain a deeper understanding of how women, who remain at home until the active phase of labour, experience the period from labour onset until admission to labour ward. Interviews were conducted with 19 women after they had given birth to their first child. A Constructivist Grounded theory method was used. 'Maintaining power' was identified as the core category, explaining the women's experience of having enough power, when the labour started. Four related categories: 'to share the experience with another', 'to listen to the rhythm of the body', 'to distract oneself' and 'to be encased in a glass vessel', explained how the women coped and thereby maintained power. The first time mothers in this study, who managed to stay at home during the latent phase of labour, had a sense of power that was expressed as a driving force towards the birth, a bodily and mental strength and the right to decide over their own bodies. This implies that women who maintain power have the ability to make choices during the birth process. The professionals need to be sensitive, supportive and respectful to women's own preferences in the health-care encounter, to promote the existing power throughout the birthing process.


Virulence of soil-borne pathogens and invasion by Prunus serotina.
*Globally, exotic invaders threaten biodiversity and ecosystem function. Studies often report that invading plants are less affected by enemies in their invaded vs home ranges, but few studies have investigated the underlying mechanisms. *Here, we investigated the variation in prevalence, species composition and virulence of soil-borne Pythium pathogens associated with the tree Prunus serotina in its native US and non-native European ranges by culturing, DNA sequencing and controlled pathogenicity trials. *Two controlled pathogenicity experiments showed that Pythium pathogens from the native range caused 38-462% more root rot and 80-583% more seedling mortality, and 19-45% less biomass production than Pythium from the non-native range. DNA sequencing indicated that the most virulent Pythium taxa were sampled only from the native range. The greater virulence of Pythium sampled from the native range therefore corresponded to shifts in species composition across ranges rather than variation within a common Pythium species. *Prunus serotina still encounters Pythium in its non-native range but encounters less virulent taxa. Elucidating patterns of enemy virulence in native and nonnative ranges adds to our understanding of how invasive plants escape disease. Moreover, this strategy may identify resident enemies in the non-native range that could be used to manage invasive plants.


Cardiovascular disease risk assessment using a deep-learning-based retinal biomarker: a comparison with existing risk scores.
This study aims to evaluate the ability of a deep-learning-based cardiovascular disease (CVD) retinal biomarker, Reti-CVD, to identify individuals with intermediate- and high-risk for CVD. We defined the intermediate- and high-risk groups according to Pooled Cohort Equation (PCE), QRISK3, and modified Framingham Risk Score (FRS). Reti-CVD's prediction was compared to the number of individuals identified as intermediate- and high-risk according to standard CVD risk assessment tools, and sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated to assess the results. In the UK Biobank, among 48 260 participants, 20 643 (42.8%) and 7192 (14.9%) were classified into the intermediate- and high-risk groups according to PCE, and QRISK3, respectively. In the Singapore Epidemiology of Eye Diseases study, among 6810 participants, 3799 (55.8%) were classified as intermediate- and high-risk group according to modified FRS. Reti-CVD identified PCE-based intermediate- and high-risk groups with a sensitivity, specificity, PPV, and NPV of 82.7%, 87.6%, 86.5%, and 84.0%, respectively. Reti-CVD identified QRISK3-based intermediate- and high-risk groups with a sensitivity, specificity, PPV, and NPV of 82.6%, 85.5%, 49.9%, and 96.6%, respectively. Reti-CVD identified intermediate- and high-risk groups according to the modified FRS with a sensitivity, specificity, PPV, and NPV of 82.1%, 80.6%, 76.4%, and 85.5%, respectively. The retinal photograph biomarker (Reti-CVD) was able to identify individuals with intermediate and high-risk for CVD, in accordance with existing risk assessment tools.


Src homology 2 domain as a specificity determinant in the c-Abl-mediated tyrosine phosphorylation of the RNA polymerase II carboxyl-terminal repeated domain.
The Src-homology (SH) 2 domain, found in a variety of proteins, has a binding site for phosphotyrosine-containing peptides. In adaptor proteins such as Grb2, the SH2 domain plays an important role in the assembly of signal transducer complexes. Many nonreceptor tyrosine kinases--e.g., Abl and Src--also contain SH2 domains. Without a functional SH2 domain, these tyrosine kinases retain catalytic activity but lose their biological function. This result suggests that the SH2 domain may be involved in the selection of biologically relevant substrates. We have previously shown that the carboxyl-terminal repeated domain (CTD) of the mammalian RNA polymerase II is a substrate for the Abl but not the Src tyrosine kinase. This specificity is conferred in part by the SH2 domain. The Abl SH2 domain binds the tyrosine-phosphorylated [Tyr(P)] CTD and is required for the processive and stoichiometric phosphorylation of the 52 tyrosines in the CTD. Mutation of the Abl SH2 or exchanging it with that of Src, which does not bind the Tyr(P)-CTD, abolished processivity and reduced the CTD kinase activity without any effect on autophosphorylation or the phosphorylation of nonspecific substrates. These results demonstrate that the SH2 domain of the Abl tyrosine kinase plays an active role in catalysis and suggests that SH2 domain and the tyrosine kinase domain may act in concert to confer substrate specificity.


Integrin and extracellular matrix interactions regulate engraftment of transplanted hepatocytes in the rat liver.
Recognition and circumvention of the hepatic endothelial barrier is critical in the engraftment of transplanted cells. We examined whether interactions between integrin and extracellular matrix component receptors could be manipulated for improving transplanted cell engraftment and liver repopulation. Fischer 344 rat hepatocytes were transplanted into syngeneic dipeptidyl peptidase IV-deficient rats. Coating of cells or of liver sinusoids with natural collagen, natural laminin, or an engineered fibronectin-like polymer was studied with analysis of cell engraftment and liver repopulation using histologic and molecular assays. Focal adhesion complexes were identified by vinculin immunostaining. The role of integrin receptors in cell engraftment was analyzed with RGD peptide inhibition assays. Coating of cells with extracellular matrix components before transplantation did not enhance cell engraftment. In contrast, intraportal infusion of collagen or fibronectin-like polymer in recipients prior to cell transplantation increased cell engraftment. Adherence of transplanted cells to the hepatic endothelium resulted in rapid activation of vinculin-containing focal adhesion complexes. Superior cell engraftment in animals treated with fibronectin-like polymer was RGD sensitive, verifying the integrin-dependent nature of this process. Moreover, studies in the retrorsine-partial hepatectomy rat model showed that intraportal infusion of the fibronectin-like polymer before cell transplantation significantly accelerated liver repopulation. Integrin-extracellular matrix component interactions can be manipulated for enhancing cell engraftment in the liver. Such mechanisms will be relevant for engraftment of other cell types and for strategies concerning liver-directed cell therapy.


