Does the Mode of Exercise Influence the Benefits Obtained by Green Exercise?
Green exercise studies have tended to use walking as a modality of exercise to establish benefits to mental health. Whether green exercise benefits translate into different forms of green exercise has been deemed an important research gap. A mixed-methods study design was used to compare psychological responses between two forms of green exercise; golf and walking. A total of 20 participants (10 in each group), with a range of ages and experience were recruited to take part in the study. Participants in the walking condition exhibited significantly greater levels of dissociative cognitions than golf condition participants. Consequently, only the walking condition significantly improved in a directed attention test. Results from the Exercise-Induced Feeling Inventory questionnaire found the walking condition demonstrated increases in all four subscales, whereas the golf condition showed no significant improvements. Based on the findings from the qualitative analysis, distinct differences were seen with regards to the perception of the environment. Participants in the golf condition noted natural elements as obstacles to effective performance, whereas the walking group noted natural stimuli as evoking positive feelings. In agreement with the Attention Restoration Theory, the current study demonstrates that the benefits of green exercise are somewhat reduced when greater levels of directed attention towards the activity are exhibited during green exercise.


Gastric Microbiota in a Low-Helicobacter pylori Prevalence General Population and Their Associations With Gastric Lesions.
Non-Helicobacter pylori microbiota might account for some cases with unexplained chronic gastritis that may in a minority eventually progress to gastric cancer through the Correa cascade. We characterized gastric microbiota by describing the normal stomach, compared it with early precancerous lesions and other disease states, and assessed whether H. pylori status affects bacterial diversity. In a population-based study of those with and without gastrointestinal symptoms, cytology brush samples were collected during endoscopy from 316 individuals. Mucosal status was classified as normal mucosa (171), nonatrophic H. pylori gastritis (33), atrophic gastritis (12), or antral chemical gastritis (61). The 16S rRNA gene sequencing and analysis were performed to characterize the microbiota. Microbiota in atrophic gastritis and nonatrophic H. pylori gastritis stomachs were dysbiotic and differed from those in the normal stomach (P = 0.001). The normal stomach had the highest microbial diversity, followed by antral chemical gastritis. The atrophic gastritis and chronic H. pylori gastritis groups had the lowest diversity, a difference that was statistically significant (P = 0.01). Besides H. pylori, non-H. pylori bacteria accounted for group differences. Microbial network analysis showed that the normal group network was most highly connected, whereas the H. pylori gastritis group had the lowest connection. We found an increasing positive co-occurrence of oral bacteria in the stomach because samples deviated from the normal network, some of which were pathogens. The H. pylori-negative group had the highest microbial diversity (Shannon index) compared with the H. pylori-positive group (P = 0.001). In this low-H. pylori prevalence general population, the gastric mucosal microbiota of the normal stomach differed significantly from those with nonatrophic or atrophic gastritis. There was an increasing abundance of pathogenic bacteria from the normal state to early precancerous states.


Effect of vibration on muscle perfusion: a systematic review.
Vibration has become of increasing interest to health professionals, primarily owing to reports that vibration can increase tissue blood flow. The aim of this review was to investigate the available scientific evidence on the effects of exogenous vibration on skeletal muscle perfusion. The databases searched from inception to December 2010 included Ovid MEDLINE, EMBASE, CINAHL via EbscoHost and CENTRAL. Experimental and observational studies, where exogenous vibration was an intervention, were included in this review. The main outcomes of interest were muscle blood volume, blood flow, blood flow velocity, arterial diameter and muscle temperature. One reviewer selected studies for inclusion, extracted data and assessed the quality of the eligible studies. Percentage change in muscle perfusion outcome was the measure of treatment effect, and regression analysis was used to investigate associations between vibratory load and muscle perfusion. Twenty-two studies with a total of 302 participants were included in this review. Muscle blood volume increased with vibration in five of nine studies and decreased in two studies; muscle blood flow velocity increased with vibration in five of six studies; muscle blood flow increased with vibration in two of three studies; vibration had a positive effect on arterial diameter in three of three studies; vibration had no effect on muscle temperature in two of two studies. The magnitude of increase in muscle perfusion was positively associated with vibratory load (P<0·001). We conclude that vibration increases muscle perfusion with the magnitude of increase positively related to the vibratory load applied.


Demonstration of OspC type diversity in invasive human lyme disease isolates and identification of previously uncharacterized epitopes that define the specificity of the OspC murine antibody response.
Outer surface protein C (OspC) of the Lyme disease spirochetes is an important virulence factor that has potential utility for vaccine development. Of the 21 OspC types that have been identified, it has been postulated that types A, B, I, and K are specifically associated with invasive infections. Through an analysis of isolates collected from patients in Maryland we found that OspC types C, D, and N are also associated with invasive infections. This observation suggests that there is greater diversity in the group of OspC types associated with invasive infection than has been previously suggested. Detailed knowledge of the antigenic structure of OspC is essential for vaccine development. To determine if the antibody response to OspC is type specific, recombinant proteins of several different OspC types were immunoblotted and screened with sera from mice infected with isolates having known OspC types. These analyses revealed a high degree of specificity in the antibody response and suggested that the immunodominant epitopes of OspC reside in the variable domains of the protein. To localize these epitopes, OspC fragments were generated and screened with serum collected from infected mice. These analyses led to identification of previously uncharacterized epitopes that define the type specificity of the OspC antibody response. These analyses provide important insight into the antigenic structure of OspC and also provide a basis for understanding the variable nature of the antibody response to this important virulence factor of the Lyme disease spirochetes.


Detection of histamine release inhibitory factor- and histamine releasing factor-like activities in bronchoalveolar lavage fluids.
Histamine releasing factors (HRF) are a group of cytokines that cause degranulation of basophils and mast cells. Recently we have described a histamine release inhibitory factor (HRIF) that inhibits HRF-induced histamine release from basophils and mast cells. The objective of this study was to investigate the presence of these cytokines in bronchoalveolar lavage (BAL) fluid from normal subjects. We found that BAL fluids from 12 to 17 volunteers contained a dialyzable (molecular weight cutoff 3500) factor that inhibited basophil histamine release by HRF, anti-IgE, concanavalin A, and N-formyl-methionyl-leucyl-phenylalanine (FMLP). In addition, BAL fluids from 83% of the tested donors contained a nondialyzable inhibitor that blocked HRF-induced histamine release from basophils. The molecular weight of this inhibitor was estimated to be 20 to 30 and 8 to 10 kD by Sephadex G-50 chromatography and TSK 2000 size-exclusion HPLC. None of the unconcentrated BAL fluids showed any HRF activity on initial screening using basophils from allergic subjects. However, when the BAL fluids were concentrated, all BAL samples that were tested (N = 10) demonstrated significant HRF activity. The molecular weight of BAL HRF has been estimated to be in the range of 15 to 25 kD by size-exclusion HPLC, similar to the HRF synthesized by mononuclear cells. Thus we have demonstrated the presence of both HRF and HRIF in the BAL fluids. We speculate that these cytokines may be involved in the local regulation of basophil and mast cell activation.


