Preventive care.
To examine the impact of provider continuity on preventive care among adults who have a regular site of care. Logistic regression analyses were conducted to explore whether continuity, categorized as having no regular care, site continuity, or provider continuity, was associated with receipt of 3 preventive care services (influenza vaccination, receipt of a mammogram, and smoking cessation advice), independent of predisposing, need, and enabling factors. This study examined 42664 persons with private, Medicaid, Medicare, or no health insurance coverage who reported either having no site of care or being seen in a physician's office, HMO, hospital outpatient department, or other health center. The 1996/1997 Community Tracking Study (CTS) household survey, a telephone-based survey providing a cross-sectional sample of 60446 U.S. adults aged 18 and older representing the U.S. housed, noninstitutionalized population. After adjustment for differences in predisposing, enabling, and need factors, site continuity was associated with significant increases of 10.4% in influenza vaccinations (P =.006) and 12.6% in mammography (P =.001), and a nonsignificant increase of 5.6% in smoking cessation advice (P =.13) compared to having no regular site of care. After adjustment for these factors, provider continuity was associated with an additional improvement of 6.0% in influenza vaccinations (P =.01) and 6.2% in mammography (P =.04), and a nonsignificant increase of 2.5% in smoking cessation advice (P =.30) compared to site continuity. Provider continuity and site continuity are independently associated with receipt of preventive services. Compared to having no regular site of care, having site continuity was associated with increased receipt of influenza vaccination and mammography and, compared to having site continuity, having provider continuity was associated with further increases in the receipt of these two preventive services.


Response to national policy imperatives for nursing education: a Western Cape case study.
Since South Africa became a democratic country in 1994, the higher education sector has been faced with the challenge of transformation and restructuring. The Minister of Education in the Education White Paper 3 stated that "the higher education system must be transformed to redress the past inequities, to serve a new social order, to meet pressing national needs and to respond to realities and opportunities" (Department of Education, 1997:2). Higher education institutions were faced with the realities of impending mergers and collaborations across programmes and between universities and technikons. The Council on Higher Education (CHE) submitted a report to the Minister of Education in February 2002 which proposed the establishment of new institutional and organizational forms within regions (Department of Education, 2002: 7-8). The Minister announced changes in higher education based on his assessment of the proposals submitted by the CHE which resulted in the reduction of the number of higher education institutions from 36 to 21 (Department of Education, 2002:11-20). There were specific implications for nursing education in the Western Cape. In December 2002 the Minister of Education, Kader Asmal announced that with effect from 2005, the University of the Western Cape (UWC) and a new institution, the Cape Peninsula University of Technology (CPUT) would be the only enrolling institutions for undergraduate nursing education in the Western Cape. The Cape Higher Education Consortium (CHEC) instead proposed the establishment of a common teaching platform for nursing education in the region to meet the objectives of national and provincial government and to make optimal use of the combined strengths of the three universities and the technikon. This proposal was accepted by the minister and the common teaching platform, a unique form of collaboration, was established in 2005.


Evaluation of BLAST-based edge-weighting metrics used for homology inference with the Markov Clustering algorithm.
Clustering protein sequences according to inferred homology is a fundamental step in the analysis of many large data sets. Since the publication of the Markov Clustering (MCL) algorithm in 2002, it has been the centerpiece of several popular applications. Each of these approaches generates an undirected graph that represents sequences as nodes connected to each other by edges weighted with a BLAST-based metric. MCL is then used to infer clusters of homologous proteins by analyzing these graphs. The various approaches differ only by how they weight the edges, yet there has been very little direct examination of the relative performance of alternative edge-weighting metrics. This study compares the performance of four BLAST-based edge-weighting metrics: the bit score, bit score ratio (BSR), bit score over anchored length (BAL), and negative common log of the expectation value (NLE). Performance is tested using the Extended CEGMA KOGs (ECK) database, which we introduce here. All metrics performed similarly when analyzing full-length sequences, but dramatic differences emerged as progressively larger fractions of the test sequences were split into fragments. The BSR and BAL successfully rescued subsets of clusters by strengthening certain types of alignments between fragmented sequences, but also shifted the largest correct scores down near the range of scores generated from spurious alignments. This penalty outweighed the benefits in most test cases, and was greatly exacerbated by increasing the MCL inflation parameter, making these metrics less robust than the bit score or the more popular NLE. Notably, the bit score performed as well or better than the other three metrics in all scenarios. The results provide a strong case for use of the bit score, which appears to offer equivalent or superior performance to the more popular NLE. The insight that MCL-based clustering methods can be improved using a more tractable edge-weighting metric will greatly simplify future implementations. We demonstrate this with our own minimalist Python implementation: Porthos, which uses only standard libraries and can process a graph with 25 m + edges connecting the 60 k + KOG sequences in half a minute using less than half a gigabyte of memory.


Pathogenomic analyses of Mycobacterium microti, an ESX-1-deleted member of the Mycobacterium tuberculosis complex causing disease in various hosts.
Mycobacterium microti is an animal-adapted member of the Mycobacterium tuberculosis complex (MTBC), which was originally isolated from voles, but has more recently also been isolated from other selected mammalian hosts, including occasionally from humans. Here, we have generated and analysed the complete genome sequences of five representative vole and clinical M. microti isolates using PacBio- and Illumina-based technologies, and have tested their virulence and vaccine potential in SCID (severe combined immune deficient) mouse and/or guinea pig infection models. We show that the clinical isolates studied here cluster separately in the phylogenetic tree from vole isolates and other clades from publicly available M. microti genome sequences. These data also confirm that the vole and clinical M. microti isolates were all lacking the specific RD1mic region, which in other tubercle bacilli encodes the ESX-1 type VII secretion system. Biochemical analysis further revealed marked phenotypic differences between isolates in type VII-mediated secretion of selected PE and PPE proteins, which in part were attributed to specific genetic polymorphisms. Infection experiments in the highly susceptible SCID mouse model showed that the clinical isolates were significantly more virulent than the tested vole isolates, but still much less virulent than the M. tuberculosis H37Rv control strain. The strong attenuation of the ATCC 35872 vole isolate in immunocompromised mice, even compared to the attenuated BCG (bacillus Calmette-Guérin) vaccine, and its historic use in human vaccine trials encouraged us to test this strain's vaccine potential in a guinea pig model, where it demonstrated similar protective efficacy as a BCG control, making it a strong candidate for vaccination of immunocompromised individuals in whom BCG vaccination is contra-indicated. Overall, we provide new insights into the genomic and phenotypic variabilities and particularities of members of an understudied clade of the MTBC, which all share a recent common ancestor that is characterized by the deletion of the RD1mic region.


A therapeutic antibody targeting osteoprotegerin attenuates severe experimental pulmonary arterial hypertension.
Pulmonary arterial hypertension (PAH) is a rare but fatal disease. Current treatments increase life expectancy but have limited impact on the progressive pulmonary vascular remodelling that drives PAH. Osteoprotegerin (OPG) is increased within serum and lesions of patients with idiopathic PAH and is a mitogen and migratory stimulus for pulmonary artery smooth muscle cells (PASMCs). Here, we report that the pro-proliferative and migratory phenotype in PASMCs stimulated with OPG is mediated via the Fas receptor and that treatment with a human antibody targeting OPG can attenuate pulmonary vascular remodelling associated with PAH in multiple rodent models of early and late treatment. We also demonstrate that the therapeutic efficacy of the anti-OPG antibody approach in the presence of standard of care vasodilator therapy is mediated by a reduction in pulmonary vascular remodelling. Targeting OPG with a therapeutic antibody is a potential treatment strategy in PAH.


Osteoclast-Released Wnt-10b Underlies Cinacalcet Related Bone Improvement in Chronic Kidney Disease.
Secondary hyperparathyroidism (SHPT) relates to high turnover bone loss and is responsible for most bone fractures among chronic kidney disease (CKD) patients. Changes in the Wingless/beta-catenin signaling (Wnt/β-catenin) pathway and Wnt inhibitors have been found to play a critical role in CKD related bone loss. A calcimimetic agent, cinacalcet, is widely used for SHPT and found to be similarly effective for parathyroidectomy clinically. A significant decrease in hip fracture rates is noted among US hemodialysis Medicare patients since 2004, which is probably related to the cinacalcet era. In our previous clinical study, it was proven that cinacalcet improved the bone mineral density (BMD) even among severe SHPT patients. In this study, the influence of cinacalcet use on bone mass among CKD mice was determined. Cinacalcet significantly reduced the cortical porosity in femoral bones of treated CKD mice. It also improved the whole-bone structural properties through increased stiffness and maximum load. Cinacalcet increased femoral bone wingless 10b (Wnt10b) expression in CKD mice. In vitro studies revealed that cinacalcet decreased osteoclast bone resorption and increased Wnt 10b release from osteoclasts. Cinacalcet increased bone mineralization when culturing the osteoblasts with cinacalcet treated osteoclast supernatant. In conclusion, cinacalcet increased bone quantity and quality in CKD mice, probably through increased bone mineralization related with osteoclast Wnt 10b secretion.


A Cross-Modal Perspective on the Relationships between Imagery and Working Memory.
Mapping the distinctions and interrelationships between imagery and working memory (WM) remains challenging. Although each of these major cognitive constructs is defined and treated in various ways across studies, most accept that both imagery and WM involve a form of internal representation available to our awareness. In WM, there is a further emphasis on goal-oriented, active maintenance, and use of this conscious representation to guide voluntary action. Multicomponent WM models incorporate representational buffers, such as the visuo-spatial sketchpad, plus central executive functions. If there is a visuo-spatial "sketchpad" for WM, does imagery involve the same representational buffer? Alternatively, does WM employ an imagery-specific representational mechanism to occupy our awareness? Or do both constructs utilize a more generic "projection screen" of an amodal nature? To address these issues, in a cross-modal fMRI study, I introduce a novel Drawing-Based Memory Paradigm, and conceptualize drawing as a complex behavior that is readily adaptable from the visual to non-visual modalities (such as the tactile modality), which opens intriguing possibilities for investigating cross-modal learning and plasticity. Blindfolded participants were trained through our Cognitive-Kinesthetic Method (Likova, 2010a, 2012) to draw complex objects guided purely by the memory of felt tactile images. If this WM task had been mediated by transfer of the felt spatial configuration to the visual imagery mechanism, the response-profile in visual cortex would be predicted to have the "top-down" signature of propagation of the imagery signal downward through the visual hierarchy. Remarkably, the pattern of cross-modal occipital activation generated by the non-visual memory drawing was essentially the inverse of this typical imagery signature. The sole visual hierarchy activation was isolated to the primary visual area (V1), and accompanied by deactivation of the entire extrastriate cortex, thus 'cutting-off' any signal propagation from/to V1 through the visual hierarchy. The implications of these findings for the debate on the interrelationships between the core cognitive constructs of WM and imagery and the nature of internal representations are evaluated.