Sexual growth dimorphism affects birth sex ratio in house mice.
We present the first empirical evidence that mammalian sex-ratio deviations result from variation in adult-weight sexual dimorphism via correlated effects on blastocyst development. Two selection lines of mice exhibiting high and low sexual dimorphism in adult weight showed correlated sexual weight differences at birth and at weaning, caused by relatively decelerated growth of males in the low line from before birth. The sex ratio at birth was significantly female-biased in the low line, and significantly lower than in the highly dimorphic line. Concomitantly, blastomere numbers were at significantly higher variance in the low than in the highly dimorphic line, owing to an increased frequency of slowly growing blastocysts. Since low-dimorphism mice produced more corpora lutea and more female pups than the high-dimorphism mice, but not more males, birth sex-ratio bias most parsimoniously resulted from the loss of slowly growing male blastocysts. This is in agreement with the observation that sex-ratio skews in mammals arise when timing of uterine responsiveness (i.e. its temporally limited capacity for implantation) varies in relation to sex-specific embryonic growth rates. Hence, natural mammalian sex-ratio variation that stems from developmental asynchrony might be a by-product of natural selection for sexual dimorphism in adult weight.


French brain tumor database: 5-year histological results on 25 756 cases.
This work aimed to prospectively record all primary central nervous system tumor (PCNST) cases in France, for which histological diagnosis is available. The objectives were to (i) create a national registry and a network to perform epidemiological studies; (ii) implement clinical and basic research protocols; and (iii) harmonize the health care of patients affected by PCNST. For 5 years, 25 756 cases of newly diagnosed and histologically confirmed PCNST have been recorded. Histological diagnoses included glioma (48.9%), all other neuroepithelial tumors (5%), meningioma (28.8%), nerve sheath tumors (8.4%), lymphoma (3.2%) and others (5.7%). Cryopreservation was reported for 6018 PCNST specimens. Tumor resections (R) were performed in 78% cases, while biopsies accounted for 22%. Median age (MA), sex, percentage R and number of cryopreserved tumors were detailed for each histology; for example, out of 6053 glioblastomas (MA 63 years, male 59.4%, R 62%, 1611 were cryopreserved), and out of 37 atypical teratoid/rhabdoid tumors (MA 2 years, male 56.8%, R 94%, 17 were cryopreserved). This database or databank dedicated to PCNST cases contains detailed data on clinical, histological and other characteristics, such as the inclusion of data on cryopreserved specimens that are not available in other European registries. Therefore, this is a valuable resource that can be used for planning future epidemiological and clinical research.


How to Receive More Funding for Your Research? Get Connected to the Right People!
Funding has been viewed in the literature as one of the main determinants of scientific activities. Also, at an individual level, securing funding is one of the most important factors for a researcher, enabling him/her to carry out research projects. However, not everyone is successful in obtaining the necessary funds. The main objective of this work is to measure the effect of several important factors such as past productivity, scientific collaboration or career age of researchers, on the amount of funding that is allocated to them. For this purpose, the paper estimates a temporal non-linear multiple regression model. According to the results, although past productivity of researchers positively affects the funding level, our findings highlight the significant role of networking and collaboration. It was observed that being a member of large scientific teams and getting connected to productive researchers who have also a good control over the collaboration network and the flow of information can increase the chances for securing more money. In fact, our results show that in the quest for the research money it is more important how researchers build their collaboration network than what publications they produce and whether they are cited.


Mn(II) Binding and Subsequent Oxidation by the Multicopper Oxidase MnxG Investigated by Electron Paramagnetic Resonance Spectroscopy.
The dynamics of manganese solid formation (as MnOx) by the multicopper oxidase (MCO)-containing Mnx protein complex were examined by electron paramagnetic resonance (EPR) spectroscopy. Continuous-wave (CW) EPR spectra of samples of Mnx, prepared in atmosphere and then reacted with Mn(II) for times ranging from 7 to 600 s, indicate rapid oxidation of the substrate manganese (with two-phase pseudo-first-order kinetics modeled using rate coefficients of: k(1obs) = 0.205 ± 0.001 s(-1) and k(2obs) = 0.019 ± 0.001 s(-1)). This process occurs on approximately the same time scale as in vitro solid MnOx formation when there is a large excess of Mn(II). We also found CW and pulse EPR spectroscopic evidence for at least three classes of Mn(II)-containing species in the reaction mixtures: (i) aqueous Mn(II), (ii) a specifically bound mononuclear Mn(II) ion coordinated to the Mnx complex by one nitrogenous ligand, and (iii) a weakly exchange-coupled dimeric Mn(II) species. These findings provide new insights into the molecular mechanism of manganese mineralization.


First Report of Bacterial Spot Caused by Xanthomonas arboricola pv. pruni on Japanese Plum in Taiwan.
Prunus salicina Lindl., also known as Japanese plum, is a temperate-zone fruit tree grown in mountainous areas of Taiwan. The planted area in Taiwan is approximately 3,000 ha. In June 2011, more than 20% of plum fruits harvested in an orchard in Lishan (elevation about 2,000 m) showed black, mostly circular, sunken necrotic lesions. Leaves with a shot-hole appearance and cankered branches were found when investigating the orchard. Bacteria were isolated from symptomatic fruits, leaves, and branches. Isolation on nutrient agar detected colonies that were yellow, mucoid, gram-negative, Xanthomonas-like, and induced hypersensitive responses on tomatoes. Three voucher isolates, BCRC80476, BCRC80478, and BCRC80481, obtained from the fruit, leaf, and branch, respectively, were deposited in the Bioresource Collection and Research Center, Hsinchu, Taiwan. Molecular analyses were conducted for species identification. Sequences of the gyrB gene of the three voucher isolates (GenBank Accession Nos. KC202288, KC202289, and KC202287) were 100% identical to that of Xanthomonas arboricola pv. pruni pathotype strain ICMP51 (2). In addition, DNA fragments of the xopE3 gene (an X. arboricola pv. pruni specific T3E gene, approximately 381 bp) were PCR amplified using the primer pair fw-5'CCGACATTGCCGTCAGCGATCACG3' and rv-5'AGCGTTCTTGGGTGTGTTGAGCATTTG3' (1). The bacterial isolates were identified as X. arboricola pv. pruni on the basis of the colony characteristics, sequence homology, and the specific PCR assay. Pathogenicity was confirmed by inoculation of greenhouse-potted P. salicina plants with strains BCRC80476, BCRC80478, and BCRC80481 using bacterial suspensions (6.7 × 108 CFU per ml) in 0.01% Tween 20. Five plants were evenly sprayed with inoculum of each bacterial isolate and covered with plastic bags for 3 days. One week post inoculation, at an average temperature of 19°C, the 15 inoculated plants produced brown-purple spots delimited by a chlorotic margin on the leaves. Three weeks post inoculation, the necrotic leaf spots completely deteriorated, leaving a shot-hole appearance, and the branches showed lesions similar to those observed in the fields. The pathogen was reisolated from the symptomatic tissues, fulfilling Koch's postulates. Control plants sprayed with 0.01% Tween 20 remained symptomless. To our knowledge, this is the first record of X. arboricola pv. pruni causing bacterial spot on P. salicina in Taiwan. References: (1) A. Hajri et al. Appl. Environ. Microbiol. 78:371, 2012. (2) J. M. Young et al. Syst. Appl. Microbiol. 31:366, 2008.