Application fields for the new Object Management Group (OMG) Standards Case Management Model and Notation (CMMN) and Decision Management Notation (DMN) in the perioperative field.
Medical processes can be modeled using different methods and notations. Currently used modeling systems like Business Process Model and Notation (BPMN) are not capable of describing the highly flexible and variable medical processes in sufficient detail. We combined two modeling systems, Business Process Management (BPM) and Adaptive Case Management (ACM), to be able to model non-deterministic medical processes. We used the new Standards Case Management Model and Notation (CMMN) and Decision Management Notation (DMN). First, we explain how CMMN, DMN and BPMN could be used to model non-deterministic medical processes. We applied this methodology to model 79 cataract operations provided by University Hospital Leipzig, Germany, and four cataract operations provided by University Eye Hospital Tuebingen, Germany. Our model consists of 85 tasks and about 20 decisions in BPMN. We were able to expand the system with more complex situations that might appear during an intervention. An effective modeling of the cataract intervention is possible using the combination of BPM and ACM. The combination gives the possibility to depict complex processes with complex decisions. This combination allows a significant advantage for modeling perioperative processes.


Bhlhb5 and Prdm8 form a repressor complex involved in neuronal circuit assembly.
Although transcription factors that repress gene expression play critical roles in nervous system development, their mechanism of action remains to be understood. Here, we report that the Olig-related transcription factor Bhlhb5 (also known as Bhlhe22) forms a repressor complex with the PR/SET domain protein, Prdm8. We find that Bhlhb5 binds to sequence-specific DNA elements and then recruits Prdm8, which mediates the repression of target genes. This interaction is critical for repressor function since mice lacking either Bhlhb5 or Prdm8 have strikingly similar cellular and behavioral phenotypes, including axonal mistargeting by neurons of the dorsal telencephalon and abnormal itch-like behavior. We provide evidence that Cadherin-11 functions as target of the Prdm8/Bhlhb5 repressor complex that must be repressed for proper neural circuit formation to occur. These findings suggest that Prdm8 is an obligate partner of Bhlhb5, forming a repressor complex that directs neural circuit assembly in part through the precise regulation of Cadherin-11.


Phosphatidylinositol 3,4,5-trisphosphate directs association of Src homology 2-containing signaling proteins with gelsolin.
Podosomes are adhesion structures in osteoclasts and are structurally related to focal adhesions mediating cell motility during bone resorption. Here we show that gelsolin coprecipitates some of the focal adhesion-associated proteins such as c-Src, phosphoinositide 3-kinase (PI3K), p130(Cas), focal adhesion kinase, integrin alpha(v)beta(3), vinculin, talin, and paxillin. These proteins were inducibly tyrosine-phosphorylated in response to integrin activation by osteopontin. Previous studies have defined unique biochemical properties of gelsolin related to phosphatidylinositol 3,4,5-trisphosphate in osteoclast podosomes, and here we demonstrate phosphatidylinositol 3,4,5-trisphosphate/gelsolin function in mediating organization of the podosome signaling complex. Overlay and GST pull-down assays demonstrated strong phosphatidylinositol 3,4,5-trisphosphate-PI3K interactions based on the Src homology 2 domains of PI3K. Furthermore, lipid extraction of lysates from activated osteoclasts eliminated interaction between gelsolin, c-Src, PI3K, and focal adhesion kinase despite equal amounts of gelsolin in both the lipid-extracted and unextracted experiment. The cytoplasmic protein tyrosine phosphatase (PTP)-proline-glutamic acid-serine-threonine amino acid sequences (PEST) was also found to be associated with gelsolin in osteoclast podosomes and with stimulation of alpha(v)beta(3)-regulated phosphorylation of PTP-PEST. We conclude that gelsolin plays a key role in recruitment of signaling proteins to the plasma membrane through phospholipid-protein interactions and by regulation of their phosphorylation status through its association with PTP-PEST. Because both gelsolin deficiency and PI3K inhibition impair bone resorption, we conclude that phosphatidylinositol 3,4,5-trisphosphate-based protein interactions are critical for osteoclast function.


Assessing harmful effects in systematic reviews.
Balanced decisions about health care interventions require reliable evidence on harms as well as benefits. Most systematic reviews focus on efficacy and randomised trials, for which the methodology is well established. Methods to systematically review harmful effects are less well developed and there are few sources of guidance for researchers. We present our own recent experience of conducting systematic reviews of harmful effects and make suggestions for future practice and further research. We described and compared the methods used in three systematic reviews. Our evaluation focused on the review question, study designs and quality assessment. One review question focused on providing information on specific harmful effects to furnish an economic model, the other two addressed much broader questions. All three reviews included randomised and observational data, although each defined the inclusion criteria differently. Standard methods were used to assess study quality. Various practical problems were encountered in applying the study design inclusion criteria and assessing quality, mainly because of poor study design, inadequate reporting and the limitations of existing tools. All three reviews generated a large volume of work that did not yield much useful information for health care decision makers. The key areas for improvement we identified were focusing the review question and developing methods for quality assessment of studies of harmful effects. Systematic reviews of harmful effects are more likely to yield information pertinent to clinical decision-making if they address a focused question. This will enable clear decisions to be made about the type of research to include in the review. The methodology for assessing the quality of harmful effects data in systematic reviews requires further development.


Glutamate transport decreases mitochondrial pH and modulates oxidative metabolism in astrocytes.
During synaptic activity, the clearance of neuronally released glutamate leads to an intracellular sodium concentration increase in astrocytes that is associated with significant metabolic cost. The proximity of mitochondria at glutamate uptake sites in astrocytes raises the question of the ability of mitochondria to respond to these energy demands. We used dynamic fluorescence imaging to investigate the impact of glutamatergic transmission on mitochondria in intact astrocytes. Neuronal release of glutamate induced an intracellular acidification in astrocytes, via glutamate transporters, that spread over the mitochondrial matrix. The glutamate-induced mitochondrial matrix acidification exceeded cytosolic acidification and abrogated cytosol-to-mitochondrial matrix pH gradient. By decoupling glutamate uptake from cellular acidification, we found that glutamate induced a pH-mediated decrease in mitochondrial metabolism that surpasses the Ca(2+)-mediated stimulatory effects. These findings suggest a model in which excitatory neurotransmission dynamically regulates astrocyte energy metabolism by limiting the contribution of mitochondria to the metabolic response, thereby increasing the local oxygen availability and preventing excessive mitochondrial reactive oxygen species production.


The Different Temozolomide Effects on Tumorigenesis Mechanisms of Pediatric Glioblastoma PBT24 and SF8628 Cell Tumor in CAM Model and on Cells In Vitro.
It is necessary to elucidate the individual effects of temozolomide (TMZ) on carcinogenesis and tumor resistance to chemotherapy mechanisms. The study aimed to investigate the TMZ 50 and 100 μM dose effect difference between PBT24 and SF8628 cell line high-grade pediatric glioblastoma (phGBM) xenografts in a chicken chorioallantoic membrane (CAM) model, on PCNA and EZH2 immunohistochemical expression in the tumor and on the expression of NKCC1, KCC2, E- and N-cadherin genes in TMZ-treated and control cell groups in vitro. TMZ at a 100 μg dose reduced the incidence of PBT24 xenograft invasion into the CAM, CAM thickening and the number of blood vessels in the CAM (p < 0.05), but did not affect the SF8628 tumor in the CAM model. The TMZ impact on PBT24 and SF8628 tumor PCNA expression was similarly significantly effective but did not alter EZH2 expression in the studied tumors. The TMZ at 50 μM caused significantly increased RNA expression of the NKCC1 gene in both studied cell types compared with controls (p < 0.05). The expression of the KCC2 gene was increased in PBT24 TMZ-treated cells (p < 0.05), and no TMZ effect was found in SF8628-treated cells. The study supports the suggestion that individual sensitivity to TMZ should be assessed when starting treatment.