Reporting standards for endovascular repair of saccular intracranial cerebral aneurysms.
The goal of this article is to provide consensus recommendations for reporting standards, terminology, and written definitions when reporting on the radiological evaluation and endovascular treatment of intracranial, cerebral aneurysms. These criteria can be used to design clinical trials, to provide uniformity of definitions for appropriate selection and stratification of patients, and to allow analysis and meta-analysis of reported data. This article was written under the auspices of the Joint Writing Group of the Technology Assessment Committee, Society of NeuroInterventional Surgery, Society of Interventional Radiology; Joint Section on Cerebrovascular Neurosurgery of the American Association of Neurological Surgeons and Congress of Neurological Surgeons; and Section of Stroke and Interventional Neurology of the American Academy of Neurology. A computerized search of the National Library of Medicine database of literature (PubMed) from January 1991 to December 2007 was conducted with the goal to identify published endovascular cerebrovascular interventional data about the assessment and endovascular treatment of cerebral aneurysms useful as benchmarks for quality assessment. We sought to identify those risk adjustment variables that affect the likelihood of success and complications. This article offers the rationale for different clinical and technical considerations that may be important during the design of clinical trials for endovascular treatment of cerebral aneurysms. Included in this guidance article are suggestions for uniform reporting standards for such trials. These definitions and standards are primarily intended for research purposes; however, they should also be helpful in clinical practice and applicable to all publications. The evaluation and treatment of brain aneurysms often involve multiple medical specialties. Recent reviews by the American Heart Association have surveyed the medical literature to develop guidelines for the clinical management of ruptured and unruptured cerebral aneurysms. Despite efforts to synthesize existing knowledge on cerebral aneurysm evaluation and treatment, significant inconsistencies remain in nomenclature and definition for research and reporting purposes. These operational definitions were selected by consensus of a multidisciplinary writing group to provide consistency for reporting on imaging in clinical trials and observational studies involving cerebral aneurysms. These definitions should help different groups to publish results that are directly comparable.


Origin of compartmentalization in food webs.
The response of an ecosystem to perturbations is mediated by both antagonistic and facilitative interactions between species. It is thought that a community's resilience depends crucially on the food web--the network of trophic interactions--and on the food web's degree of compartmentalization. Despite its ecological importance, compartmentalization and the mechanisms that give rise to it remain poorly understood. Here we investigate several definitions of compartments, propose ways to understand the ecological meaning of these definitions, and quantify the degree of compartmentalization of empirical food webs. We find that the compartmentalization observed in empirical food webs can be accounted for solely by the niche organization of species and their diets. By uncovering connections between compartmentalization and species' diet contiguity, our findings help us understand which perturbations can result in fragmentation of the food web and which can lead to catastrophic effects. Additionally, we show that the composition of compartments can be used to address the long-standing question of what determines the ecological niche of a species.


Alternative cereals can improve water use and nutrient supply in India.
Humanity faces the grand challenge of feeding a growing, more affluent population in the coming decades while reducing the environmental burden of agriculture. Approaches that integrate food security and environmental goals offer promise for achieving a more sustainable global food system, yet little work has been done to link potential solutions with agricultural policies. Taking the case of cereal production in India, we use a process-based crop water model and government data on food production and nutrient content to assess the implications of various crop-shifting scenarios on consumptive water demand and nutrient production. We find that historical growth in wheat production during the rabi (non-monsoon) season has been the main driver of the country's increased consumptive irrigation water demand and that rice is the least water-efficient cereal for the production of key nutrients, especially for iron, zinc, and fiber. By replacing rice areas in each district with the alternative cereal (maize, finger millet, pearl millet, or sorghum) with the lowest irrigation (blue) water footprint (WFP), we show that it is possible to reduce irrigation water demand by 33% and improve the production of protein (+1%), iron (+27%), and zinc (+13%) with only a modest reduction in calories. Replacing rice areas with the lowest total (rainfall + irrigation) WFP alternative cereal or the cereal with the highest nutritional yield (metric tons of protein per hectare or kilograms of iron per hectare) yielded similar benefits. By adopting a similar multidimensional framework, India and other nations can identify food security solutions that can achieve multiple sustainability goals simultaneously.


Lolland-Falster Health Study: Study protocol for a household-based prospective cohort study.
Introduction: Lolland-Falster consists of two islands in the southern part of Denmark where income is lower and life expectancy is shorter than in the general Danish population. It is a mixed rural-provincial area with approximately 100,000 inhabitants. The Lolland-Falster Health Study was initiated to gain knowledge on the determinants of health in this disadvantaged area. Methods: The study is a household-based prospective cohort study including people of all ages. The entire household of randomly selected inhabitants is allocated either to an invited group or to an uninvited, non-contacted control group. The data collection encompasses questionnaires, physical examination and biological samples, i.e. blood and urine for same-day analysis and biobank storage, and saliva and faeces also for biobank storage. The civil registration number links collected data for each individual, family and household, with information in Danish registers. The data collection started in February 2016 and is estimated to end by 2019 after the enrolment of 20,000 people. Analysis: A number of in-depth sub-studies are planned. Emphasis will be given to analysis of intra- and inter-family variations in health determinants, genetics, lifestyle and health status. Ethics: Region Zealand's Ethical Committee on Health Research (SJ-421) and the Danish Data Protection Agency (REG-24-2015) approved the study. Trial registration: Clinicaltrials.gov (NCT02482896). Strength and limitations of this study: The strength of this study is that Lolland-Falster Health Study is a useful scientific resource for investigating cross-sectional difference and time trends within and between individuals, families and households. LOFUS adds diversity to the previously collected Danish population studies in urbanized areas. The limitation is that data collection is expensive. Conclusions: LOFUS will contribute to the knowledge on health in disadvantaged, rural-provincial areas.


Internal brow elevation at blepharoplasty.
To present data on a transblepharoplasty technique that provides a safe and reliable brow elevation and glabellar furrow reduction by releasing inferior tethering and weakening the brow depressor muscles. Nonrandomized retrospective case series and surgical technique description. One thousand patients who underwent internal brow elevation for cosmesis associated with upper blepharoplasty over the past 9 years were reviewed. Follow-up ranged from 6 months to 9 years. There were no serious long-term complications. All patients experienced forehead hypesthesia, which was temporary in most patients. Only 2 patients complained of prolonged and bothersome forehead hypesthesia lasting longer than 2 years. The internal brow elevation at blepharoplasty is a reproducibly safe and effective technique to improve eyebrow appearance without fixation.


Identification of a tyrosine-phosphorylated 35 kDa carboxy-terminal fragment (p35CagA) of the Helicobacter pylori CagA protein in phagocytic cells: processing or breakage?
Helicobacter pylori is a very common bacterial pathogen that causes gastric disease by inducing the infiltration of immune cells as an initial event. Virulent H. pylori strains express a type IV secretion system composed of several virulence (Vir) proteins encoded by the cag pathogenicity island (cag PAI). During infection of phagocytic cells (U937, Josk-M and J774A.1) we have detected a de novo tyrosine-phosphorylated protein (p35p-Tyr) with sizes of 30 kDa, 38 kDa or 40 kDa, depending on the H. pylori strain. p35p-Tyr occurrence required functional virB4, virB7, virB10, virB11, virD4 and cagA (cytotoxin-associated gene A) genes encoded by the cag PAI suggesting that p35p-Tyr is a bacterial protein of variable size. We have biochemically purified p35p-Tyr from infected U937 cells. Tryptic peptides of p35p-Tyr determined by matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) identified the carboxy (C)-terminal part of the H. pylori CagA protein. Subsequent analysis by two-dimensional electrophoresis (2-DE) and immunoblotting using anti-CagA antibodies revealed the presence of three stable CagA protein species in phagocytes: (i) 130-140 kDa full-length CagA (p135CagA), (ii) a 100-105 kDa fragment (p100CagA) and (iii) a 30-40 kDa fragment (p35CagA). Unlike p135CagA, p35CagA and p100CagA were also detected in much lower amounts in H. pylori without host cell contact. Therefore, breakage or processing leads to the production of p35CagA and p100CagA, a process that is enhanced after translocation into host cells. MALDI-MS data and the isoelectric point determined by both 2-DE and sequence analysis suggested that p35CagA represents the C-terminal part of CagA and p100CagA corresponds to the remaining amino (N)-terminal fragment. The possible function of CagA in host signal transduction and development of gastric disease is discussed.


Mechanistic contrasts between manganese and rhenium bipyridine electrocatalysts for the reduction of carbon dioxide.
[Re(bpy)(CO)3](-) is a well-established homogeneous electrocatalyst for the reduction of CO2 to CO. Recently, substitution of the more abundant transition metal Mn for Re yielded a similarly active electrocatalyst, [Mn(bpy)(CO)3](-). Compared to the Re catalyst, this Mn catalyst operates at a lower applied reduction potential but requires the presence of a weak acid in the solution for catalytic activity. In this study, we employ quantum chemistry combined with continuum solvation and microkinetics to examine the mechanism of CO2 reduction by each catalyst. We use cyclic voltammetry experiments to determine the turnover frequencies of the Mn catalyst with phenol as the added weak acid. The computed turnover frequencies for both catalysts agree to within one order of magnitude of the experimental ones. The different operating potentials for these catalysts indicate that different reduction pathways may be favored during catalysis. We model two different pathways for both catalysts and find that, at their respective operating potentials, the Mn catalyst indeed is predicted to take a different reaction route than the Re catalyst. The Mn catalyst can access both catalytic pathways, depending on the applied potential, while the Re catalyst does not show this flexibility. Our microkinetics analysis predicts which intermediates should be observable during catalysis. These intermediates for the two catalyzed reactions have qualitatively different electronic configurations, depending on the applied potential. The observable intermediate at higher applied potentials possesses an unpaired electron and therefore should be EPR-active; however, the observable intermediate at lower applied potentials, accessible only for the Mn catalyst, is diamagnetic and therefore should be EPR-silent. The differences between both catalysts are rationalized on the basis of their electronic structure and different ligand binding affinities.