No Evidence of Toxoplasma Gondii Exposure in South Australian Koalas (Phascolarctos cinereus).
Infection with the cat-borne parasite Toxoplasma gondii has been detected in numerous Australian marsupials and can lead to severe disease (toxoplasmosis) in some cases. The seroprevalence of Toxoplasma on Kangaroo Island, South Australia has been reported to be higher than the South Australian mainland in macropods, cats, and sheep, suggesting an increased risk of infection on this island. However, Toxoplasma seroprevalence in small- and medium-sized terrestrial mammals was almost zero on the island and did not differ from that on the mainland. We surveyed Toxoplasma seroprevalence in koala (Phascolarctos cinereus) populations on the island and on the mainland and assessed their risk of infection and their role in the life cycle of Toxoplasma. All screened koalas from the island (n = 94) and the mainland (n = 63) were seronegative. This represents the largest Toxoplasma seroprevalence survey in this species and provided sufficient evidence to confidently demonstrate freedom from parasite exposure in both island and mainland populations at the time of the survey. Because koalas are extensively arboreal and predominately consume tree foliage, they appear to be at negligible risk of Toxoplasma infection. Furthermore, as koalas are rarely consumed by cats, we suggest that they have a minor role in the parasite's life cycle.


Higher Serum Calcium Levels Are Associated with Preclinical Peripheral Arterial Disease among the Apparently Healthy Individuals.
Epidemiological studies suggest that serum calcium levels correlate with cardiovascular events. An ankle-brachial index (ABI) between 0.9 and 1.00 is a surrogate estimation of preclinical peripheral arterial disease (PAD). Prior studies have shown that an ABI of 0.9-1.0 is also associated with endothelial dysfunction. Therefore, we sought to investigate the relationship between serum calcium levels and preclinical PAD in apparently healthy Korean individuals. We evaluated the association between serum calcium levels and preclinical PAD in 596 participants (334 males, 262 females) in a health examination program. Preclinical PAD was defined by an ABI of 0.9-1.0. Multiple logistic regression analysis was used to determine whether the serum calcium level was an independent determinant of preclinical PAD. The overall prevalence of preclinical PAD was 14.3%. The mean age was 44.0±12.5 years in the non-PAD group and 48.3±11.4 years in the preclinical PAD group (P=0.001). After adjusting for age, gender, systolic blood pressure, fasting plasma glucose, high-density lipoprotein cholesterol, triglycerides, C-reactive protein, g-glutamyltransferase, uric acid, hypertension medication, diabetes medication, and hyperlipidemia medication, the odds ratio (95% confidence intervals) for preclinical PAD was 2.28 (1.02-5.11) with a 1-mg/dL increase in the serum calcium. These findings suggest that increased serum calcium is independently and positively associated with preclinical PAD regardless of the presence of classic cardiovascular risk factors.


Biofilm growth-percolation models and channeling in biofilter clogging.
Biomass accumulation is a load-limiting factor in the operation of biofilters used for air pollution control. As the biofilm thickens, portions at the base are no longer exposed to contaminants and oxygen and, thus, provide no treatment. Smaller pores are filled with biomass so that air no longer flows into them. As airflow paths are restricted, air may be prevented from reaching some pores even before they are filled. Eventually blockage becomes sufficiently widespread so that increasing head loss and decreasing removal efficiency require that the system be shut down. Optimization of biofilter design requires a better understanding of the mechanisms by which biofilters clog. In this work, a numerical percolation model of the blockage process was developed for application to biofilters. It allows comparison of pore blockage histories for various pore size distributions and predicts biomass accumulation, head loss, and treatment efficiency as a function of time, as well as total time, until blockage prevents further operation. Although the model was reasonably accurate in predicting the time before complete clogging, it underestimated intermediate values of head loss. Observations of a clogged biofilter suggest that this occurs because clogging later in the process is nonuniform at scales that are large in comparison with individual pores.


Impact of climate change on marine pelagic phenology and trophic mismatch.
Phenology, the study of annually recurring life cycle events such as the timing of migrations and flowering, can provide particularly sensitive indicators of climate change. Changes in phenology may be important to ecosystem function because the level of response to climate change may vary across functional groups and multiple trophic levels. The decoupling of phenological relationships will have important ramifications for trophic interactions, altering food-web structures and leading to eventual ecosystem-level changes. Temperate marine environments may be particularly vulnerable to these changes because the recruitment success of higher trophic levels is highly dependent on synchronization with pulsed planktonic production. Using long-term data of 66 plankton taxa during the period from 1958 to 2002, we investigated whether climate warming signals are emergent across all trophic levels and functional groups within an ecological community. Here we show that not only is the marine pelagic community responding to climate changes, but also that the level of response differs throughout the community and the seasonal cycle, leading to a mismatch between trophic levels and functional groups.


Frontal intermittent rhythmic delta activity (FIRDA) in patients with dementia with Lewy bodies: a diagnostic tool?
The accuracy of the clinical diagnosis of dementia with Lewy bodies (DLB) remains poor, especially in early phases of the disease, in spite of applying current consensus diagnostic criteria. The need for supportive diagnostic tools is therefore warranted. In this study EEG recordings showed a main pattern of bilateral frontal intermittent rhythmic delta activity (FIRDA) in 7 of 10 patients, aged 58-83 years, 8 of whom were diagnosed as affected by "probable" and 2 by "possible" DLB. Conversely, the same EEG abnormality was found only in 2 of 9 age-matched patients, 8 of whom had "probable" and 1 "possible" Alzheimer's disease, according to NINCDS-ADRDA criteria, taken as controls. The degree of cognitive impairment was comparable among the two groups of patients. If these findings will be confirmed in a larger series, FIRDA, even though an aspecific EEG pattern, could be of value in improving the diagnostic accuracy of DLB.


Serological and viraemic status of human cytomegalovirus infection in patients with colorectal cancer is not correlated with viral replication and transcription in tumours.
Colorectal cancer (CRC) is amongst the leading causes of cancer-related mortality worldwide. Emerging evidence suggests that human cytomegalovirus (HCMV) exists in the tumour tissue of CRC and is associated with disease outcome. To study whether tumoral HCMV is related to viral reactivation in blood, tumour specimens and pre- and post-operative blood samples from CRC patients were collected prospectively. PCR and quantitative PCR were performed to detect HCMV DNA. HCMV IgG and IgM antibodies were measured using a microparticle enzyme immunoassay. Transcription of a spliced HCMV UL73 gene transcript was analysed by quantitative reverse transcription PCR. HCMV was detected in 42.2% (35/83) of the tumour samples, with a low median viral load (30.08, range 2.33-5704 copies per 500 ng genomic DNA). The vast majority (80/81, 98.8%) of the CRC patients were seropositive for HCMV IgG. HCMV DNA was positive in 11.3% (22/194) of the pre-operative and 8.9% (15/168) of the post-operative blood samples. However, presence of HCMV and its viral load in tumours were not associated with the detection or viral loads in blood samples. About 26.67% (8/30) of the HCMV-positive tumours with available RNA had detectable viral UL73 transcripts, whilst none of the blood samples were positive for viral RNA (P < 0.0001). Therefore, presence of HCMV in tumours does not correlate with the serological or viraemic status of CRC patients. Active viral gene transcription occurred in the tumour but not in the blood of CRC patients. HCMV reactivation in CRC patients is possibly due to virus-cancer interactions in the CRC tumour microenvironment.