Extending the Kolmogorov-Zurbenko filter: application to ozone, particulate matter, and meteorological trends.
Tropospheric ozone (O3) and particulate matter (PM) are pollutants of great concern to air quality managers. Federal standards for these pollutants have been promulgated in recent years because of the known adverse effects of the pollutants on human health, the environment, and visibility. Local meteorological conditions exert a strong influence over day-to-day variations in pollutant concentrations; therefore, the meteorological signal must be removed in order for air quality planners and managers to examine underlying emissions-related trends and make better air quality management decisions for the future. Although the Kolmogorov-Zurbenko (KZ) filter has been widely used for this type of trend separation in O3 studies in the eastern United States, this article aims to extend the method in three key ways. First, whereas the KZ filter is known as a useful tool for O3 analysis, this study also evaluates its effectiveness when applied to PM. Second, the method was applied to Tucson, AZ, a city in the semi-arid southwestern United States (Southwest), to evaluate the appropriateness of the method in a region with weaker synoptic weather controls on air quality than the eastern United States. Third, additional forms of output were developed and tailored to be more applicable to decision-makers' needs through a partnership between academic researchers and air quality planners and managers. Results of the study indicate that the KZ filter is a useful method for examining emissions-related PM trends, resulting in small, but potentially significant, differences after adjustment. For the Tucson situation with weaker synoptic controls, the KZ method identified mixing height as a more important variable than has been found in other cities.


Effect of nonviable preparations from human immunodeficiency virus type 1 on nuclear matrix-associated DNA polymerase alpha and DNA topoisomerase II activities.
In a previous paper, we determined that treatment of lymphocytes with nonviable preparations of human immunodeficiency virus type 1 (HIV-1) results in an impairment of the phosphatidylinositol/protein kinase C pathway, most likely due to an inhibition of the cleavage of phosphatidylinositol bisphosphate into inositol trisphosphate and diacylglycerol, mediated by phospholipase C. Here we show that one consequence of these changes is a reduced phosphorylation of nuclear matrix-associated DNA topoisomerase II, resulting in an inhibition of the activity of this enzyme. Antibodies to the viral proteins suppressed the inhibitory effects caused by the HIV-1 preparation. Furthermore, the phytohemagglutinin A-caused augmentation of nuclear matrix-associated DNA polymerase alpha and beta activities was found to be abolished by coincubation with the HIV preparation or with the HIV-1 gp120. The phytohemagglutinin A-enhanced matrix association and processivity of DNA polymerase alpha was determined to be reduced if the lymphocytes were in contact with HIV-1 preparation. These results suggest that the reduced proliferative response of lymphocytes to phytohemagglutinin A in the presence of disrupted HIV-1 preparation is due to inhibition of at least two, perhaps separate, pathways, one involving protein kinase C resulting in a reduced phosphorylation of DNA topoisomerase II and the other changing the state of matrix association of DNA polymerase alpha and beta.


Usefulness of S100P in diagnosis of adenocarcinoma of pancreas on fine-needle aspiration biopsy specimens.
Even though the cytologic criteria for pancreatic ductal adenocarcinoma (PDA) on fine-needle aspiration biopsy (FNAB) specimens have been well defined, a diagnostic challenge is still present. We immunohistochemically evaluated the diagnostic value of S100P on cell-block and/or smear preparations in 58 cases of FNAB specimens of the pancreas. The 58 cases were divided into 4 groups: 1, 32 cases of PDA; 2, 6 cases with an atypical or "suspicious" diagnosis; 3, 14 cases of benign or reactive ductal epithelium; and 4, 6 cases of endocrine tumor. Positive immunoreactivity for S100P was observed in all cases in groups 1 and 2, whereas only 1 of 14 cases in group 3 was positive for S100P. All cases in group 4 were negative for S100P. S100P is a sensitive and specific marker for the detection of PDA on FNAB specimens on cell-block and smear preparations.


T4 DNA ligase structure reveals a prototypical ATP-dependent ligase with a unique mode of sliding clamp interaction.
DNA ligases play essential roles in DNA replication and repair. Bacteriophage T4 DNA ligase is the first ATP-dependent ligase enzyme to be discovered and is widely used in molecular biology, but its structure remained unknown. Our crystal structure of T4 DNA ligase bound to DNA shows a compact α-helical DNA-binding domain (DBD), nucleotidyl-transferase (NTase) domain, and OB-fold domain, which together fully encircle DNA. The DBD of T4 DNA ligase exhibits remarkable structural homology to the core DNA-binding helices of the larger DBDs from eukaryotic and archaeal DNA ligases, but it lacks additional structural components required for protein interactions. T4 DNA ligase instead has a flexible loop insertion within the NTase domain, which binds tightly to the T4 sliding clamp gp45 in a novel α-helical PIP-box conformation. Thus, T4 DNA ligase represents a prototype of the larger eukaryotic and archaeal DNA ligases, with a uniquely evolved mode of protein interaction that may be important for efficient DNA replication.


A finite-element method model for droplets moving down a hydrophobic surface.
We set up a 2D computational Finite-Element Method (FEM) model describing the initial descent of a droplet down an inclined hydrophobic substrate. We solve the full Navier-Stokes equations inside the drop domain, and use the arbitrary Lagrangian-Eulerian method to keep track of the droplet surface. The contact angle is included by using the Frennet-Serret equations. We investigate the behaviour of the drop velocity as a function of the slip length and compare with experimental results. Furthermore, we quantify the energy associated with centre-of-mass translation and internal fluid motion, and we also compute the local dissipation of energy inside the drop. The model predicts trajectories for tracer particles deposited inside the drop, and satisfactorily describes the sliding motion of steadily accelerating droplets. The model can be used for determining a characteristic slip parameter, associated with slip lengths and drag reduction for hydrophobic surfaces.


Did Darwin change his mind about the Fuegians?
Shocked by what he considered to be the savagery he encountered in Tierra del Fuego, Charles Darwin ranked the Fuegians lowest among the human races. An enduring story has it, however, that Darwin was later so impressed by the successes of missionaries there, and by the grandeur they discovered in the native tongue, that he changed his mind. This story has served diverse interests, religious and scientific. But Darwin in fact continued to view the Fuegians as he had from the start, as lowly but improvable. And while his case for their unity with the other human races drew on missionary evidence, that evidence concerned emotional expression, not language.