Direct Visualization of Atomic-Scale Heterogeneous Structure Dynamics in MnO2 Nanowires.
Manganese oxides are attracting great interest owing to their rich polymorphism and multiple valent states, which give rise to a wide range of applications in catalysis, capacitors, ion batteries, and so forth. Most of their functionalities are connected to transitions among the various polymorphisms and Mn valences. However, their atomic-scale dynamics is still a great challenge. Herein, we discovered a strong heterogeneity in the crystalline structure and defects, as well as in the Mn valence state. The transitions are studied by in situ transmission electron microscopy (TEM), and they involve a complex ordering of [MnO6] octahedra as the basic building tunnels. MnO2 nanowires synthesized using solution-based hydrothermal methods usually exhibit a large number of multiple polymorphism impurities with different tunnel sizes. Upon heating, MnO2 nanowires undergo a series of stoichiometric polymorphism changes, followed by oxygen release toward an oxygen-deficient spinel and rock-salt phase. The impurity polymorphism exhibits an abnormally high stability with interesting small-large-small tunnel size transition, which is attributed to a preferential stabilizer (K+) concentration, as well as a strong competition of kinetics and thermodynamics. Our results unveil the complicated intergrowth of polymorphism impurities in MnO2, which provide insights into the heterogeneous kinetics, thermodynamics, and transport properties of the tunnel-based building blocks.


Clinco-epidemiologic study of cutaneous leishmaniasis in Bikaner, Rajasthan, India.
Cutaneous leishmaniasis is endemic to the Thar Desert of Rajasthan, Bikaner, India. The present study describes clinico-epidemiologcial data of all cases of cutaneous leishmaniasis CL in this region during 2001-2011. A total of 1,379 patients with 2,730 lesions were reported during the study period. Ages of patients ranged from 3 months to 86 years, and there was a predominance of infections in males. Most patients were from urban areas and lower middle socioeconomic groups. Lesions were dry, ulcerated nodules or plaques of different sizes commonly over face and upper limb. Skin smears were positive for parasites in 958 (69.5%) patients, and the remaining 45.8% (193 of 421) patients were positive by skin biopsy. Histopathologic analysis of the skin showed mixed granulomas consisting of macrophages, lymphocytes, epitheloid, and plasma cells. Species identification was conducted for 45 randomly selected patients by polymerase chain reaction, the infective species was Leishmania tropica. Most patients were treated with intra-lesional injections of sodium stibogluconate.


Effect of Moderate to Vigorous Physical Activity on All-Cause Mortality in Middle-aged and Older Australians.
Few studies have examined how different proportions of moderate and vigorous physical activity affect health outcomes. To examine whether the proportion of total moderate to vigorous activity (MVPA) that is achieved through vigorous activity is associated with all-cause mortality independently of the total amount of MVPA. We performed a prospective cohort study with activity data linked to all-cause mortality data from February 1, 2006, through June 15, 2014, in 204,542 adults aged 45 through 75 years from the 45 and Up population-based cohort study from New South Wales, Australia (mean [SD] follow-up, 6.52 [1.23] years). Associations between different contributions of vigorous activity to total MVPA and mortality were examined using Cox proportional hazards models, adjusted for total MVPA and sociodemographic and health covariates. Different proportions of total MVPA as vigorous activity. Physical activity was measured with the Active Australia Survey. All-cause mortality during the follow-up period. During 1,444,927 person-years of follow-up, 7435 deaths were registered. Compared with those who reported no MVPA (crude death rate, 8.34%), the adjusted hazard ratios for all-cause mortality were 0.66 (95% CI, 0.61-0.71; crude death rate, 4.81%), 0.53 (95% CI, 0.48-0.57; crude death rate, 3.17%), and 0.46 (95% CI, 0.43-0.49; crude death rate, 2.64%) for reporting 10 through 149, 150 through 299, and 300 min/wk or more of activity, respectively. Among those who reported any MVPA, the proportion of vigorous activity revealed an inverse dose-response relationship with all-cause mortality: compared with those reporting no vigorous activity (crude death rate, 3.84%) the fully adjusted hazard ratio was 0.91 (95% CI, 0.84-0.98; crude death rate, 2.35%) in those who reported some vigorous activity (but <30% of total activity) and 0.87 (95% CI, 0.81-0.93; crude death rate, 2.08%) among those who reported 30% or more of activity as vigorous. These associations were consistent in men and women, across categories of body mass index and volume of MVPA, and in those with and without existing cardiovascular disease or diabetes mellitus. Among people reporting any activity, there was an inverse dose-response relationship between proportion of vigorous activity and mortality. Our findings suggest that vigorous activities should be endorsed in clinical and public health activity guidelines to maximize the population benefits of physical activity.


Resolving near-field from high order signals of scattering near-field scanning optical microscopy.
The ability of using scattering-type near-field scanning optical microscopy (s-NSOM) to characterize amplitude and phase of optical near fields was investigated. We employ numerical simulations to compute signals scattered by the tip, using a bowtie nano-aperture as the example, and compare with the data obtained from s-NSOM measurements. Through demodulation of higher order harmonic signals, we show that, with the increasing order of harmonic signals, both the simulated and measured near fields are in closer agreement with the anticipated near field results. The polarization-resolved detection also helps to establish a tip-dependent transfer matrix that relates the local field components with the s-NSOM signals, which characterizes the scattering of the tip with respect to different field components. This work illustrates the importance of using higher order signals in obtaining near field in an s-NSOM measurement.


Membrane wounding triggers ATP release and dysferlin-mediated intercellular calcium signaling.
Dysferlin is a Ca(2+)-binding protein found in many different cell types. It is required for membrane wound repair in muscle, but it is not known whether it has the same function in other cells. Here we report the activation of an intercellular signaling pathway in sea urchin embryos by membrane wounding that evokes Ca(2+) spikes in neighboring cells. This pathway was mimicked by ATP application, and inhibited by apyrase, cadmium, and omega-agatoxin-IVA. Microinjection of dysferlin antisense phosphorodiamidate morpholino oligonucleotides blocked this pathway, whereas control morpholinos did not. Co-injection of mRNA encoding human dysferlin with the inhibitory morpholino rescued signaling activity. We conclude that in sea urchin embryos dysferlin mediates Ca(2+)-triggered intercellular signaling in response to membrane wounding.


Phase III, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300.
There currently are no internationally recognised treatment guidelines for patients with advanced gastric cancer/gastro-oesophageal junction cancer (GC/GEJC) in whom two prior lines of therapy have failed. The randomised, phase III JAVELIN Gastric 300 trial compared avelumab versus physician's choice of chemotherapy as third-line therapy in patients with advanced GC/GEJC. Patients with unresectable, recurrent, locally advanced, or metastatic GC/GEJC were recruited at 147 sites globally. All patients were randomised to receive either avelumab 10 mg/kg by intravenous infusion every 2 weeks or physician's choice of chemotherapy (paclitaxel 80 mg/m2 on days 1, 8, and 15 or irinotecan 150 mg/m2 on days 1 and 15, each of a 4-week treatment cycle); patients ineligible for chemotherapy received best supportive care. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. A total of 371 patients were randomised. The trial did not meet its primary end point of improving OS {median, 4.6 versus 5.0 months; hazard ratio (HR)=1.1 [95% confidence interval (CI) 0.9-1.4]; P = 0.81} or the secondary end points of PFS [median, 1.4 versus 2.7 months; HR=1.73 (95% CI 1.4-2.2); P > 0.99] or ORR (2.2% versus 4.3%) in the avelumab versus chemotherapy arms, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 90 patients (48.9%) and 131 patients (74.0%) in the avelumab and chemotherapy arms, respectively. Grade ≥3 TRAEs occurred in 17 patients (9.2%) in the avelumab arm and in 56 patients (31.6%) in the chemotherapy arm. Treatment of patients with GC/GEJC with single-agent avelumab in the third-line setting did not result in an improvement in OS or PFS compared with chemotherapy. Avelumab showed a more manageable safety profile than chemotherapy. ClinicalTrials.gov: NCT02625623.


Localization of collagen XVIII and the endostatin portion of collagen XVIII in aged human control eyes and eyes with age-related macular degeneration.
Endostatin, a C-terminal fragment of collagen XVIII (coll XVIII) formed by proteolysis, specifically inhibits endothelial cell migration and proliferation in vitro and potently inhibits angiogenesis and tumor growth in vivo. The purpose of this study was to examine the immunolocalization of endostatin and coll XVIII in the retina and choroid of human donor tissue sections from aged control donor eyes and to determine whether the localization or relative levels are changed in age-related macular degeneration (AMD). Ocular tissues were obtained from six aged control donors (age range, 75-86 years; mean age, 80.5 years) without evidence or history of chorioretinal disease and from nine donors with AMD (age range, 74-105 years; mean age, 88.6 years). Tissues were cryopreserved, and streptavidin alkaline phosphatase immunohistochemistry was performed with goat anti-human and mouse anti-human endostatin antibodies and rabbit anti-mouse coll XVIII. Blood vessels were identified with mouse anti-human CD-34 antibody in adjacent sections. Pigment in RPE and choroidal melanocytes was bleached. Three independent observers scored the immunohistochemical reaction product. In aged control eyes, coll XVIII and endostatin (the endostatin portion of coll XVIII) immunoreactivity was observed in large retinal blood vessels and in capillaries in some individuals, but the internal limiting membrane (ILM) had the most intense retinal immunostaining. There was no significant difference in immunoreactivity to both antibodies in retinal blood vessels in aged control eyes. In the choroid, endostatin and coll XVIII were localized to blood vessels, Bruch's membrane, and RPE basal lamina. AMD retina and choroid had a similar pattern and intensity of coll XVIII immunostaining, as observed in control eyes but reaction product was more diffuse in the choroid. Endostatin immunoreactivity was significantly higher in ILM (P = 0.037) in AMD retina and significantly lower in the choriocapillaris, Bruch's membrane, and RPE basal lamina of AMD choroids (P < 0.05) and completely negative in some areas of AMD choroids. These data suggest that reduced levels of the endostatin portion of coll XVIII in Bruch's membrane, RPE basal lamina, intercapillary septa, and choriocapillaris in eyes with AMD may be permissive for choroidal neovascularization.