Cannabis-related stroke: case series and review of literature.
Marijuana, or cannabis, is one of the most commonly used illicit drugs worldwide. Although there are some case reports of stroke associated with cannabis use, there is no information on a causal role of cannabis in stroke. We identified 14 patients admitted to St Louis University Hospital between January 2004 and July 2007 with ischemic stroke who had documented clear exposure to cannabis during or before symptom onset and a positive urine screen for cannabis. We report this series, along with 3 cases previously reported by our group, for a total of 17 patients (13 men and 4 women), with a mean age of 41 years (range, 15-63 years). Nine patients were under age 45 years, 4 had a history of hypertension, and 10 sustained stroke in the posterior circulation. Headache, dysarthria, and ataxia were the most common presenting symptoms. Five patients had recurrent stroke with reexposure to cannabis. No patient had a prothrombotic state or cardiac source of embolism. Autopsy performed in 2 patients revealed hemorrhagic infarct with no evidence of vasculitis or embolus. The absence of other vascular risk factors in most of our patients, the temporal relation of symptom onset to cannabis exposure, and the recurrence of symptoms in a few patients with reexposure suggest a causal role of cannabis in these cases of ischemic stroke. However, this causal association cannot be definitely ascertained, given the descriptive nature of our series. More research is needed to explore this possible causal association.


The dark side of occupation within the context of modern-day beauty pageants.
The desire to be physically beautiful is inherent among human beings. In particular, some women who participate in modern-day beauty pageants tend to spend more time, energy, money and emotional resources to alter their natural body and looks to fit socially and culturally constructed standards of beauty. The authors frame beauty pageants as the context where diverse occupations are at play with the purpose of becoming a 'beauty queen'. This commentary aims to discuss the origins and culture of beauty pageants, the different perspectives on pageantry work, and essential and hidden occupations performed within the context of this form of performing art. Using the conceptual lens of the dark side of occupation, hidden occupations are characterised by the doings of pageant hopefuls that are less explored and acknowledged because they are perceived as health-compromising, risky, dishonest, illicit, and socially or personally undesirable. Furthermore, this commentary calls for the exploration of occupations beyond the conventional scope of its understanding and the acknowledgment of hidden occupations intertwined into people's everyday doings specifically in the context of desiring to be 'beautiful'.


Normal caudate nucleus in obsessive-compulsive disorder assessed by quantitative neuroimaging.
Prior neuroimaging studies have not consistently demonstrated a structural or functional abnormality of the caudate nucleus in patients with obsessive-compulsive disorder (OCD). However, there is theoretical support for some associated dysfunction of the caudate nucleus. We examined volumes of the caudate nucleus and putamen with magnetic resonance imaging in 24 patients with adult-onset OCD and 21 control subjects, group-matched on age, race, education, and sex. Patients were relatively free from tics. To evaluate function (metabolism or blood flow) of the caudate nucleus, we performed a quantitative review, including a meta-analysis, of normalized data from functional neuroimaging studies that compared patients who had OCD with normal control subjects. All structural basal ganglia measures failed to exhibit differences between patients with OCD and matched normal control subjects. Patients did not demonstrate evidence of ventricular enlargement. Quantitative meta-analysis of the functional neuroimaging literature did not demonstrate a consistent abnormality of the caudate nucleus. We did not observe evidence of a structural abnormality of the caudate nucleus in patients with OCD. Prior reports of a structural aberration of the caudate nucleus were mixed. We also did not find strong support for relative caudate metabolic or perfusion dysfunction in the literature, although increased function in the frontal cerebral cortex was identified. The heterogeneous nature of this disorder may account for inconsistencies between studies. For example, ventricular enlargement or reduced caudate volume or blood flow might be evident in patients with soft neurological signs (eg, tics), while patients in the current study were relatively free from tics. Although theories of OCD suggest a dysfunction of the caudate nucleus, the structural and functional neuroimaging literature has not consistently verified this.


Lymphokine-activated killer cells. Analysis of progenitors and effectors.
IL-2 has been examined for its ability to regulate lymphokine-activated killer (LAK) activity. IL-2 is a potent activator of cytolytic activity against a wide array of tumor cells, including those from fresh autologous and allogeneic tumors. Using subpopulations of lymphoid cells that were separated on Percoll density gradients, and subsequently purified by immunoadsorbance, studies were performed to examine the phenotypes of progenitor and effector cells of human LAK cells and to compare them with the phenotype of activated NK cells. From these studies, it was evident that several lymphoid subsets, including CD3+, CDw16- and CD3-, CDw16+ cells could mediate LAK lysis of fresh tumor cells. Our examination of the kinetics of activation revealed that CDw16+, NKH1+ (NK-active) cells were maximally activated by 1-2 d. In contrast, CD3+ cells appeared not to achieve maximal cytolytic activity against fresh and cultured tumor cells until days 2-3. Using limiting-dilution frequency analysis, we showed that a large percentage of cytolytically active progenitors was present among the CDw16+, NKH1+ cells. The progenitor and effector cell frequencies appear to be 10-50 times higher in these populations compared to CD3+ cells. In addition, the selective blockage by mAb to the CD3 determinant of the T cell receptor complex indicated that these two effector cell phenotypes relied on different receptors to mediate their cytotoxic activity against tumor cells. Therefore, the accumulated data suggest that there is not a single unique progenitor of LAK activity, but rather that multiple subsets of lymphocytes become cytotoxic in response to IL-2. However, the NK cell population forms the largest single component of LAK cell activity in human peripheral blood.


Characterization of electrowetting processes through force measurements.
A new method of characterizing electrowetting is presented. In this method, the electrowetting actuation forces are measured rather than the contact angle. The forces on the liquid are measured by trapping a droplet between a flat nanoindenter tip and the test substrate. When voltage is applied to electrodes in the substrate, lateral and normal forces are exerted on the tip and measured by the nanoindenter transducer. Proper selection of the tip geometry permits direct prediction of the resulting in-plane lateral forces using analytical formulas derived from the Young-Lippmann equation. Experimental results show good agreement with both analytical and numerical predictions. Numerical modeling using SURFACE EVOLVER shows that the lateral forces are relatively insensitive to most alignment errors and that the analytical model is most accurate when the flat tip is close to the substrate. Evaporation of the test liquid can introduce modest errors in long measurements, but compensation methods are presented. As the droplet undergoes almost no movement, the fluid dynamics have minimal impact on the measured forces and transient electrowetting events are readily detected. Experimental results show significant response at frequencies up to 40 Hz. This setup is useful in measuring electrowetting responses at high speeds and in measuring system degradation processes.