A review of diseases associated with household air pollution due to the use of biomass fuels.
Nearly one third of the world's population use biomass fuels such as coal, wood, animal dung, and crop residues as their primary source of domestic energy. Due to their incomplete combustion, a multitude of pollutants associated with high levels of indoor air pollution (IAP) are released which include suspended particulate matter (SPM), carbon monoxide, formaldehyde, nitrogen dioxide, polycyclic aromatic hydrocarbons (PAH), etc. There is a line of evidence that exposure to those pollutants can lead to increased risk of diseases including respiratory infections (e.g., pneumonia, tuberculosis and chronic obstructive pulmonary disease (COPD), lung cancer, and asthma), low birth weight, cataracts, and cardiovascular events. It is one of the major global public health threats that require greater efforts for prevention through research and policy-making. This review summarizes the available information on potential health risks associated with biomass fuel use.


Bio-inspired drug delivery systems: an emerging platform for targeted cancer therapy.
The quest for an ideal cancer treatment has led to the exploration of a variety of platforms to facilitate highly desirable and efficient drug delivery. As most anticancer drugs possess therapeutic potency to destroy tumor cells, there is a need to steer the compounds to their required sites using site-specific drug delivery vehicles. This has inspired the investigation of various natural particulates and biomaterials for the purpose. Bio-inspired platforms that directly mimic natural components in the body have demonstrated their ability to serve as one of the most versatile and innovative drug delivery systems in cancer therapy and diagnosis. The primary advantage of this innovation lies in the fundamental changes in systemic biodistribution that non-native drug delivery does not possess. This review will try to provide a comprehensive understanding and a succinct evaluation of various intelligent bio-inspired delivery platforms, which have become prominent in recent studies. Recent innovative examples and their advantages and limitations as well as future clinical potential will also be thoroughly discussed.


The Decline in Hydrocodone/Acetaminophen Prescriptions in Emergency Departments in the Veterans Health Administration Between 2009 to 2015.
The purpose of the study was to measure national prescribing patterns for hydrocodone/acetaminophen among veterans seeking emergency medical care, and to see if patterns have changed since this medication became a Schedule II controlled substance. We conducted a retrospective cohort study of emergency department (ED) visits within the Veterans Health Administration (VA) between January 2009 and June 2015. We looked at demographics, comorbidities, utilization measures, diagnoses, and prescriptions. During the study period, 1,709,545 individuals participated in 6,270,742 ED visits and received 471,221 prescriptions for hydrocodone/acetaminophen (7.5% of all visits). The most common diagnosis associated with a prescription was back pain. Prescriptions peaked at 80,776 in 2011 (8.7% of visits), and declined to 35,031 (5.6%) during the first half of 2015 (r=-0.99, p<0.001). The percentage of hydrocodone/acetaminophen prescriptions limited to 12 pills increased from 22% (13,949) in 2009 to 31% (11,026) in the first half of 2015. A prescription was more likely written for patients with a pain score≥7 (OR 3.199, CI [3.192-3.205]), a musculoskeletal (OR 1.622, CI [1.615-1.630]) or soft tissue (OR 1.656, CI [1.649-1.664]) diagnosis, and those below the first quartile for total ED visits (OR 1.282, CI [1.271-1.293]) and total outpatient ICD 9 codes (OR 1.843, CI [1.833-1.853]). Hydrocodone/acetaminophen is the most frequently prescribed ED medication in the VA. The rate of prescribing has decreased since 2011, with the rate of decline remaining unchanged after it was classified as a Schedule II controlled substance. The proportion of prescriptions falling within designated guidelines has increased but is not at goal.


Design of a scanning ellipsometer by synchronous rotation of the polarizer and analyzer.
We have designed and constructed a new type of spectroscopic ellipsometer to study the optical properties of materials in the 3500-8000-Å wavelength range. In the system, the analyzer and polarizer are driven 10(4) steps/revolution by two stepping motors that have hollow shafts and rotate synchronously with a speed ratio of 2:1, i.e., A = 2P. Both the polarizer and analyzer are mounted directly on the shafts to avoid mechanical transmission and vibration problems entirely and make the system simple and reliable. An additional source polarizer was placed in the optical path to reduce the slight polarization effects of the light source. The light intensity finally received by the detector contained five components, one dc and four ac, with frequencies of ω(0), 2ω(0), 3ω(0), and 4ω(0), respectively. One can independently obtain the ellipsometric parameters of ψ and Δ as well as the optical constants by calculating any one of the two sets of ac signals, with a raw data self-consistency of better than 0.5%. The incident angle, aligned precisely by a laser beam, was continuously variable through a mechanical system with a computercontrolled resolution of 0.001° or a visual resolution of 0.005°. The system operations, including data acquisition and reduction, high-voltage control of the photomultiplier, incident angle, as well as wavelength setting and scanning, were fully and automatically controlled by a 386-based microcomputer. We self-calibrated the system by adjusting and setting precisely the initial azimuthal angles of the prisms. The results from the measured spectra of the complex refractive index for a gold-film sample are presented, and we show that the data obtained at three different incident angles of 65°, 70°, and 75° are remarkably consistent with one another. A comparison of the two results from the ellipsometry and reflectance measurements is given. The experimental skills and system error reduction are discussed in detail.


Anon-Pass: Practical Anonymous Subscriptions.
We present the design, security proof, and implementation of an anonymous subscription service. Users register for the service by providing some form of identity, which might or might not be linked to a real-world identity such as a credit card, a web login, or a public key. A user logs on to the system by presenting a credential derived from information received at registration. Each credential allows only a single login in any authentication window, or epoch. Logins are anonymous in the sense that the service cannot distinguish which user is logging in any better than random guessing. This implies unlinkability of a user across different logins. We find that a central tension in an anonymous subscription service is the service provider's desire for a long epoch (to reduce server-side computation) versus users' desire for a short epoch (so they can repeatedly "re-anonymize" their sessions). We balance this tension by having short epochs, but adding an efficient operation for clients who do not need unlinkability to cheaply re-authenticate themselves for the next time period. We measure performance of a research prototype of our protocol that allows an independent service to offer anonymous access to existing services. We implement a music service, an Android-based subway-pass application, and a web proxy, and show that adding anonymity adds minimal client latency and only requires 33 KB of server memory per active user.


Formal modeling of robot behavior with learning.
We present formal specification and verification of a robot moving in a complex network, using temporal sequence learning to avoid obstacles. Our aim is to demonstrate the benefit of using a formal approach to analyze such a system as a complementary approach to simulation. We first describe a classical closed-loop simulation of the system and compare this approach to one in which the system is analyzed using formal verification. We show that the formal verification has some advantages over classical simulation and finds deficiencies our classical simulation did not identify. Specifically we present a formal specification of the system, defined in the Promela modeling language and show how the associated model is verified using the Spin model checker. We then introduce an abstract model that is suitable for verifying the same properties for any environment with obstacles under a given set of assumptions. We outline how we can prove that our abstraction is sound: any property that holds for the abstracted model will hold in the original (unabstracted) model.