Optimizing medical data quality based on multiagent web service framework.
One of the most important issues in e-healthcare information systems is to optimize the medical data quality extracted from distributed and heterogeneous environments, which can extremely improve diagnostic and treatment decision making. This paper proposes a multiagent web service framework based on service-oriented architecture for the optimization of medical data quality in the e-healthcare information system. Based on the design of the multiagent web service framework, an evolutionary algorithm (EA) for the dynamic optimization of the medical data quality is proposed. The framework consists of two main components; first, an EA will be used to dynamically optimize the composition of medical processes into optimal task sequence according to specific quality attributes. Second, a multiagent framework will be proposed to discover, monitor, and report any inconstancy between the optimized task sequence and the actual medical records. To demonstrate the proposed framework, experimental results for a breast cancer case study are provided. Furthermore, to show the unique performance of our algorithm, a comparison with other works in the literature review will be presented.


Testing the cancer stem cell hypothesis in melanoma: the clinics will tell.
Whether tumorigenic cancer stem cells (CSCs) exist in melanoma has been the focus of much controversy in recent years. A number of studies have pointed to the existence of melanoma cell sub-populations that act as CSCs and can be distinguished from other tumor cells based on specific surface marker expression or specific properties such as the capacity for extensive self-renewal. Other studies failed to identify melanoma stem cells and proposed that the potential to initiate tumors is a wide spread feature in melanoma inherent to most if not all cells of the tumor mass. As with normal stem cells, the term CSC is based on an operational definition, indicating not just a tumor-initiating cell, but also a cell with the capacity to sustain long-term tumor propagation. Therefore, the experimental set-up chosen to identify putative CSCs in melanoma is crucial: Both the method of tumor cell preparation and the procedure used to assess CSC properties in vivo influence the experimental outcome and hence its interpretation. In this review, we summarize our current knowledge on CSCs and the role of stem cell properties in melanoma and discuss recent findings with respect to their clinical relevance.


Laser ablation is superior to TACE in large-sized hepatocellular carcinoma: a pilot case-control study.
Limited therapies are available for large (≥40 mm) unresectable hepatocellular carcinoma (HCC). Currently, the standard treatment with transarterial chemoembolisation (TACE) is unsatisfactory with high recurrence rate and limited effect on survival. Laser Ablation (LA) has emerged as a relatively new technique characterized by high efficacy and good safety. This study is aimed to evaluate the efficacy of LA in comparison to TACE in patients with large HCC. Eighty-two patients with a single HCC nodule ≥40 mm (BCLC stage A or B) were enrolled in this case-control study. Forty-one patients were treated with LA and 41 patients were treated with TACE. Response to therapy was evaluated according to the mRECIST criteria. Survival was calculated with Kaplan-Meier from the time of cancer diagnosis to death with values censored at the date of the last follow-up. Twenty-six (63.4%) and 8 (19.5%) patients had a complete response after LA and TACE, respectively (p < 0.001). Subsequently we stratified the HCCs in 3 categories according to the nodule size: 40-50 mm, 51-60 mm, and >60 mm. LA resulted superior to TACE especially in nodules ranging between 51 and 60 mm in diameter, with a complete response rate post-LA and post-TACE of 75% and 14.3%, respectively (p = 0.0133). The 36 months cumulative survival rate in patients treated with LA and TACE was 55.4% and 48.8%, respectively. The disease recurrence rates after LA and TACE were 19.5% and 75.0%, respectively. LA is a more effective therapeutic option than TACE in patients with solitary large HCC.


Double discrimination avoidance with a single stimulus.
Four white rats were trained to avoid electric shocks by depressing a bar after the onset of a stimulus and releasing it after termination of the stimulus. All subjects acquired the behavior of holding the bar in the presence of the stimulus and releasing it in the absence of the stimulus, but one animal almost always required a "priming" shock. The others exhibited a high level of shock avoidance.


Evaluation of neonatal-intensive-care programs.
Within the past 15 years, regional neonatal-intensive-care programs have been introduced and have expanded rapidly. The efficacy of some of the individual interventions that constitute neonatal intensive care has been validated in randomized, controlled clinical trials. It is therefore generally assumed that neonatal-intensive-care programs that incorporate these maneuvers are effective in reducing death and disability. However, the overall effectiveness of these programs has not been tested experimentally. Moreover, much of the non-experimental evidence supporting their value is based on the experience of referral units and does not measure the impact on the populations they serve. A definitive economic evaluation of neonatal intensive care has not yet been reported, despite the high cost of such programs. We conclude that neonatal-intensive care programs require further evaluation with rigorous scientific methods.


Global approaches to study protein-protein interactions among viruses and hosts.
While high-throughput protein-protein interaction screens were first published approximately 10 years ago, systematic attempts to map interactions among viruses and hosts started only a few years ago. HIV-human interactions dominate host-pathogen interaction databases (with approximately 2000 interactions) despite the fact that probably none of these interactions have been identified in systematic interaction screens. Recently, combinations of protein interaction data with RNAi and other functional genomics data allowed researchers to model more complex interaction networks. The rapid progress in this area promises a flood of new data in the near future, with clinical applications as soon as structural and functional genomics catches up with next-generation sequencing of human variation and structure-based drug design.


Religious and philosophical exemptions from vaccination requirements and lessons learned from conscientious objectors from conscription.
All jurisdictions in the US require proof of vaccination for school entrance. Most states permit non-medical exemptions. Public health officials must balance the rights of individuals to choose whether or not to vaccinate their children with the individual and societal risks associated with choosing not to vaccinate (i.e., claiming an exemption). To assist the public health community in optimally reaching this balance, this analysis examines the constitutional basis of non-medical exemptions and examines policies governing conscientious objection to conscription as a possible model. The jurisprudence that the US Supreme Court has developed in cases in which religious beliefs conflict with public or state interests suggests that mandatory immunization against dangerous diseases does not violate the First Amendment right to free exercise of religion. Accordingly, states do not have a constitutional obligation to enact religious exemptions. Applying the model of conscientious objectors to conscription suggests that if states choose to offer nonmedical exemptions, they may be able to optimally balance individual freedoms with public good by considering the sincerity of beliefs and requiring parents considering exemptions to attend individual educational counseling.


Travel Volume to the United States from Countries and U.S. Territories with Local Zika Virus Transmission.
Air, land, and sea transportation can facilitate rapid spread of infectious diseases. In May 2015 the Pan American Health Organization (PAHO) issued an alert regarding the first confirmed Zika virus infection in Brazil. As of March 8, 2016, the U.S. Centers for Disease Control and Prevention (CDC) had issued travel notices for 33 countries and 3 U.S. territories with local Zika virus transmission. Using data from five separate datasets from 2014 and 2015, we estimated the annual number of passenger journeys by air and land border crossings to the United States from the 33 countries and 3 U.S. territories listed in the CDC's Zika travel notices as of March 8, 2016. We also estimated the annual number of passenger journeys originating in and returning to the United States (primarily on cruises) with visits to seaports in areas with local Zika virus transmission. Because of the adverse pregnancy and birth outcomes that have been associated with Zika virus disease, the number of passenger journeys completed by women of childbearing age and pregnant women was also estimated. An estimated 216.3 million passenger journeys by air, land, and sea are made annually to the United States from areas with local Zika virus transmission (as of March 8). The destination states with the largest numbers of arrivals were Texas (by land) and Florida (by air and sea). An estimated 51.7 million passenger journeys were made by women of childbearing age and an estimated 2.3 million were made by pregnant women. Travel volume analyses provide important information that can be used to effectively target public health interventions as well as direct public health resources and efforts at local, regional, and country-specific levels.


Cavity-induced microstreaming for simultaneous on-chip pumping and size-based separation of cells and particles.
We present a microfluidic platform for simultaneous on-chip pumping and size-based separation of cells and particles without external fluidic control systems required for most existing platforms. The device utilizes an array of acoustically actuated air/liquid interfaces generated using dead-end side channels termed Lateral Cavity Acoustic Transducers (LCATs). The oscillating interfaces generate local streaming flow while the angle of the LCATs relative to the main channel generates a global bulk flow from the inlet to the outlet. The interaction of these two competing velocity fields (i.e. global bulk velocity vs. local streaming velocity) is responsible for the observed separation. It is shown that the separation of 5 μm and 10 μm polystyrene beads is dependent on the ratio of these two competing velocity fields. The experimental and simulation results suggest that particle trajectories based only on Stokes drag force cannot fully explain the separation behavior and that the impact of additional forces due to the oscillating flow field must be considered to determine the trajectory of the beads and ultimately the separation behavior of the device. To demonstrate an application of this separation platform with cellular components, smaller red blood cells (7.5 ± 0.8 μm) are separated from larger K562 cells (16.3 ± 2.0 μm) with viabilities comparable to those of controls based on a trypan blue exclusion assay.


Concord grape juice supplementation improves memory function in older adults with mild cognitive impairment.
Concord grape juice contains polyphenol compounds, which have antioxidant and anti-inflammatory properties and influence neuronal signalling. Concord grape juice supplementation has been shown to reduce inflammation, blood pressure and vascular pathology in individuals with CVD, and consumption of such flavonoid-containing foods is associated with a reduced risk for dementia. In addition, preliminary animal data have indicated improvement in memory and motor function with grape juice supplementation, suggesting potential for cognitive benefit in ageing humans. In this initial investigation of neurocognitive effects, we enrolled twelve older adults with memory decline but not dementia in a randomised, placebo-controlled, double-blind trial with Concord grape juice supplementation for 12 weeks. We observed significant improvement in a measure of verbal learning and non-significant enhancement of verbal and spatial recall. There was no appreciable effect of the intervention on depressive symptoms and no effect on weight or waist circumference. A small increase in fasting insulin was observed for those consuming grape juice. These preliminary findings suggest that supplementation with Concord grape juice may enhance cognitive function for older adults with early memory decline and establish a basis for more comprehensive investigations to evaluate potential benefit and assess mechanisms of action.