Prediction and prevention of failure: an early intervention to assist at-risk medical students.
Consistent identification and prevention of failure for at-risk medical students is challenging, failing courses is costly to all stakeholders, and there is need for further research into duration, timing and structure of interventions to help students in difficulty. To verify the value of a new exam two weeks into medical school as a predictor of failure, and explore the requirements for a preventative intervention. Students who failed the two-week exam were invited to a series of large-group workshops and small-group follow-up meetings. Participants' subsequent exam performance was compared with non-participants. About 71% of students who performed poorly in the new exam subsequently failed a course. Attendance at the workshops made no difference to short- or long-term pass rates. Attendance at more than three follow-up small group sessions significantly improved pass rates two semesters later, and was influenced by teacher experience. Close similarity between predictor task and target task is important for accurate prediction of failure. Consideration should be given to dose effect and class size in the prevention of failure of at-risk students, and we recommend a systemic approach to intervention/remediation programmes, involving a whole semester of mandatory, weekly small group meetings with experienced teachers.


Recurrence of preeclampsia in northern Tanzania: a registry-based cohort study.
Preeclampsia occurs in about 4 per cent of pregnancies worldwide, and may have particularly serious consequences for women in Africa. Studies in western countries have shown that women with preeclampsia in one pregnancy have a substantially increased risk of preeclampsia in subsequent pregnancies. We estimate the recurrence risks of preeclampsia in data from Northern Tanzania. A prospective cohort study was designed using 19,811 women who delivered singleton infants at a hospital in Northern Tanzania between 2000 and 2008. A total of 3,909 women were recorded with subsequent deliveries in the hospital with follow up through 2010. Adjusted recurrence risks of preeclampsia were computed using regression models. The absolute recurrence risk of preeclampsia was 25%, which was 9.2-fold (95% CI: 6.4 - 13.2) compared with the risk for women without prior preeclampsia. When there were signs that the preeclampsia in a previous pregnancy had been serious either because the baby was delivered preterm or had died in the perinatal period, the recurrence risk of preeclampsia was even higher. Women who had preeclampsia had increased risk of a series of adverse pregnancy outcomes in future pregnancies. These include perinatal death (RR= 4.3), a baby with low birth weight (RR= 3.5), or a preterm birth (RR= 2.5). These risks were only partly explained by recurrence of preeclampsia. Preeclampsia in one pregnancy is a strong predictor for preeclampsia and other adverse pregnancy outcomes in subsequent pregnancies in Tanzania. Women with previous preeclampsia may benefit from close follow-up during their pregnancies.


Seminal plasma composition from ejaculates collected by artificial vagina and electroejaculation in Guirra ram.
This study was conducted to evaluate changes in ram seminal plasma composition from ejaculates obtained using artificial vagina (AV) and electroejaculation (EE). To address this question, we assessed the effect of semen collection method on volume, sperm concentration, sodium concentration, potassium concentration, sodium/potassium ratio, total protein content and protein profile using sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and 2-D polyacrylamide gel electrophoresis. The main findings from this study were: (i) similar volume was obtained, while sperm concentration was significantly lower for EE method; (ii) potassium and sodium/potassium concentration ratio were not influenced by recovery method, while sodium concentration increased significantly when semen was recovered using EE; (iii) approximately 80% of the total relative seminal plasma protein is represented by four protein fractions of molecular weights around 15, 21, 24 and 50 kDa and there were not differences and (iv) focussing the two-dimensional SDS-PAGE gel on the 10-25 kDa rank, the IMAGE ANALYSIS software detected around 22 spots with isoelectric points ranging from 5.1 to 6.1. Two protein spots (15 kDa and 5.5 and 22 kDa and 5.2 for molecular weight and isoelectric point respectively) increased significantly when semen was recovered using EE. One spot protein with molecular weight around 25 kDa and isoelectric point of 5.2 were only found in the seminal plasma from the semen recovery by AV. As it was demonstrated, ejaculates obtained with EE modify the sodium concentration, alter two proteins concentration and induced the loss of one protein in seminal plasma.


No evidence that consistent auditory cues facilitate learning of spatial relations among locations.
Human participants searched in a dynamic three-dimensional computer-generated virtual-environment open-field search task for four hidden goal locations arranged in a diamond configuration located in a 5×5 matrix of raised bins. Participants were randomly assigned to one of two groups: Consistent or Inconsistent. All participants experienced 30 trials in which four goal locations maintained the same spatial relations to each other (i.e., a diamond pattern), but this diamond pattern moved to random locations within the 5×5 matrix from trial-to-trial. For participants in the Consistent group, each goal location within the pattern always provided a unique and consistent auditory cue throughout the experimental session. For participants in the Inconsistent group, the same distinct auditory cues were provided for each goal location; however, the locations of these auditory cues within the pattern itself were randomized from trial-to-trial throughout the experimental session. Results indicated that participants in both groups learned the spatial configuration of goal locations, but the presence of consistent auditory cues did not facilitate the learning of spatial relations among locations.


Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo.
Immunization with defined tumor antigens is currently limited to a small number of cancers where candidates for tumor rejection antigens have been identified. In this study we investigated whether pulsing dendritic cells (DC) with tumor-derived RNA is an effective way to induce CTL and tumor immunity. DC pulsed with in vitro synthesized chicken ovalbumin (OVA) RNA were more effective than OVA peptide-pulsed DC in stimulating primary, OVA-specific CTL responses in vitro. DC pulsed with unfractionated RNA (total or polyA+) from OVA-expressing tumor cells were as effective as DC pulsed with OVA peptide at stimulating CTL responses. Induction of OVA-specific CTL was abrogated when polyA+ RNA from OVA-expressing cells was treated with an OVA-specific antisense oligodeoxynucleotide and RNase H, showing that sensitization of DC was indeed mediated by OVA RNA. Mice vaccinated with DC pulsed with RNA from OVA-expressing tumor cells were protected against a challenge with OVA-expressing tumor cells. In the poorly immunogenic, highly metastatic, B16/F10.9 tumor model a dramatic reduction in lung metastases was observed in mice vaccinated with DC pulsed with tumor-derived RNA (total or polyA+, but not polyA- RNA). The finding that RNA transcribed in vitro from cDNA cloned in a bacterial plasmid was highly effective in sensitizing DC shows that amplification of the antigenic content from a small number of tumor cells is feasible, thus expanding the potential use of RNA-pulsed DC-based vaccines for patients bearing very small, possibly microscopic, tumors.