Fabrication, densification, and replica molding of 3D carbon nanotube microstructures.
The introduction of new materials and processes to microfabrication has, in large part, enabled many important advances in microsystems, lab-on-a-chip devices, and their applications. In particular, capabilities for cost-effective fabrication of polymer microstructures were transformed by the advent of soft lithography and other micromolding techniques (1, 2), and this led a revolution in applications of microfabrication to biomedical engineering and biology. Nevertheless, it remains challenging to fabricate microstructures with well-defined nanoscale surface textures, and to fabricate arbitrary 3D shapes at the micro-scale. Robustness of master molds and maintenance of shape integrity is especially important to achieve high fidelity replication of complex structures and preserving their nanoscale surface texture. The combination of hierarchical textures, and heterogeneous shapes, is a profound challenge to existing microfabrication methods that largely rely upon top-down etching using fixed mask templates. On the other hand, the bottom-up synthesis of nanostructures such as nanotubes and nanowires can offer new capabilities to microfabrication, in particular by taking advantage of the collective self-organization of nanostructures, and local control of their growth behavior with respect to microfabricated patterns. Our goal is to introduce vertically aligned carbon nanotubes (CNTs), which we refer to as CNT "forests", as a new microfabrication material. We present details of a suite of related methods recently developed by our group: fabrication of CNT forest microstructures by thermal CVD from lithographically patterned catalyst thin films; self-directed elastocapillary densification of CNT microstructures; and replica molding of polymer microstructures using CNT composite master molds. In particular, our work shows that self-directed capillary densification ("capillary forming"), which is performed by condensation of a solvent onto the substrate with CNT microstructures, significantly increases the packing density of CNTs. This process enables directed transformation of vertical CNT microstructures into straight, inclined, and twisted shapes, which have robust mechanical properties exceeding those of typical microfabrication polymers. This in turn enables formation of nanocomposite CNT master molds by capillary-driven infiltration of polymers. The replica structures exhibit the anisotropic nanoscale texture of the aligned CNTs, and can have walls with sub-micron thickness and aspect ratios exceeding 50:1. Integration of CNT microstructures in fabrication offers further opportunity to exploit the electrical and thermal properties of CNTs, and diverse capabilities for chemical and biochemical functionalization (3).


Structural and Mechanistic Insights into C-S Bond Formation in Gliotoxin.
Glutathione-S-transferases (GSTs) usually detoxify xenobiotics. The human pathogenic fungus Aspergillus fumigatus however uses the exceptional GST GliG to incorporate two sulfur atoms into its virulence factor gliotoxin. Because these sulfurs are essential for biological activity, glutathionylation is a key step of gliotoxin biosynthesis. Yet, the mechanism of carbon-sulfur linkage formation from a bis-hydroxylated precursor is unresolved. Here, we report structures of GliG with glutathione (GSH) and its reaction product cyclo[-l-Phe-l-Ser]-bis-glutathione, which has been purified from a genetically modified A. fumigatus strain. The structures argue for stepwise processing of first the Phe and second the Ser moiety. Enzyme-mediated dehydration of the substrate activates GSH and a helix dipole stabilizes the resulting anion via a water molecule for the nucleophilic attack. Activity assays with mutants validate the interactions of GliG with the ligands and enrich our knowledge about enzymatic C-S bond formation in gliotoxin and epipolythiodioxopiperazine (ETP) natural compounds in general.


Suprasternal direct aortic approach transcatheter aortic valve replacement avoids sternotomy and thoracotomy: first-in-man experience†.
Direct aortic deployment of a transcatheter aortic valve eliminates the need to traverse the aortic arch with the valve delivery system, enables placement of large sheaths in the aorta and innominate artery, provides maximal precision during deployment and ensures a safe, conventional surgical aortotomy closure. We describe the initial experience with the Suprasternal Aortic Access System (SuprAA System, Aegis Surgical Ltd, Dublin, Ireland) for direct transaortic/innominate valve delivery. Patients with severe, symptomatic aortic stenosis who were candidates for transcatheter aortic valve replacement (TAVR) via a direct transaortic approach were enrolled in the SuprAA-TAVR First-in-Man Study. Under general anaesthesia, the innominate artery and aortic arch were exposed in each patient, using the SuprAA System via a 2.5-cm incision directly above the sternal notch. The TAVR delivery sheath was positioned and the transcatheter valve deployed routinely under fluoroscopic guidance. Upon sheath removal, haemostasis at the aortotomy site was confidently secured using a double purse-string suture closure. All were extubated immediately. A meta-analysis of the direct aortic approach was done for comparison. Four male patients (mean 82.5 years) underwent SuprAA-TAVR (2 CoreValve; 2 SAPIEN). Anatomical visualization was excellent and suprasternal valve deployment was accurate regardless of sheath size with 100% Valve Academic Research Consortium-2 procedural success. The average total procedure time was 109.5 min without perioperative wound or vascular complications. The SuprAA System provides direct aortic/innominate access without sternal or thoracotomy incision. Patient recovery to normal activity is maximized, sheath size limitations are eliminated and valve deployment is precise. This innovative system creates a new and exciting minimally invasive approach for high-risk patients with aortic stenosis.


7-dehydrocholesterol efficiently supports Ret signaling in a mouse model of Smith-Opitz-Lemli syndrome.
Smith-Lemli-Opitz syndrome (SLOS) is a rare disorder of cholesterol synthesis. Affected individuals exhibit growth failure, intellectual disability and a broad spectrum of developmental malformations. Among them, renal agenesis or hypoplasia, decreased innervation of the gut, and ptosis are consistent with impaired Ret signaling. Ret is a receptor tyrosine kinase that achieves full activity when recruited to lipid rafts. Mice mutant for Ret are born with no kidneys and enteric neurons, and display sympathetic nervous system defects causing ptosis. Since cholesterol is a critical component of lipid rafts, here we tested the hypothesis of whether the cause of the above malformations found in SLOS is defective Ret signaling owing to improper lipid raft composition or function. No defects consistent with decreased Ret signaling were found in newborn Dhcr7(-/-) mice, or in Dhcr7(-/-) mice lacking one copy of Ret. Although kidneys from Dhcr7(-/-) mice showed a mild branching defect in vitro, GDNF was able to support survival and downstream signaling of sympathetic neurons. Consistently, GFRα1 correctly partitioned to lipid rafts in brain tissue. Finally, replacement experiments demonstrated that 7-DHC efficiently supports Ret signaling in vitro. Taken together, our findings do not support a role of Ret signaling in the pathogenesis of SLOS.