Transgenic Expression of the Mitochondrial Chaperone TNFR-associated Protein 1 (TRAP1) Accelerates Prostate Cancer Development.
Protein homeostasis, or proteostasis, is required for mitochondrial function, but its role in cancer is controversial. Here we show that transgenic mice expressing the mitochondrial chaperone TNFR-associated protein 1 (TRAP1) in the prostate develop epithelial hyperplasia and cellular atypia. When examined on a Pten+/- background, a common alteration in human prostate cancer, TRAP1 transgenic mice showed accelerated incidence of invasive prostatic adenocarcinoma, characterized by increased cell proliferation and reduced apoptosis, in situ Conversely, homozygous deletion of TRAP1 delays prostatic tumorigenesis in Pten+/- mice without affecting hyperplasia or prostatic intraepithelial neoplasia. Global profiling of Pten+/--TRAP1 transgenic mice by RNA sequencing and reverse phase protein array reveals modulation of oncogenic networks of cell proliferation, apoptosis, cell motility, and DNA damage. Mechanistically, reconstitution of Pten+/- prostatic epithelial cells with TRAP1 increases cell proliferation, reduces apoptosis, and promotes cell invasion without changes in mitochondrial bioenergetics. Therefore, TRAP1 is a driver of prostate cancer in vivo and an "actionable" therapeutic target.


Factors influencing the outcome of paediatric cardiac surgical patients during extracorporeal circulatory support.
Veno-arterial extracorporeal membrane oxygenation (ECMO) is a common modality of circulatory assist device used in children. We assessed the outcome of children who had ECMO following repair of congenital cardiac defects (CCD) and identified the risk factors associated with hospital mortality. From April 1990 to December 2003, 53 patients required ECMO following surgical correction of CCD. Retrospectively collected data was analyzed with univariate and multivariate logistic regression analysis. Median age and weight of the patients were 150 days and 5.4 kgs respectively. The indications for ECMO were low cardiac output in 16, failure to wean cardiopulmonary bypass in 13, cardiac arrest in 10 and cardio-respiratory failure in 14 patients. The mean duration of ECMO was 143 hours. Weaning off from ECMO was successful in 66% and of these 83% were survival to hospital-discharge. 37.7% of patients were alive for the mean follow-up period of 75 months. On univariate analysis, arrhythmias, ECMO duration >168 hours, bleeding complications, renal replacement therapy on ECMO, arrhythmias and cardiac arrest after ECMO were associated with hospital mortality.On multivariate analysis, abnormal neurology, bleeding complications and arrhythmias after ECMO were associated with hospital mortality. Extra and intra-thoracic cannulations were used in 79% and 21% of patients respectively and extra-thoracic cannulation had significantly less bleeding complications (p = 0.031). ECMO provides an effective circulatory support following surgical repair of CCD in children. Extra-thoracic cannulation is associated with less bleeding complications. Abnormal neurology, bleeding complications on ECMO and arrhythmias after ECMO are poor prognostic indicators for hospital survival.


Life's timekeeper.
Life's timekeeper is a 'free-running' intracellular oscillator synchronised across all cells. It runs throughout life splitting lifespan into equal length phases. During the maturational period it controls the overall rate of progression whereas in the post-maturational period it controls the overall rate of ageing. This includes the rate of senescence and hence time to death. As such life's timekeeper equates maturational and post-maturational time, hence explains the tight correlation between these time periods that has existed throughout mammalian evolution. Life's timekeeper is proposed to have played an important role in vertebrate evolution. A slower oscillatory frequency results in proportional life phase prolongation. This leads to increased body and brain size, together with extended lifespan. Higher brain centres, neocortex in mammals, are disproportionately enlarged. Hence behavioural capacity is increased. The extended post-maturational period ensures that there is enough time in order that the behavioural advantages can be fully manifest in the environment. A faster oscillatory frequency would result in proportional life phase reduction. This process however would lead to reduced behavioural capacity, and is hence unlikely to be positively selected. Therefore throughout evolution life's timekeeper has operated to extend lifespan. It has hence functioned to promote longevity as opposed to ageing.


Measurement of reduced glutathione (GSH) in human brain using LCModel analysis of difference-edited spectra.
The concentration of reduced glutathione (GSH), an antioxidant, may be altered in various brain diseases. MEGA-PRESS was used to edit for the (1)H NMR signal from GSH in the occipital lobe of 12 normal humans. In all studies, GSH was clearly detected with a spectral pattern consistent with spectra acquired from a phantom containing GSH. Retention of singlet resonances in the subspectra, a key advantage of this difference-editing technique, provided an unambiguous reference for the offset and phase of the edited signal. Linear combination model (LCModel) analysis provided an unbiased means for quantifying signal contribution from edited metabolites. GSH concentration was estimated from the in vivo spectra as 1.3 +/- 0.2 micro mol/g (mean +/- SD, n = 12).


Low electro-synthesis potentials improve permselectivity of polymerized natural phenols in biosensor applications.
First-generation amperometric biosensors are often based on the electro-oxidation of oxidase-generated H2O2. At the applied potential used in most studies, other molecules such as ascorbic acid or dopamine can be oxidized. Phenylenediamines are commonly used to avoid this problem: when these compounds are electro-deposited onto the transducer surface in the form of poly-phenylenediamine, a highly selective membrane is formed. Although there is no evidence of toxicity of the resulting polymer, phenylenediamine monomers are considered carcinogenic. An aim of this work was to evaluate the suitability of natural phenols as non-toxic alternatives to the ortho isomer of phenylenediamine. Electrosynthesis over Pt-Ir electrodes of 2-methoxy phenols (guaiacol, eugenol and isoeugenol), and hydroxylated biphenyls (dehydrodieugenol and magnolol) was achieved. The potentials used in the present study are significantly lower than values commonly applied during electro-polymerization. Polymers were obtained by means of constant potential amperometry, instead of cyclic voltammetry, in order to achieve multiple polymerizations, hence decreasing the time of realization and variability. Permselective properties of natural phenols were significantly improved at low polymerization potentials. Among the tested compounds, isoeugenol and magnolol, polymerized respectively at +25mV and +170mV against Ag/AgCl reference electrode, proved as permselective as poly-ortho-phenylenediamine and may be considered as effective polymeric alternatives. The natural phenol-coated electrodes were stable and responsive throughout 14 days. A biosensor prototype based on acetylcholine esterase and choline oxidase was electro-coated with poly-magnolol in order to evaluate the interference-rejecting properties of the electrosynthesized film in an amperometric biosensor; a moderate decrease in ascorbic acid rejection was observed during in vitro calibration of biosensors.


Brain-metastatic melanoma: a neurotrophic perspective.
The brain is a unique microenvironment enclosed by the skull and maintaining a highly regulated vascular transport barrier. To metastasize to the brain, malignant tumor cells must attach to microvessel endothelial cells, invade the blood-brain barrier (BBB), and respond to brain survival and growth factors. Neurotrophins (NT) are important in brain invasion because they stimulate this process. In brain-metastatic melanoma cells, NT can promote invasion by enhancing the production of extracellular matrixdegradative enzymes such as heparanase, an enzyme capable of locally destroying both the extracellular matrix and the basement membrane of the BBB. We have examined human and murine melanoma cell lines exhibiting varying abilities to form brain metastases, and have found that they express low-affinity neurotrophin receptor p75NTR in relation to their brain-metastatic potentials. They do not, however, express trkA, the gene encoding the tyrosine kinase receptor TrkA, the high-affinity receptor for nerve growth factor (NGF), the prototypic NT. Presence of functional TrkC, the putative receptor for the invasion-promoting neurotrophin NT-3, was also expressed in these cells. Brain-metastatic melanoma cells can also produce autocrine factors and inhibitors that influence their growth, invasion, and survival in the brain. Synthesis of these factors may influence NT production by brain cells adjacent to the neoplastic invasion front, such as oligodendrocytes and astrocytes. In brain biopsies, we observed increased amounts of NGF and NT-3 in tumor-adjacent tissues at the invasion front of human melanoma tumors. Additionally, we found that astrocytes contribute to the brain-metastatic specificity of melanoma cells by producing NT-regulated heparanase. Trophic, autocrine, and paracrine growth factors may therefore determine whether metastatic cells can successfully invade, colonize, and grow in the central nervous system (CNS).


Selection on the human bitter taste gene, TAS2R16, in Eurasian populations.
Bitter taste is one of the most important senses alerting humans to noxious foods. In gatherer communities, sensitivity to bitterness is presumably advantageous because of various noxious plants. TAS2R16 is the gene coding the taste receptor molecules for some of the most common toxins in plants. A previous study of this gene indicated selection has increased the frequency of a derived allele in this gene that arose before the human expansion out of Africa. We have applied a different methodology for detecting selection, the Long Range Haplotype (LRH) analysis, to TAS2R16 in a larger sampling of populations from around the world. The haplotype with the derived alleles at both the functional polymorphism and a polymorphism in the regulatory region of TAS2R16 showed evidence for recent positive selection in most of the Eurasian populations, though the highest selection signal occurs in Mbuti Pygmies, an African hunter-gatherer group. In Eurasia, only populations of Mesopotamia and the southeast coast of China have no signals of selection. The evidence of recent selection found in most Eurasian populations differs from the geographic pattern seen in the earlier study of selection. One can speculate that the difference may result from a gathering lifestyle extending into the most recent 10,000 yrs and the need to recognize newly encountered bitter natural toxins as populations expanded into new environments and the biota changes with the ending of the most recent ice age. Alternatively, the promoter region variant may be a marker for altered function beyond what the derived amino acid allele conferred.