Preparation and characterization of a lamotrigine imprinted polymer and its application for drug assay in human serum.
A molecularly imprinted polymer (MIP) against lamotrigine (LTG) was prepared, characterized, and its recognition properties were compared with a blank nonimprinted polymer (NIP). Two classes of binding sites were found in the MIP--high affinity (K(D) = 16.2 microM) and low affinity (K(D) = 161.3 microM). Selectivity of the synthesized MIP was examined using compounds with similar structures or therapeutic uses to LTG. In compounds which had structural similarity to LTG, the presence of amine groups appeared to affect binding to the MIP, however overall shape of the molecule was also important. Under the optimal conditions developed, other anticonvulsant drugs tested did not bind the MIP. A molecularly imprinted SPE (MISPE) procedure was developed which had a recovery of 84-89%, interday variation of less than 3.4% and intraday variation of less than 2.8%. The MISPE procedure was compared with a routine liquid-liquid extraction (LLE) procedure used for the HPLC determination of LTG in serum from patients. The data indicated that the MIP synthesized showed both good selectivity and high affinity for LTG and could be used for the extraction of the drug from serum samples or as the receptor layer for an LTG selective biosensor.


Is the acetylcholine-regulated inwardly rectifying potassium current a viable antiarrhythmic target? Translational discrepancies of AZD2927 and A7071 in dogs and humans.
We aimed at examining the acetylcholine-dependent inward-rectifier current (IKAch) as a target for the management of atrial fibrillation (AF). The investigative agents AZD2927 and A7071 concentration-dependently blocked IKACh in vitro with minimal off-target activity. In anaesthetized dogs (n = 17) subjected to 8 weeks of rapid atrial pacing (RAP), the left atrial effective refractory period (LAERP) was maximally increased by 50 ± 7.4 and 50 ± 4.8 ms following infusion of AZD2927 and A7071. Ventricular refractoriness and the QT interval were unaltered. During sustained AF, both drugs significantly reduced AF frequency and effectively restored sinus rhythm. AZD2927 successfully restored sinus rhythm at 10/10 conversion attempts and A7071 at 14/14 attempts, whereas saline converted 4/17 episodes only (P<0.001 vs. AZD2927 and A7071). In atrial flutter patients (n = 18) undergoing an invasive investigation, AZD2927 did not change LAERP, the paced QT interval, or ventricular refractoriness when compared with placebo. To address the discrepancy on LAERP by IKACh blockade in man and dog and the hypothesis that atrial electrical remodelling is a prerequisite for IKACh blockade being efficient, six dogs were studied after 8 weeks of RAP followed by sinus rhythm for 4 weeks to reverse electrical remodelling. In these dogs, both AZD2927 and A7071 were as effective in increasing LAERP as in the dogs studied immediately after the 8-week RAP period. Based on the present series of experiments, an important role of IKACh in human atrial electrophysiology, as well as its potential as a viable target for effective management of AF, may be questioned.


An evidence-based approach to assessing surgical versus clinical diagnosis of symptomatic endometriosis.
Challenges intrinsic to the accurate diagnosis of endometriosis contribute to an extended delay between the onset of symptoms and clinical confirmation. Intraoperative visualization, preferably with histologic verification, is considered by many professional organizations to be the gold standard by which endometriosis is diagnosed. Clinical diagnosis of symptomatic endometriosis via patient history, physical examination, and noninvasive tests, though more easily executed, is generally viewed as less accurate than surgical diagnosis. Technological advances and increased understanding of the pathophysiology of endometriosis warrant continuing reevaluation of the standard method for diagnosing symptomatic disease. A review of the published literature was therefore performed with the goal of comparing the accuracy of clinical diagnostic measures with that of surgical diagnosis. The current body of evidence suggests that clinical diagnosis of symptomatic endometriosis is more reliable than previously recognized and that surgical diagnosis has limitations that could be underappreciated. Regardless of the methodology used, women with suspected symptomatic endometriosis would be well served by a diagnostic paradigm that is reliable, conveys minimal risk of under- or over-diagnosis, lessens the time from symptom development to diagnosis, and guides the appropriate use of medical and surgical management strategies.


Detection and phylogenetic analysis of peste des petits ruminants virus isolated from outbreaks in Punjab, Pakistan.
Peste des Petits Ruminants (PPR) is an important viral disease of small ruminants and is endemic in Pakistan. In the following study, samples from two outbreaks of PPR in goats have been subjected to laboratory investigations. The Peste des Petits Ruminants virus (PPRV) genome was detected using both conventional and real-time PCR. Genetic characterization of the local PPRV field isolates was conducted by sequencing 322 bp of the fusion (F) gene and 255 bp of the nucleoprotein (N) gene. The phylogenetic tree based on the F gene clustered samples from both outbreaks into lineage 4 along with other Asian isolates, specifically into subcluster 1 along with isolates from Middle East. Analysis of N gene revealed a different pattern. In this case, the Pakistani samples clustered with Chinese, Tajikistani and Iranian isolates, which probably represents the true geographical pattern of virus circulation. This is the first report presenting the phylogenetic tree based on N gene as well as performing a parallel comparison of the trees of F and N gene together from Pakistani isolates. The results of this study shed light on the PPRV population in Pakistan and emphasize the importance of using molecular methods to understand the epidemiology. Such understanding is essential in any efforts to control the number and impact of outbreaks that are occurring in endemic countries such as Pakistan, especially in the current scenario where OIE and FAO are eager to control and subsequently eradicate PPR from the globe, as has been achieved for Rinderpest.


Zinc, iron and calcium are major limiting nutrients in the complementary diets of rural Kenyan children.
Poor quality infant and young child (IYC) diets contribute to chronic under-nutrition. To design effective IYC nutrition interventions, an understanding of the extent to which realistic food-based strategies can improve dietary adequacy is required. We collected 24-h dietary recalls from children 6-23 months of age (n = 401) in two rural agro-ecological zones of Kenya to assess the nutrient adequacy of their diets. Linear programming analysis (LPA) was used to identify realistic food-based recommendations (FBRs) and to determine the extent to which they could ensure intake adequacy for 12 nutrients. Mean nutrient densities of the IYC diets were below the desired level for four to nine of the 10 nutrients analysed, depending on the age group. Mean dietary diversity scores ranged from 2.1 ± 1.0 among children 6-8 months old in Kitui County to 3.7 ± 1.1 food groups among children 12-23 months old in Vihiga County. LPA confirmed that dietary adequacy for iron, zinc and calcium will be difficult to ensure using only local foods as consumed. FBRs for breastfed children that promote the daily consumption of cows'/goats' milk (added to porridges), fortified cereals, green leafy vegetables, legumes, and meat, fish or eggs, 3-5 times per week can ensure dietary adequacy for nine and seven of 12 nutrients for children 6-11 and 12-23 months old, respectively. For these rural Kenyan children, even though dietary adequacy could be improved via realistic changes in habitual food consumption practices, alternative interventions are needed to ensure dietary adequacy at the population level.


Search for a Heavy Neutral Particle Decaying to eμ, eτ, or μτ in pp Collisions at sqrt[s]=8 TeV with the ATLAS Detector.
This Letter presents a search for a heavy neutral particle decaying into an opposite-sign different-flavor dilepton pair, e^{±}μ^{∓}, e^{±}τ^{∓}, or μ^{±}τ^{∓} using 20.3 fb^{-1} of pp collision data at sqrt[s]=8 TeV collected by the ATLAS detector at the LHC. The numbers of observed candidate events are compatible with the standard model expectations. Limits are set on the cross section of new phenomena in two scenarios: the production of ν[over ˜]_{τ} in R-parity-violating supersymmetric models and the production of a lepton-flavor-violating Z^{'} vector boson.