Epidemiology and etiology of gliomas.
Gliomas of astrocytic, oligodendroglial and ependymal origin account for more than 70% of all brain tumors. The most frequent (65%) and most malignant histological type is the glioblastoma. Since the introduction of computerized tomography and magnetic resonance imaging, the incidence rates of brain tumors have been rather stable, with a tendency of higher rates in highly developed, industrialized countries. Some reports indicate that Caucasians have higher incidence than black or Asian populations, but to some extent, this may reflect socio-economic differences and under-ascertainment in some regions, rather than a significant difference in genetic susceptibility. With the exception of pilocytic astrocytomas, the prognosis of glioma patients is still poor. Less than 3% of glioblastoma patients are still alive at 5 years after diagnosis, higher age being the most significant predictor of poor outcome. Brain tumors are a component of several inherited tumor syndromes, but the prevalence of these syndromes is very low. Several occupations, environmental carcinogens, and diet (N-nitroso compounds) have been reported to be associated with an elevated glioma risk, but the only environmental factor unequivocally associated with an increased risk of brain tumors, including gliomas, is therapeutic X-irradiation. In particular, children treated with X-irradiation for acute lymphoblastic leukemia show a significantly elevated risk of developing gliomas and primitive neuroectodermal tumor (PNET), often within 10 years after therapy. TP53 mutations are frequent in low-grade gliomas and secondary glioblastomas derived therefrom. Approximately 60% of mutations are located in the hot spot codons 248 and 273, and the majority of these are G:C-->A:T transitions at CpG sites. TP53 mutations are significantly more frequent in low-grade astrocytomas with promoter methylation of the O(6)-methylguanine-DNA methyltransferase repair gene, suggesting that, in addition to deamination of 5-methylcytosine, exogenous or endogenous alkylation in the O(6) position of guanine may contribute to the formation of these mutations.


Acceptable HLA-mismatching in unrelated donor bone marrow transplantation for patients with acquired severe aplastic anemia.
We retrospectively analyzed the effect of HLA mismatching (HLA-A, -B, -C, -DRB1, -DQB1) with molecular typing on transplantation outcome for 301 patients with acquired severe aplastic anemia (SAA) who received an unrelated BM transplant through the Japan Marrow Donor Program. Additional effect of HLA-DPB1 mismatching was analyzed for 10 of 10 or 9 of 10 HLA allele-matched pairs (n = 169). Of the 301 recipient/donor pairs, 101 (33.6%) were completely matched at 10 of 10 alleles, 69 (23%) were mismatched at 1 allele, and 131 (43.5%) were mismatched at ≥ 2 alleles. Subjects were classified into 5 subgroups: complete match group (group I); single-allele mismatch group (groups II and III); multiple alleles restricted to HLA-C, -DRB1, and -DQB1 mismatch group (group IV); and others (group V). Multivariate analysis indicated that only HLA disparity of group V was a significant risk factor for poor survival and grade II-IV acute GVHD. HLA-DPB1 mismatching was not associated with any clinical outcome. We recommend the use of an HLA 10 of 10 allele-matched unrelated donor. However, if such a donor is not available, any single-allele or multiple-allele (HLA-C, -DRB1, -DQB1) mismatched donor is acceptable as an unrelated donor for patients with severe aplastic anemia.


Non-steroidal anti-inflammatory drug use does not appear to be associated with increased cardiovascular mortality in patients with inflammatory polyarthritis: results from a primary care based inception cohort of patients.
There is controversy about the effects of non-steroidal anti-inflammatory drugs (NSAIDs) on cardiovascular disease (CVD) mortality. The aim of this study was to explore associations between NSAID use and mortality in patients with inflammatory polyarthritis (IP). A total of 923 patients with new onset (IP), recruited to the UK Norfolk Arthritis Register (NOAR) between 1990-1994, were followed up to the end of 2004. Current medication was recorded annually for the first 6 years and then every 2-3 years. Rheumatoid factor (RF) and C-reactive protein (CRP) were measured. Logistic regression was used to calculate all cause and CVD mortality odds ratios (OR) for NSAID use at baseline and during follow-up, adjusting for gender and time-varying covariates: RF, CRP, joint counts, smoking, steroid use, DMARD use and other medication use. By 2004 there were 203 deaths, 85 due to CVD. At baseline, NSAIDs were used by 66% of patients. In final multivariate models, baseline NSAID use was inversely associated with all cause mortality (adjusted OR 0.62, 95% CI 0.45 to 0.84) and CVD mortality (adjusted OR 0.54, 95% CI 0.34 to 0.86). Interval NSAID use had weaker mortality associations: all cause mortality (adjusted OR 0.72, 95% CI 0.52 to 1.00), CVD mortality (adjusted hazard ratio (HR) 0.66, 95% CI 0.40 to 1.08). No excess CVD or all cause mortality was observed in NSAID users in this cohort of patients with IP. This is at variance with the literature relating to NSAID use in the general population. It is unclear whether this represents unmeasured confounders influencing a doctor's decision to avoid NSAIDs in the treatment of IP.


Structural Vulnerability Among Migrating Women and Children Fleeing Central America and Mexico: The Public Health Impact of "Humanitarian Parole".
Since October 2013, US Customs and Border Patrol has apprehended 15,979 families on the Southwest Border of the US. Daily, migrating women and children from Mexico and Central America that qualify for humanitarian parole are released from immigration detention to a humanitarian aid organization in Southern Arizona. After several days in detention facilities, these families arrive tired, hungry, dehydrated, and with minimal direction regarding their final destination, and adherence to the parameters of their parole. Project helping hands (PHHs) utilizes a network of volunteers to provide the women and children with food, water, clothing, hygiene products, hospitality, and legal orientation. The aim of this assessment was to document the experiences of families granted humanitarian parole through the lens of structural vulnerability. Here, we apply qualitative methods to elicit PHH lead volunteer perspectives regarding the migration experience of migrating families. Using inductive analysis, we found six major themes emerged from the qualitative data: reasons for leaving, experience on the journey, dehumanization in detention, family separation, vulnerability, and resiliency. These findings elucidate the different physical and psychological distresses that migrating families from Mexico and Central America experience before, during and after their arrival at the US-Mexico border. We posit that these distresses are a result of, or exacerbated by, structural vulnerability. Structural vulnerability has life-long health implications for a sub-population of young mothers and their children. The number of migrating families who have experienced traumatic events before and during their migration experience continues to expand and thus warrants consideration of mental health surveillance and intervention efforts for these families. More public health research is needed to better understand and combat the health challenges of this growing population.


Increased monocyte level is a risk factor for radiological progression in patients with early fibrotic interstitial lung abnormality.
Interstitial lung abnormalities (ILA) are specific spatial patterns on computed tomography (CT) scan potentially compatible with early interstitial lung disease. A proportion will progress; management involves risk stratification and surveillance. Elevated blood monocyte levels have been shown to associate with progression of idiopathic pulmonary fibrosis. The aims of the present study were: 1) to estimate the proportion of "early fibrotic" (EF)-ILAs (reticular±ground-glass opacities, excluding traction bronchiectasis and honeycombing) on CT scans of patients attending all-indications thoracic CTs, and proportion demonstrating radiological progression; and 2) to explore association between peripheral blood leukocyte levels and ILA progression. We analysed all thoracic CT reports in individuals aged 45-75 years performed between January 2015 and December 2020 in one large teaching hospital (Oxford, UK) to identify patient CT reports consistent with EF-ILA. CT-contemporaneous blood leukocyte counts were examined to explore contribution to progression and all-cause mortality, using multivariate Cox regression. 40 711 patients underwent thoracic CT imaging during this period. 1259 (3.1%) demonstrated the EF-ILA pattern (mean±sd age 65.4±7.32 years; 735 (47.8%) male). EF-ILA was significantly associated with all-cause mortality (hazard ratio 1.87, 95% CI 1.25-2.78; p=0.002). 362 cases underwent at least one follow-on CT. Radiological progression was observed in 157 (43.4%) cases: increase in reticulation n=51, new traction bronchiectasis n=84, honeycombing n=22. Monocyte count, neutrophil count, monocyte:lymphocyte ratio, neutrophil:lymphocyte ratio and "systemic inflammatory response index" were significantly associated with radiological progression. 3.1% of subjects requiring thoracic CT during a 6-year period demonstrated EF-ILA. Monocyte levels and blood leukocyte-derived indexes were associated with radiological progression and could indicate which patients may require closer follow-up.