Seeing through the dust: martian crustal heterogeneity and links to the SNC meteorites.
Through the application of new analytical techniques to high spatial resolution imaging spectrometer data, the ferrous mineralogy of major volcanic terrains on Mars is shown to consist of significant fractions of both low- and high-calcium pyroxene. Changes in the relative abundances of these pyroxenes are observed for units of different age and morphology, even in regions with higher degrees of alteration and contamination from dust. Volcanic rocks with these characteristics are uncommon on Earth but are typical of the basaltic SNC meteorites (shergottites, nakhlites, and chassignites) thought to be from Mars. Thus, it is possible to infer, even through the veil of dust, that the SNC meteorites have mineralogic affinities to major volcanic provinces on Mars and are therefore truly representative of the heterogeneity observed on the surface of the "red planet".


Beneficial effects of hydrogen gas in a rat model of traumatic brain injury via reducing oxidative stress.
Traumatic brain injury (TBI) is a leading cause of mortality and disability among the young population. It has been shown that hydrogen gas (H(2)) exerts a therapeutic antioxidant activity by selectively reducing hydroxyl radical (OH, the most cytotoxic ROS). Recently, we have found that H(2) inhalation significantly improved the survival rate and organ damage of septic mice. In the present study, we investigated the effectiveness of H(2) therapy on brain edema, blood-brain barrier (BBB) breakdown, neurological dysfunction and injury volume in TBI-challenged rats. In addition, we investigated the effects of H(2) treatment on the changes of oxidative products and antioxidant enzymes in brain tissue of TBI-challenged rats. Hydrogen treatment was given by exposure to 2% H(2) from 5 min to 5h after sham or TBI operation, respectively. Here, we found that TBI-challenged rats showed significant brain injuries characterized by the increase of BBB permeability, brain edema and lesion volume as well as neurological dysfunction, which was significantly attenuated by 2% H(2) treatment. In addition, we found that the decrease of oxidative products and the increase of endogenous antioxidant enzymatic activities in the brain tissue may be associated with the protective effects of H(2) treatment in TBI-challenged rats. The present study supports that H(2) inhalation may be a more effective therapeutic strategy for patients with TBI.


Highly-efficient coupling of linearly- and radially-polarized femtosecond pulses in hollow-core photonic band-gap fibers.
We demonstrate extremely efficient excitation of linearly-, radially-, and azimuthally-polarized modes in a hollow-core photonic band-gap fiber with femtosecond laser pulses. We achieve coupling efficiencies as high as 98% with linearly polarized input Gaussian beams and with high-power pulses we obtain peak intensities greater than 10(14) W/cm(2) inside and transmitted through the fiber. With radially polarized pulses, we achieve 91% total transmission through the fiber while maintaining the polarization state. Alternatively with azimuthally-polarized pulses, the mode is degraded in the fiber, and the pure polarization state is not maintained.


The diagnosis and management of pleural effusions in the ICU.
Pleural effusions are common in critically ill patients. Most effusions in intensive care unit (ICU) patients are of limited clinical significance; however, some are important and require aggressive management. Transudative effusions in the ICU are commonly caused by volume overload, decreased plasma oncotic pressure, and regions of altered pleural pressure attributable to atelectasis and mechanical ventilation. Exudates are sequelae of pulmonary or pleural infection, pulmonary embolism, postsurgical complications, and malignancy. Increases in pleural fluid volume are accommodated principally by chest wall expansion and, to a lesser degree, by lung collapse. Studies in mechanically ventilated patients suggest that pleural fluid drainage can result in improved oxygenation for up to 48 hours, but data on clinical outcomes are limited. Mechanically ventilated patients with pleural effusions should be semirecumbant and treated with higher levels of positive-end expiratory pressure. Rarely, large effusions can cause cardiac tamponade or tension physiology, requiring urgent drainage. Bedside ultrasound is both sensitive and specific for diagnosing pleural effusions in mechanically ventilated patients. Sonographic findings of septation and homogenous echogenicity may suggest an exudative effusion, but definitive diagnosis requires pleural fluid sampling. Thoracentesis should be carried out under ultrasound guidance. Antibiotic regimens for parapneumonic effusions should be based on current pneumonia guidelines, and anaerobic coverage should be included in the case of empyema. Decompression of the pleural space may be necessary to improve respiratory mechanics, as well as to treat complicated effusions. While small-bore catheters inserted under ultrasound guidance may be used for nonseptated effusions, surgical consultation should be sought in cases where this approach fails, or where the effusion appears complex and septated at the outset. Further research is needed to determine the effects of pleural fluid drainage on clinical outcomes in mechanically ventilated patients, to evaluate weaning strategies that include pleural fluid drainage, and to better identify patients in whom pleural effusions are more likely to be infected.


Three Growth Spurts in Global Physical Activity Policies between 2000 and 2019: A Policy Document Analysis.
Non-communicable diseases (NCDs) contribute significantly to global mortality and are of particular concern in growing urban populations of low- and-middle income countries (LMICs). Physical inactivity is a key NCD determinant and requires urgent addressing. Laudable global and regional efforts to promote physical activity are being made, but the links between physical activity (PA), NCD reduction, and integrated intersectoral approaches to reducing obesogenic environments are not consistently made. This study applied a document analysis approach to global PA and NCD policies to better understand the current global policy environment and how this may facilitate integrated PA promotion. A total of 34 global policies related to PA, from different sectors, were analyzed. PA policy in mitigation of NCDs has evolved exponentially, with a progression towards addressing structural determinants alongside individual behavior change. The global PA agenda is primarily driven by the World Health Organization. Intersectoral collaboration is importantly regarded, but the contributions of other sectors, outside of health, education, transport, and urban planning, are less clear. Improving PA among key sub-populations-women, girls, and adolescents-requires greater policy consideration. It is imperative for PA-relevant sectors at all levels to recognize the links with NCDs and work towards integrated policy and practice in mitigation of the rising NCD pandemic.


Information-Pooling Bias in Collaborative Security Incident Correlation Analysis.
Incident correlation is a vital step in the cybersecurity threat detection process. This article presents research on the effect of group-level information-pooling bias on collaborative incident correlation analysis in a synthetic task environment. Past research has shown that uneven information distribution biases people to share information that is known to most team members and prevents them from sharing any unique information available with them. The effect of such biases on security team collaborations are largely unknown. Thirty 3-person teams performed two threat detection missions involving information sharing and correlating security incidents. Incidents were predistributed to each person in the team based on the hidden profile paradigm. Participant teams, randomly assigned to three experimental groups, used different collaboration aids during Mission 2. Communication analysis revealed that participant teams were 3 times more likely to discuss security incidents commonly known to the majority. Unaided team collaboration was inefficient in finding associations between security incidents uniquely available to each member of the team. Visualizations that augment perceptual processing and recognition memory were found to mitigate the bias. The data suggest that (a) security analyst teams, when conducting collaborative correlation analysis, could be inefficient in pooling unique information from their peers; (b) employing off-the-shelf collaboration tools in cybersecurity defense environments is inadequate; and (c) collaborative security visualization tools developed considering the human cognitive limitations of security analysts is necessary. Potential applications of this research include development of team training procedures and collaboration tool development for security analysts.


X-ray spectroscopic study of the charge state and local ordering of room-temperature ferromagnetic Mn-doped ZnO.
The charge state and local ordering of Mn doped into a pulsed laser deposited single-phase thin film of ZnO are investigated by using x-ray absorption spectroscopy at the O K-edge, Mn K-edge and L-edge, and x-ray emission spectroscopy at the O K-edge and Mn L-edge. This film is ferromagnetic at room temperature. EXAFS measurement shows that Mn(2+) replaces the Zn site in tetrahedral symmetry, and there is no evidence for either metallic Mn or MnO in the film. Upon Mn doping, the top of O 2p valence band extends into the bandgap, indicating additional charge carriers being created.


Differential effects of age and history of hypertension on regional brain volumes and iron.
Aging affects various structural and metabolic properties of the brain. However, associations among various aspects of brain aging are unclear. Moreover, those properties and associations among them may be modified by age-associated increase in vascular risk. In this study, we measured volume of brain regions that vary in their vulnerability to aging and estimated local iron content via T2* relaxometry. In 113 healthy adults (19-83 years old), we examined prefrontal cortex (PFC), primary visual cortex (VC), hippocampus (HC), entorhinal cortex (EC), caudate nucleus (Cd), and putamen (Pt). In some regions (PFC, VC, Cd, and Pt) age-related differences in iron and volume followed similar patterns. However, in the medial-temporal structures, volume and iron content exhibited different age trajectories. Whereas age-related volume reduction was mild in HC and absent in EC, iron content evidenced significant age-related declines. In hypertensive participants significantly greater iron content was noted in all examined regions. Thus, iron content as measured by T2* may be a sensitive index of regional brain aging and may reveal declines that are more prominent than gross anatomical shrinkage.


Violence, sensation seeking, and impulsivity in schizophrenics found unfit to stand trial.
Many studies have confirmed an association between violent behavior, impulsivity, and sensation seeking in nonpsychotic subjects. Schizophrenic patients (n = 49) who had been found unfit to stand trial were investigated for violence, according to index offenses and longitudinal histories (before and after admission) for violence. Those charged with violent offenses were significantly more often married with children, and were equally likely to direct their assaultiveness to strangers, acquaintances, and family members. The nature of the index offense seemed to be a good indicator of general violent propensity. No significant differences were found on Barratt's Impulsivity Scale and Zuckerman's Sensation Seeking Scale, except that schizophrenic patients with negative histories of violence scored higher on the thrill and adventure subscale. No pattern of substance abuse differentiated the groups. Patients charged with violent offenses more often presented with persecutory delusions, but this did not extend to those whose histories were positive for repetitive violence. Although impulsivity and sensation seeking do not seem to cause violent behavior in this group, psychopathology can also only be regarded as a necessary but not sufficient determinant.