Hepatic deficiency of the pioneer transcription factor FoxA restricts hepatitis B virus biosynthesis by the developmental regulation of viral DNA methylation.
The FoxA family of pioneer transcription factors regulates hepatitis B virus (HBV) transcription, and hence viral replication. Hepatocyte-specific FoxA-deficiency in the HBV transgenic mouse model of chronic infection prevents the transcription of the viral DNA genome as a result of the failure of the developmentally controlled conversion of 5-methylcytosine residues to cytosine during postnatal hepatic maturation. These observations suggest that pioneer transcription factors such as FoxA, which mark genes for expression at subsequent developmental steps in the cellular differentiation program, mediate their effects by reversing the DNA methylation status of their target genes to permit their ensuing expression when the appropriate tissue-specific transcription factor combinations arise during development. Furthermore, as the FoxA-deficient HBV transgenic mice are viable, the specific developmental timing, abundance and isoform type of pioneer factor expression must permit all essential liver gene expression to occur at a level sufficient to support adequate liver function. This implies that pioneer transcription factors can recognize and mark their target genes in distinct developmental manners dependent upon, at least in part, the concentration and affinity of FoxA for its binding sites within enhancer and promoter regulatory sequence elements. This selective marking of cellular genes for expression by the FoxA pioneer factor compared to HBV may offer the opportunity for the specific silencing of HBV gene expression and hence the resolution of chronic HBV infections which are responsible for approximately one million deaths worldwide annually due to liver cirrhosis and hepatocellular carcinoma.


A comparison of reduced coordinate sets for describing protein structure.
In all-atom molecular simulation studies of proteins, each atom in the protein is represented by a point mass and interactions are defined in terms of the atomic positions. In recent years, various simplified approaches have been proposed. These approaches aim to improve computational efficiency and to provide a better physical insight. The simplified models can differ widely in their description of the geometry and the interactions inside the protein. This study explores the most fundamental choice in the simplified protein models: the choice of a coordinate set defining the protein structure. A simplified model can use fewer point masses than the all-atom model and/or eliminate some of the internal coordinates of the molecule by setting them to an average or ideal value. We look at the implications of such choices for the overall protein structure. We find that care must be taken for angular coordinates, where even very small variations can lead to significant changes in the positions of far away atoms. In particular, we show that the φ/ψ torsion angles are not a sufficient coordinate set, whereas another coordinate set with two degrees of freedom per residue, virtual Cα backbone bond, and torsion angles performs satisfactorily.


Prolonged post-differentiation culture influences the expression and biophysics of Na+ and Ca2+ channels in induced pluripotent stem cell-derived ventricular-like cardiomyocytes.
Several studies have been reported in various domains from induction methods to utilities of somatic cell pluripotent reprogramming. However, one of the major struggles facing the research field of induced pluripotent stem cell (iPSC)-derived target cells is the lack of consistency in observations. This could be due to variety of reasons including varied culture periods post-differentiation. The cardiomyocytes (CMs) derived from iPSCs are commonly studied and proposed to be utilized in the comprehensive in vitro proarrhythmia initiative for drug safety screening. As the influence of varied culture periods on the electrophysiological properties of iPSC-CMs is not clearly known, using whole-cell patch clamp technique, we compared two groups of differentiated ventricular-like iPSC-CMs that are cultured for 10 to 15 days (D10-15) and more than 30 days (≥ D30) both under current and voltage clamps. The prolonged culture imparts increased excitability with high-frequency spontaneous action potentials, robust increase in the magnitude of peak Na+ current density, relatively shallow inactivation kinetics of Na+ channels, faster recovery from inactivation, and augmented Ca2+ current density. Quantitative real-time PCR studies of α-subunit transcripts showed enhanced mRNA expression of SCN1A, SCN5A Na+ channel subtypes, and CACNA1C, CACNA1G, and CACNA1I Ca2+ channel subtypes, in ≥ D30 group. Conclusively, the prolonged culture of differentiated iPSC-CMs affects the excitability, single-cell electrophysiological properties, and ion channel expressions. Therefore, following standard periods of culture across research studies while utilizing ventricular-like iPSC-CMs for in vitro health/disease modeling to study cellular functional mechanisms or test high-throughput drugs' efficacy and toxicity becomes crucial.


Presenting phenotypes of acute heart failure patients in the ED: Identification and implications.
There is little known about the baseline hemodynamic (HD) profiles (beyond pulse/blood pressure) of patients presenting to the Emergency department (ED) with acute heart failure (AHF). Assessing these baseline parameters could help differentiate underlying HD phenotypes which could be used to develop specific phenotypic specific approaches to patient care. Patients with suspected AHF were enrolled in the PREMIUM (Prognostic Hemodynamic Profiling in the Acutely Ill Emergency Department Patient) multinational registry and continuous HD monitoring was initiated on ED presentation using noninvasive finger cuff technology (Nexfin, BMEYE, Edwards Lifesciences, Irvine, California). Individuals with clinically suspected and later confirmed AHF were included in this analysis and initial 15minute averages for available HD parameters were calculated. K-means clustering was performed to identify out of 23 HD variables a set that provided the greatest level of inter-cluster discrimination and intra-cluster cohesions. A total of 127 patients had confirmed AHF. The final model, using mean normalized patient baseline HD values was able to differentiate these individuals into 3 distinct phenotypes. Cluster 1: normal cardiac index (CCI) and systemic vascular resistance index (SVRI); cluster 2: very low CI and markedly increased SVRI: and cluster 3: low CI and an elevated SVRI. These clusters were not differentiated using clinically available ED information. Three distinct clusters were defined using novel noninvasive presenting HD monitoring technology in this cohort of ED AHF patients. Further studies are needed to determine whether phenotypic specific therapies based on these clusters can improve outcomes.


High relapse rate of T cell acute lymphoblastic leukemia in adults treated with Hyper-CVAD chemotherapy in Sweden.
Hyper-CVAD is widely used to treat acute lymphoblastic leukemia (ALL) and aggressive lymphomas. This multicenter, population-based study assessed the efficacy of Hyper-CVAD as first-line therapy in patients with T-cell ALL (T-ALL). Between October 2002 and September 2006, 24 patients were diagnosed with T-ALL in Sweden; 19 were eligible for treatment with the protocol. The median age was 32 yr (range 18-72 yr). Complete remission (CR) was obtained in 17 of 19 (89%) patients, and the treatment was relatively well tolerated. Allogeneic stem cell transplantation (SCT) was recommended in high-risk disease and was performed in four patients upfront. Two- and 5-yr leukemia-free survivals (LFS) in 17 patients with CR achievement were identical, at 29% (95% confidence interval [CI]: 8-51). Two- and 5-yr overall survival (OS) in whole cohort was 63% (95% CI: 42-85) and 47% (95% CI: 26-69), respectively. The 5-yr LFS for 15 patients who did not receive allogeneic SCT upfront were 20% (95% CI: 0-40), although 14 of 15 completed the protocol (eight cycles). Relapse occurred in 2 of 4 upfront-transplanted patients and in 12 of 15 patients treated with chemotherapy alone, six of whom received allogeneic SCT in CR2. Age ≥35 yr influenced OS negatively in univariate analysis (HR 5.1, 95% CI: 1.55-16.7). Hyper-CVAD treatment resulted in a high CR rate and appeared safe, but it showed poor efficacy at preventing relapse. Therefore, this treatment is no longer recommended for adults with T-ALL in Sweden.