Prevalence and antimicrobial susceptibility pattern of pathogens isolated from patients with juvenile periodontitis in Jamaica: a prospective multi-centre study of 15 cases over a 15-year period.
Prevalence and antimicrobial susceptibility pattern of most frequent pathogens isolated from patients treated with juvenile periodontitis at three separate dental centres in Jamaica from 1989 to 2003 were studied. Swabs were taken from these patients periodontal pathologic pocket or root of most of their teeth with active disease processes. These swabs were processed at the microbiology department of the University Hospital of the West Indies Kingston, Jamaica and the Microbiology laboratory, School of Veterinary Medicine, Faculty of Medical Sciences, University of the West Indies, St. Augustine, Trinidad and Tobago. The identification of the micro-organisms from positive cultures and their antimicrobial susceptibility profile were performed using standard microbiological procedures and dick diffusion (Kirby-Bauer) methods. Over 80% of the patients were females. The most frequent micro-organisms isolated were Enterobacter (40.5%), followed by Klebsiella species (19%) and Acinetobacter species (10.8%). Actinobacillus actinomycetemcomitans, a widely known key pathogen in juvenile periodontal diseases was encountered only in 5.4% (2/37) of the cases in this study The most frequent organism isolated were still highly susceptibility to the commonly used and available antimicrobials such as amoxycillin/clavulanate, trimethoprim/sulphamethoxazole, chloramphenicol and aminoglycosides. The most frequent pathogens encountered in this study were totally different from what obtains in other places. There is the need to be aware of microbes in other countries during the microbiology investigations ofjuvenile periodontitis and that the antimicrobial chemotherapy should always be based on susceptibility test results. Surgical treatment for mechanical debridement of the site and bone grafting with guided tissue regeneration should be mandatory in conjunction with specific antimicrobial chemotherapy


Quality-of-life assessment of adults with growth hormone deficiency. Implications for drug therapy.
Growth hormone (GH) deficiency in adults affects many physiological functions. It may result in reduced muscle volume and strength, changes in body mass, lowered metabolic rate, low energy and sexual drive and impaired cognitive function. GH deficiency may also lead to an increase in mortality due to vascular disorders. However, the benefits of GH replacement are still controversial. Recently, investigators have looked at the effects of GH replacement therapy on the well-being of patients. However, the studies which have been published generally have small sample sizes, use inadequate methodology and employ health status measures that lack the necessary sensitivity. Despite these weaknesses, results suggest that replacement GH does have a positive effect on well-being. A GH-specific quality-of-life measure has now been produced, which will provide a clearer view of the benefits of replacement therapy for patients. The use of this measure should help guide decisions about the necessity of providing replacement therapy for GH-deficient patients.


Pelvic floor symptoms improve similarly after pessary and behavioral treatment for stress incontinence.
The objective of this study was to determine if differences exist in pelvic symptom distress and impact on women randomized to pessary versus behavioral therapy for treatment of stress urinary incontinence (SUI). Change in symptom and condition-specific health-related quality-of-life (HRQOL) measures were compared between pessary and behavioral groups 3 months after randomization in the Ambulatory Treatments for Leakage Associated With Stress Incontinence trial. Four hundred forty-six women with symptoms of SUI were randomized to continence pessary, behavioral therapy (pelvic floor muscle training and continence strategies) or combination therapy. Validated measures utilized included urinary, prolapse, and colorectal scales of the Pelvic Floor Distress Inventory; urinary, prolapse, and colorectal scales of the Pelvic Floor Impact Questionnaire; and Stress and Urge scales of the Questionnaire for Urinary Incontinence Diagnosis. Student t test and analysis of variance were used to compare scores within and between groups. Mean age of participants was 49.8 (SD, 11.9) years; 84% were white, and 10% were African American. One hundred forty-nine were randomized to pessary, and 146 to behavioral therapy. Baseline symptoms and HRQOL scores were significantly reduced within treatment arms at 3 months after randomization, but there was no statistically significant difference between groups. There was no difference in pelvic floor symptom bother and HRQOL between the pessary and behavioral therapy arms in women undergoing conservative treatment for SUI. Individualized preference issues should be considered in the approach to the nonsurgical treatment of SUI.


Genetic analysis of hypertropic mutants of Phycomyces.
A new class of Phycomyces behavioral mutants with enhanced tropic responses has been analyzed genetically to determine the number of genes involved and the nature of their expression. These hypertropic mutants carry pleiotropic nuclear mutations. Besides their effects on sensory behavior, they also affect morphology and meiotic processes. Behavioral analyses of heterokaryons containing hypertropic and wild-type nuclei in varying proportions show that the hypertropic mutations in strains L82, L84, L86, and L88 are strongly dominant. Conversely, the hypertropic mutations carried by the strains L83, L85, and L87 are strongly recessive. We performed recombination analyses between hypertropic mutants and mutants with diminished phototropism, affected in the seven genes madA to madG. We found no evidence of linkage between the hypertropic mutations and any of these mad mutations. From crosses, we isolated double mutants carrying hypertropic mutations together with madC (night blind) and madG (stiff) mutations. The behavioral phenotypes of the double mutants are intermediate between those of the parentals. Complementation analyses show that the three recessive hypertropic mutations affect the same gene, which we call madH. The expression of the recessive hypertropic allele becomes dominant in heterokaryons carrying madC and madH nuclei; the madC gene has been implicated separately with the photoreceptor at the input to the sensory pathway, while the madH gene is associated with the growth control output. This result suggests the physical interaction of both gene products, madH and madC, in a molecular complex for the photosensory transduction chain.