Introduction of human pharmaceuticals from wastewater treatment plants into the aquatic environment: a rural perspective.
Incomplete removal of pharmaceuticals during wastewater treatment can result in their discharge into the aquatic environment. The discharge of pharmaceuticals in wastewater treatment plant (WWTP) effluents into rivers, lakes and the oceans has led to detectable concentrations of pharmaceuticals in the aquatic environment in many countries. However, to date studies of WWTP discharges into the aquatic environment have largely been confined to areas of relatively high population density, industrial activity or systems impacted on by such areas. In this work, two sites in the far north of Scotland were used to assess whether, and which, pharmaceuticals were being introduced into natural waters in a rural environment with low population density. Samples from two WWTPs (with differing modes of operation), and one receiving water, the River Thurso, were analysed for the presence of 12 pharmaceuticals (diclofenac, clofibric acid, erythromycin, ibuprofen, mefenamic acid, paracetamol, propranolol, sulfamethoxazole, tamoxifen, trimethoprim and dextropropoxyphene). Ten of the 12 pharmaceuticals investigated were detected in at least one of the 40 WWTP effluent samples. Maximum concentrations ranged from 7 ng L(-1) (sulfamethoxazole) to 22.8 μg L(-1) (paracetamol) with diclofenac and mefenamic acid being present in all of samples analysed at concentrations between 24.2 and 927 ng L(-1) and 11.5 and 22.8 μg L(-1), respectively. Additionally, the presence of four pharmaceuticals at ng L(-1) levels in the River Thurso, into which one of the WWTPs discharges, shows that such discharges result in measurable levels of pharmaceuticals in the environment. This provides direct evidence that, even in rural areas with low population densities, effluents from WWTPs can produce quantifiable levels of human pharmaceutical in the natural aquatic environment. These observations indicate that human pharmaceuticals may be considered as contaminants, with potential to influence water quality, management and conservation not only in urban and industrial regions but also those more rural in nature.


Oxygen uptake kinetics measured at the onset of comfortable self-paced walking in elderly women after hip fracture.
The objectives of this study were to (1) evaluate the suitability of "comfortable" self-paced walking as a mode of exercise to study VO(2) kinetics, and (2) to investigate VO(2) kinetics after hip fracture using self-paced walking as the exercise mode. The study took place in a Scottish rehabilitation hospital physiotherapy gymnasium [hip fracture (HF) group] and a Scottish University Gymnasium [young (Y) and healthy elderly (HE) groups]. Fifteen women after HF (median age 81 years) and five Y and five older HE women (median ages 22 and 78 years, respectively) took part in the study. Volunteers completed three repeats of 3 min of "comfortable" self-paced walking on two occasions. The ensemble averaged VO(2) response from walks 2 and 3 on visits 1 and 2 were combined and characterised using nonlinear regression techniques to derive a Mean Response Time (MRT). Self-paced walking was described as "constant-load" exercise (coefficient of variation of lap speeds of <or=6%) in 13 of 15 cases in the HF group on at least one visit (100% of cases in Y and HE groups). Steady-state VO(2) was achieved in 3 min in 8 of HF group on Visit 1 and 10 on Visit 2 (100% of cases in Y and HE groups). MRTs for the HF group (51 s, N = 5, 4 repeats; N = 7, 2 repeats) were significantly higher than the Y and HE groups [Y group 22 s (N = 5, 4 repeats); HE group 36 s (N = 5, 4 repeats)]. Self-paced walking provided a suitable mode of exercise to investigate VO(2) kinetics in frail older women after HF and permitted the first characterisation of VO(2) kinetics in this patient group. This test provides a promising methodology to evaluate rehabilitation efforts in frail individuals.


Towards an aligned luminophore solar concentrator.
Luminescent solar concentrators promise to reduce the cost of solar energy, but are hindered by a number of losses. Escape of luminescence through the large waveguide-air interfaces can be attenuated through alignment of the optical transition dipole of the luminophore along the waveguide surface normal, directing the maximum possible proportion of luminescence into waveguide modes. We demonstrate such alignment using a guest-host dye-doped liquid crystal sandwiched between conductive glass slides. Application of a potential while illuminating through a narrow edge caused a drop in the intensity of luminescence escaping the large surfaces, and an increase in the intensity of light escaping the narrow edges of the system. This is explained in terms of alignment of the transition dipoles of the dye. We discuss implementation in a luminescent solar concentrator.


Improved Method to Stratify Elderly Patients With Cancer at Risk for Competing Events.
To compare a novel generalized competing event (GCE) model versus the standard Cox proportional hazards regression model for stratifying elderly patients with cancer who are at risk for competing events. We identified 84,319 patients with nonmetastatic prostate, head and neck, and breast cancers from the SEER-Medicare database. Using demographic, tumor, and clinical characteristics, we trained risk scores on the basis of GCE versus Cox models for cancer-specific mortality and all-cause mortality. In test sets, we examined the predictive ability of the risk scores on the different causes of death, including second cancer mortality, noncancer mortality, and cause-specific mortality, using Fine-Gray regression and area under the curve. We compared how well models stratified subpopulations according to the ratio of the cumulative cause-specific hazard for cancer mortality to the cumulative hazard for overall mortality (ω) using the Akaike Information Criterion. In each sample, increasing GCE risk scores were associated with increased cancer-specific mortality and decreased competing mortality, whereas risk scores from Cox models were associated with both increased cancer-specific mortality and competing mortality. GCE models created greater separation in the area under the curve for cancer-specific mortality versus noncancer mortality (P < .001), indicating better discriminatory ability between these events. Comparing the GCE model to Cox models of cause-specific mortality or all-cause mortality, the respective Akaike Information Criterion scores were superior (lower) in each sample: prostate cancer, 28.6 versus 35.5 versus 39.4; head and neck cancer, 21.1 versus 29.4 versus 40.2; and breast cancer, 24.6 versus 32.3 versus 50.8. Compared with standard modeling approaches, GCE models improve stratification of elderly patients with cancer according to their risk of dying from cancer relative to overall mortality.


Telomere length and brain imaging phenotypes in UK Biobank.
Telomeres form protective caps at the ends of chromosomes, and their attrition is a marker of biological aging. Short telomeres are associated with an increased risk of neurological and psychiatric disorders including dementia. The mechanism underlying this risk is unclear, and may involve brain structure and function. However, the relationship between telomere length and neuroimaging markers is poorly characterized. Here we show that leucocyte telomere length (LTL) is associated with multi-modal MRI phenotypes in 31,661 UK Biobank participants. Longer LTL is associated with: i) larger global and subcortical grey matter volumes including the hippocampus, ii) lower T1-weighted grey-white tissue contrast in sensory cortices, iii) white-matter microstructure measures in corpus callosum and association fibres, iv) lower volume of white matter hyperintensities, and v) lower basal ganglia iron. Longer LTL was protective against certain related clinical manifestations, namely all-cause dementia (HR 0.93, 95% CI: 0.91-0.96), but not stroke or Parkinson's disease. LTL is associated with multiple MRI endophenotypes of neurodegenerative disease, suggesting a pathway by which longer LTL may confer protective against dementia.


Induction of telomere dysfunction mediated by the telomerase substrate precursor 6-thio-2'-deoxyguanosine.
The relationships between telomerase and telomeres represent attractive targets for new anticancer agents. Here, we report that the nucleoside analogue 6-thio-2'-deoxyguanosine (6-thio-dG) is recognized by telomerase and is incorporated into de novo-synthesized telomeres. This results in modified telomeres, leading to telomere dysfunction, but only in cells expressing telomerase. 6-Thio-dG, but not 6-thioguanine, induced telomere dysfunction in telomerase-positive human cancer cells and hTERT-expressing human fibroblasts, but not in telomerase-negative cells. Treatment with 6-thio-dG resulted in rapid cell death for the vast majority of the cancer cell lines tested, whereas normal human fibroblasts and human colonic epithelial cells were largely unaffected. In A549 lung cancer cell-based mouse xenograft studies, 6-thio-dG caused a decrease in the tumor growth rate superior to that observed with 6-thioguanine treatment. In addition, 6-thio-dG increased telomere dysfunction in tumor cells in vivo. These results indicate that 6-thio-dG may provide a new telomere-addressed telomerase-dependent anticancer approach. Telomerase is an almost universal oncology target, yet there are few telomerase-directed therapies in human clinical trials. In the present study, we demonstrate a small-molecule telomerase substrate approach that induces telomerase-mediated targeted "telomere uncapping," but only in telomerase-positive cancer cells, with minimal effects in normal telomerase-negative cells.


Quality of analgesic treatment in patients with advanced prostate cancer: do we do a better job now? The Swiss Group for Clinical Cancer Research (SAKK) experience.
The aim of this study was to evaluate pain intensity and the application of the WHO guidelines for cancer pain treatment in patients with prostate cancer treated at Swiss cancer centers. We analyzed a series of five multicenter phase II clinical trials which examined the palliative effect of different chemotherapies in patients with advanced hormone-refractory prostate carcinoma. Of 170 patients, 1,018 visits were evaluable for our purpose, including ratings of pain intensity by patients and prescribed analgesics. No or mild pain was indicated by patients in 36 to 55% of the visits, more than mild pain in 30 to 46%. In 21% of the visits, the WHO pain treatment criteria (treatment according to one of the three steps; oral, rectal or transdermal application of the main dose; administration on a regular schedule) were fulfilled, and the Cleeland index was positive according to all recommendations. In 6% of the visits, neither the WHO criteria were fulfilled nor was the Cleeland index positive. This indicates insufficient pain treatment not following the WHO guidelines and that the prescribed analgesics were not sufficiently potent for the rated pain intensity. In this selective Swiss sample, the standard of analgesic treatment is high. However, there is still scope for improvement. This cannot solely be solved by improving the knowledge of the physicians. Programs to change the patients' attitude towards cancer pain, training to improve the physicians' communication skills, and institutional changes may be promising strategies.