Association between acute lead exposure in indoor firing ranges and iron metabolism.
Iron deficiency and lead poisoning are common and are often associated. This association has been suggested previously, mainly by retrospective cross-sectional studies. To assess the impact of short-term lead exposure at indoor firing ranges, and its relationship to iron, ferritin, lead, zinc protoporphyrin, and hemoglobin concentrations in young adults. We conducted a clinical study in 30 young healthy soldiers serving in the Israel Defense Forces. Blood samples were drawn for lead, zinc protoporphyrin, iron, hemoglobin and ferritin prior to and after a 6 week period of intensive target practice in indoor firing ranges. After a 6 week period of exposure to lead dust, a mean blood lead level increase (P < 0.0001) and a mean iron (P < 0.0005) and mean ferritin (P < 0.0625) decrease occurred simultaneously. We found a trend for inverse correlation between pre-exposure low ferritin levels and post-exposure high blood lead levels. The decrease in iron and ferritin levels after short-term lead exposure can be attributed to competition between iron and lead absorption via divalent metal transport-1, suggesting that lead poisoning can cause iron depletion and that iron depletion can aggravate lead poisoning. This synergistic effect should come readily to every physician's mind when treating patients with a potential risk for each problem separately.


Subtype-specific influenza A virus antibodies in Canada geese (Branta canadensis).
Historically, surveillance for influenza A viruses (IAVs) in wild birds has relied on viral detection assays. This was largely due to poor performance of serological assays in wild birds; however, recently developed commercial serological assays have improved the ability to detect IAV antibodies in wild birds. Serological surveillance for IAV antibodies in Canada geese (Branta canadensis) has shown that, despite a low prevalence of virus isolations, Canada geese are frequently exposed to IAVs and that exposure increases with latitude, which follows virus isolation prevalence patterns observed in dabbling ducks. The objectives of this study were to further evaluate IAV antibodies in Canada geese using a subtype-specific serological assay to determine if Canada geese are exposed to subtypes that commonly circulate in dabbling ducks. We collected serum samples from Canada geese in Minnesota, New Jersey, Pennsylvania, and Wisconsin and tested for antibodies to IAVs using a blocking ELISA. Positive samples were further tested by hemagglutination inhibition for 10 hemagglutinin IAV subtypes (H1-H10). Overall, we detected antibodies to NP in 24% (714/2919) of geese. Antibodies to H3, H4, H5, and H6 subtypes predominated, with H5 being detected most frequently. A decrease in H5 HI antibody prevalence and titers was observed from 2009 to 2012. We also detected similar exposure pattern in Canada geese from New Jersey, Minnesota, Washington and Wisconsin. Based on the published literature, H3, H4, and H6 viruses are the most commonly reported IAVs from dabbling ducks. These results indicate that Canada geese also are frequently exposed to viruses of the same HA subtypes; however, the high prevalence of antibodies to H5 viruses was not expected as H5 IAVs are generally not well represented in reported isolates from ducks.


Avoiding Peg-Filgrastim Prophylaxis During the Paclitaxel Portion of the Dose-Dense Doxorubicin-Cyclophosphamide and Paclitaxel Regimen: A Prospective Study.
The use of growth factors adds considerable expense and some toxicity to adjuvant breast cancer chemotherapy. We tested the feasibility and safety of omitting routine peg-filgrastim use during the paclitaxel portion of the dose-dense doxorubicin-cyclophosphamide-paclitaxel regimen. This was a prospective, single-arm study in which patients 18 to 65 years of age who completed 4 cycles of dose-dense doxorubicin-cyclophosphamide for stage I-III breast cancer received paclitaxel 175 mg/m2 every 2 weeks. Peg-filgrastim was administered after paclitaxel only if patients had had febrile neutropenia in a prior cycle or at investigator discretion if patients had infections or treatment delays of > 1 week. Once a patient received peg-filgrastim, it was administered in all future cycles. The primary end point was the rate of paclitaxel completion within 7 weeks from cycle 1 day 1 to cycle 4 day 1. If ≥ 100 out of 125 patients completed 4 cycles of paclitaxel without dose delay, the regimen would be considered feasible. The enrollment goal of 125 patients was met. Median age was 46 years (range, 21-65 years), and 112 patients (90% [95% CI, 83% to 94%]) completed dose-dense paclitaxel within 7 weeks. Omission of peg-filgrastim was not causally related to noncompletion of paclitaxel in any patients. The most common reasons for dose reduction or delays were nonhematologic. One patient experienced febrile neutropenia but was able to complete paclitaxel on time. Eight patients (6.4%) received peg-filgrastim during the trial. Overall, peg-filgrastim was administered in only 4.3% of paclitaxel cycles. Omission of routine peg-filgrastim during dose-dense paclitaxel according to a prespecified algorithm seems to be safe and feasible and was associated with a 95.7% reduction in the use of peg-filgrastim relative to the current standard of care.


High Reproducibility of an Automated Measurement of Mobility for Patients with Axial Spondyloarthritis.
Conventional measures of spinal mobility used in the assessment of patients with axial spondyloarthritis (axSpA), such as the Bath Ankylosing Spondylitis Metrology Index and its components, are subject to interobserver variability. The University of Córdoba Ankylosing Spondylitis Metrology Index (UCOASMI) is a validated composite index based on a motion video-capture system, UCOTrack. Our objective was to assess its reproducibility in clinical practice settings. We carried out an observational study of repeated measures in 3 centers. Video-capture systems were installed and adapted to clinical rooms. Patients with axSpA and stable disease were selected by consecutive stratified sampling [disease duration, sex, and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)]. Intraobserver reliability of the UCOASMI and of conventional measures was tested 3-5 days apart. For interobserver reliability, 3 patients from each center were evaluated in the other centers, within 3-7 days. The intraclass correlation coefficients (ICC) were calculated. Thirty patients were included (73% men, mean age 53 yrs, mean BASDAI 3.0). Interobserver and intraobserver ICC of the UCOASMI was 0.98. Conventional measurements showed lower but adequate reproducibility as well, except for interobserver reliability of lateral flexion (0.41), cervical rotation (0.61), and Schöber test (0.07), and intraobserver reliability of tragus-to-wall distance (0.30). Reproducibility of the UCOASMI seems very high, and apparently more reliable than conventional measures of mobility.