Timing of peak blood glucose after breakfast meals of different glycemic index in women with gestational diabetes.
This study aims to determine the peak timing of postprandial blood glucose level (PBGL) of two breakfasts with different glycemic index (GI) in gestational diabetes mellitus (GDM). Ten women with diet-controlled GDM who were between 30 and 32 weeks of gestation were enrolled in the study. They consumed two carbohydrate controlled, macronutrient matched bread-based breakfasts with different GI (low vs. high) on two separate occasions in a random order after an overnight fast. PBGLs were assessed using a portable blood analyser. Subjects were asked to indicate their satiety rating at each blood sample collection. Overall the consumption of a high GI breakfast resulted in a greater rise in PBGL (mean ± SEM peak PBGL: low GI 6.7 ± 0.3 mmol/L vs. high GI 8.6 ± 0.3 mmol/L; p < 0.001) and an earlier peak PBGL time (16.9 ± 4.9 min earlier; p = 0.015), with high variability in PBGL time between subjects. There was no significant difference in subjective satiety throughout the test period. In conclusion, the low GI breakfast produced lower postprandial glycemia, and the peak PBGL occurred closer to the time recommended for PBGL monitoring (i.e., 1 h postprandial) in GDM than a macronutrient matched high GI breakfast.


Transfer of Therapeutic Genes into Fetal Rhesus Monkeys Using Recombinant Adeno-Associated Type I Viral Vectors.
Neuromuscular disorders such as Pompe disease (glycogen storage disease, type II), result in early and potentially irreversible cellular damage with a very limited opportunity for intervention in the newborn period. Pompe disease is due to deficiency in acid α-glucosidase (GAA) leading to lysosomal accumulation of glycogen in all cell types, abnormal myofibrillogenesis, respiratory insufficiency, neurological deficits, and reduced contractile function in striated muscle. Previous studies have shown that fetal delivery of recombinant adeno-associated virus (rAAV) encoding GAA to the peritoneal cavity of Gaa-/- mice resulted in high-level transduction of the diaphragm. While progression of other genetic disorders may occur later in life, the potential of fetal gene delivery to avoid the onset of irreversible damage suggests it is an attractive option for many inherited diseases. In this study, rhesus monkey fetuses were administered 4.5 × 1012 particles of rAAV type 1 expressing human GAA (rAAV1-CMV-hGAA), human α-1-antitrypsin (rAAV1-CBA-hAAT), or human mini-dystrophin (rAAV1-CMV-miniDMD) in the late first trimester using an established intraperitoneal ultrasound-guided approach. Fetuses were monitored sonographically and newborns delivered at term for postnatal studies. All animals remained healthy during the study period (growth, hematology, and clinical chemistry), with no evidence of adverse effects. Tissues were collected at a postnatal age of 3 months (∼7 months post-fetal gene transfer) for immunohistochemistry (IHC) and quantitative PCR. Both the diaphragm and peritoneum from vector-treated animals were strongly positive for expression of human GAA, AAT, or dystrophin by IHC, similar to findings when reporter genes were used. Protein expression in the diaphragm and peritoneum correlated with high vector copy numbers detected by real-time PCR. Other anatomical areas were negative, although the liver showed minimal evidence of human GAA, AAT, and DMD, vector genomes. In summary, delivery of rAAV vectors provided stable transduction of the muscular component of the diaphragm without any evidence of adverse effects.


Antibiotic susceptibilities of two Coxiella burnetii isolates implicated in distinct clinical syndromes.
Antibiotic susceptibility testing of two isolates of the Q-fever agent, Coxiella burnetii, was performed with recently and persistently infected L929 fibroblast cells. The two genetically distinct isolates, Nine Mile and Priscilla, are implicated in two different clinical disease syndromes, acute and chronic Q fever, respectively. We compared the efficacies of rifampin, doxycycline, and five 4-quinolone compounds (ciprofloxacin, difloxacin, ofloxacin, norfloxacin, and pefloxacin) in reducing persistent C. burnetii infection of L929 fibroblasts. In persistently infected cells, the Priscilla isolate was less susceptible to all antibiotics tested when compared with the Nine Mile isolate. The most effective antibiotics against the Priscilla isolate were ofloxacin, pefloxacin, and ciprofloxacin (50% inhibitory concentrations of 0.5, 2.2, and 2.5 micrograms/ml, respectively). In persistently infected cells, the Nine Mile isolate was highly susceptible to all antibiotics tested except doxycycline. In contrast, the Priscilla and Nine Mile isolates in recently infected cells were somewhat susceptible to doxycycline; the Priscilla isolate was significantly more susceptible to ofloxacin and rifampin in recently infected host cells than in persistently infected cells. Persistently infected L929 cells were also treated with antibiotic combinations. Although ciprofloxacin and doxycycline had no synergistic effect on the Priscilla isolate, ciprofloxacin and rifampin acted synergistically. Collectively, these in vitro results are in accord with the fact that chronic Q fever in humans is generally not successfully managed with antibiotics. They also indicate that early diagnosis may be essential and that combination antibiotic therapy that includes quinolones may be effective in treating chronic Q fever.


Communicating radon risk via a smartphone app: a pilot intervention study.
Residential radon is a major preventable cause of lung cancer. However, prevention requires radon testing and it has proven very challenging to motivate individuals to test their homes for hazards like radon that are invisible and whose health effects occur after a long latency following exposure. Novel approaches to radon communication are urgently needed. We created a novel radon-education app for smartphones and examined its effectiveness in increasing radon knowledge and radon testing. We studied radon knowledge and attitudes and behavior relevant to radon testing before and after app use. Ninety-seven undergraduates installed the app on their smartphones and used it for a month. App use resulted in higher scores in the domains of radon knowledge (p < .001); self-efficacy (p < .001), and response efficacy (p < .001). Twenty-three participants (24%) used the app to obtain a free radon test kit. Self-efficacy (p < .05) and response efficacy (p < .01) were positive predictors of ordering a test kit. The test process completion rate (the fraction of participants who ordered test kits, used them to test their houses and sent the kits to the lab) was 9%. A smartphone app is a promising venue for communicating radon risk and for stimulating radon testing. Future interventions designed to increase actual test kit use are required to maximize the benefit of the app.


Role of the Bcl-2 gene family in prostate cancer progression and its implications for therapeutic intervention.
Prostate cancer (PC) is an escalating health burden in the western world. A large number of patients still present with extraprostatic (i.e., T3/T4, N0, M0/M1 or any T category and M1 disease or involved lymph nodes) and therefore incurable disease. Since the work of Huggins in 1940, there have been no major therapeutic advances and androgen ablation remains the best treatment option for extraprostatic androgen-responsive PC. Eighty to ninety percent of PC patients respond well to this form of treatment initially. After a median time of approximately 2 years, however, relapse to an androgen-independent (AI) state occurs, followed by death after a further median 6 months. Androgen ablation is rarely curative. The major molecular defect in extraprostatic and AI PC is the inability of PC cells to initiate apoptosis in response to a variety of stimuli, including different forms of androgen ablation and cytotoxic agents. The balance between cellular proliferation and cell death is regulated by multiple genes or families of genes through the cell cycle. The exact mechanisms governing this intricate and complex process are as yet not fully understood. One family of genes involved in cell survival/death control is the Bcl-2 gene family, which consists of homologous proteins that function to regulate distal and crucial commitment steps of the apoptotic pathway. The Bcl-2 family constitutes both agonists and antagonists of apoptosis that function at least in part through protein-protein interactions between various members of the family. The final outcome depends on the relative ratio of death agonists and antagonists. Bcl-2 expression has been closely associated with the AI phenotype of PC. Cytotoxic chemotherapy may be used as palliative therapy in AI PC but has not been found effective. Most chemotherapeutic cytotoxic agents induce apoptosis in cancer cells by direct and indirect action on the cell cycle. In vitro and in vivo studies have established that Bcl-2 expression confers an antiapoptotic activity against androgen withdrawal and cytotoxic chemotherapy. It thus offers a tempting potential target for therapeutic manipulations of PC.


Metabolic activity of neutrophils in patients suffering from chronic viral hepatitis.
The aim of the study was to evaluate the functional state of peripheral blood neutrophils in patients with chronic active viral hepatitis. Twenty-six patients with HBV, HCV or CMV in different clinical status were included in the analysis. In the study, the number of leukocytes and neutrophils was determined. The metabolic activity of neutrophils was examined in NBT reduction tests i.e. spontaneous (NBTsp) test and the one stimulated with LPS E. coli (NBTst). The results were analysed in relation to disease advancement and the type of viral infection. The data obtained from the affected patients were compared with the results from 46 healthy subjects. Most patients displayed neutropenia. It was found that the number of NBT positive cells and the coefficient of neutrophil metabolic activity (CNMA) in NBT sp test were highly significantly increased. The majority of patients had reduced values in NBTst test, which suggested lack of response to LPS E. coli by neutrophils. These findings may reflect the state of inflammation in the body. NBT reduction tests may be useful in monitoring metabolic activity of neutrophils in patients with chronic active viral hepatitis.


The possible absence of a healthy-worker effect: a cross-sectional survey among educated Japanese women.
Despite being highly educated in comparison with women in other member countries of the Organisation for Economic Cooperation and Development, Japanese women are expected to assume traditional gender roles, and many dedicate themselves to full-time housewifery. Women working outside the home do so under poor conditions, and their health may not be better than that of housewives. This study compared the self-rated health status and health behaviours of housewives and working women in Japan. Cross-sectional survey. A national university in Tokyo with 9864 alumnae. A total 1344 women who graduated since 1985 and completed questionnaires in an anonymous mail-based survey. Health anxiety and satisfaction, receipt of health check-ups, eating breakfast, smoking, and sleep problems according to job status and family demands: housewives (n=247) and working women with (n=624) and without (n=436) family demands. ORs were used for risk assessment, with housewives as a reference. After adjustment for satisfaction with present employment status and other confounding factors, working women were more likely than housewives to feel health anxiety (with family demands, OR: 1.68, 95% CI1.10 to 2.57; without family demands, OR: 3.57, 95% CI 2.19 to 4.50) and health dissatisfaction (without family demands, OR: 3.50, 95% CI 2.35 to 5.21); they were also more likely than housewives to eat an insufficient breakfast (with family demands, OR: 1.91, 95% CI 1.22 to 3.00; without family demands, OR: 4.02, 95% CI 2.47 to 6.57) and to have sleep problems (ORs: 2.08 to 4.03). No healthy-worker effect was found among Japanese women. Housewives, at least those who are well educated, appear to have better health status and health-related behaviours than do working women with the same level of education.