Vitamin A supplements for reducing mother-to-child HIV transmission.
Strategies to reduce the risk of mother-to-child transmission of the human immunodeficiency virus (HIV) include lifelong antiretroviral therapy (ART) for HIV-positive women, exclusive breastfeeding from birth for six weeks plus nevirapine or replacement feeding plus nevirapine from birth for four to six weeks, elective Caesarean section delivery, and avoiding giving children chewed food. In some settings, these interventions may not be practical, feasible, or affordable. Simple, inexpensive, and effective interventions (that could potentially be implemented even in the absence of prenatal HIV testing programmes) would be valuable. Vitamin A, which plays a role in immune function, is one low-cost intervention that has been suggested in such settings. To summarize the effects of giving vitamin A supplements to HIV-positive women during pregnancy and after delivery. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) up to 25 August 2017, and checked the reference lists of relevant articles for eligible studies. We included randomized controlled trials conducted in any setting that compared vitamin A supplements to placebo or no intervention among HIV-positive women during pregnancy or after delivery, or both. At least two review authors independently assessed study eligibility and extracted data. We expressed study results as risk ratios (RR) or mean differences (MD) as appropriate, with their 95% confidence intervals (CI), and conducted random-effects meta-analyses. This is an update of a review last published in 2011. Five trials met the inclusion criteria. These were conducted in Malawi, South Africa, Tanzania, and Zimbabwe between 1995 and 2005 and none of the participants received ART. Women allocated to intervention arms received vitamin A supplements at a variety of doses (daily during pregnancy; a single dose immediately after delivery, or daily doses during pregnancy plus a single dose after delivery). Women allocated to comparison arms received identical placebo (6601 women, 4 trials) or no intervention (697 women, 1 trial). Four trials (with 6995 women) had low risk of bias and one trial (with 303 women) had high risk of attrition bias.The trials show that giving vitamin A supplements to HIV-positive women during pregnancy, the immediate postpartum period, or both, probably has little or no effect on mother-to-child transmission of HIV (RR 1.07, 95% CI 0.91 to 1.26; 4428 women, 5 trials, moderate certainty evidence) and may have little or no effect on child death by two years of age (RR 1.06, 95% CI 0.92 to 1.22; 3883 women, 3 trials, low certainty evidence). However, giving vitamin A supplements during pregnancy may increase the mean birthweight (MD 34.12 g, 95% CI -12.79 to 81.02; 2181 women, 3 trials, low certainty evidence) and probably reduces the incidence of low birthweight (RR 0.78, 95% CI 0.63 to 0.97; 1819 women, 3 trials, moderate certainty evidence); but we do not know whether vitamin A supplements affect the risk of preterm delivery (1577 women, 2 trials), stillbirth (2335 women, 3 trials), or maternal death (1267 women, 2 trials). Antepartum or postpartum vitamin A supplementation, or both, probably has little or no effect on mother-to-child transmission of HIV in women living with HIV infection and not on antiretroviral drugs. The intervention has largely been superseded by ART which is widely available and effective in preventing vertical transmission.


Effect of vitamin E alone and in combination with lycopene on biochemical and histopathological alterations in isoproterenol-induced myocardial infarction in rats.
The present study has been designed to evaluate the combined cardioprotective effect of vitamin E and lycopene on biochemical and histopathological alteration in isoproterenol-induced myocardial infarction in rats. Adult male albino rats of Wistar strain were treated with isoproterenol (200 mg/kg, s.c.) for 2 days at an interval of 24 h to develop myocardial infarction. Vitamin E (100 mg/kg/day, p.o.) and lycopene (10 mg/kg/day, p.o.) were administered alone and in combination for 30 days. Change in body weight and organ weight were monitored. Levels of serum marker enzymes (AST, ALT, LDH and CK-MB), lipid peroxidation, endogenous antioxidants (GSH, GPX, GST, SOD and CAT), membrane bound enzymes (Na(+)/K(+) ATPases, Mg(2+) ATPases and Ca(2+) ATPases) were evaluated. LDH isoenzyme separation was carried out using gel electrophoresis. Histopathology of heart tissue was performed. Induction of rats with isoproterenol resulted in a significant elevation in organ weight, lipid peroxidation, serum marker enzymes (AST, ALT, CK-MB and LDH), and Ca( 2+) ATPases, whereas it caused a significant (P < 0.001) decrease in body weight, activities of endogenous antioxidants (GSH, GP(x), GST, SOD and CAT), Na(+)/K(+) and Mg(2+) ATPases. ISO treated rats showed high intensity band of LDH1-LDH2 isoenzymes. Treatment with the combination of Vitamin E and lycopene for 30 days significantly attenuated these changes as compared to the individual treatment and ISO treated groups. Histopathological observations were also in correlation with the biochemical parameters. These findings indicate the synergistic cardioprotective effects of vitamin E and lycopene during ISO-induced myocardial infarction in rats.


Serum concentrations of vitamins A and E in impaired glucose tolerance.
Serum concentrations of vitamins A and E were measured in 32 subjects with impaired glucose tolerance (IGT) and 148 subjects with normal glucose tolerance using reversed-phase high-performance liquid chromatography. Fasting glucose, insulin and lipid concentrations were also measured. Serum vitamin A concentrations were higher in subjects with IGT 2.5 (1.1-3.4) vs. 2.1 (1.4-3.2) mumol/l [median (2.5-97.5 percentiles)] (P = 0.002), the difference remaining significant after adjustment for triglycerides (P = 0.028). There was a univariate association between vitamin A levels and insulin resistance (r = 0.164; P = 0.02) and in multivariate logistic regression analysis the relative risk of subjects with high vitamin A concentrations having IGT was 3.8 (P = 0.002). There were no differences in serum vitamin E concentrations between the groups. These data suggest that higher vitamin A concentrations found in non-insulin-dependent diabetes pre-date the onset of diabetes. Further studies are required to confirm this finding and to investigate the possibility of a role for vitamin A in the aetiology of diabetes and IGT.


Annexin A2 mediates Mycoplasma pneumoniae community-acquired respiratory distress syndrome toxin binding to eukaryotic cells.
Mycoplasma pneumoniae synthesizes a novel human surfactant protein A (SP-A)-binding cytotoxin, designated community-acquired respiratory distress syndrome (CARDS) toxin, that exhibits ADP-ribosylating and vacuolating activities in mammalian cells and is directly linked to a range of acute and chronic airway diseases, including asthma. In our attempt to detect additional CARDS toxin-binding proteins, we subjected the membrane fraction of human A549 airway cells to affinity chromatography using recombinant CARDS toxin as bait. A 36-kDa A549 cell membrane protein bound to CARDS toxin and was identified by time of flight (TOF) mass spectroscopy as annexin A2 (AnxA2) and verified by immunoblotting with anti-AnxA2 monoclonal antibody. Dose-dependent binding of CARDS toxin to recombinant AnxA2 reinforced the specificity of the interaction, and further studies revealed that the carboxy terminus of CARDS toxin mediated binding to AnxA2. In addition, pretreatment of viable A549 cells with anti-AnxA2 monoclonal antibody or AnxA2 small interfering RNA (siRNA) reduced toxin binding and internalization. Immunofluorescence analysis of CARDS toxin-treated A549 cells demonstrated the colocalization of CARDS toxin with cell surface-associated AnxA2 upon initial binding and with intracellular AnxA2 following toxin internalization. HepG2 cells, which express low levels of AnxA2, were transfected with a plasmid expressing AnxA2 protein, resulting in enhanced binding of CARDS toxin and increased vacuolization. In addition, NCI-H441 cells, which express both AnxA2 and SP-A, upon AnxA2 siRNA transfection, showed decreased binding and subsequent vacuolization. These results indicate that CARDS toxin recognizes AnxA2 as a functional receptor, leading to CARDS toxin-induced changes in mammalian cells. Host cell susceptibility to bacterial toxins is usually determined by the presence and abundance of appropriate receptors, which provides a molecular basis for toxin target cell specificities. To perform its ADP-ribosylating and vacuolating activities, community-acquired respiratory distress syndrome (CARDS) toxin must bind to host cell surfaces via receptor-mediated events in order to be internalized and trafficked effectively. Earlier, we reported the binding of CARDS toxin to surfactant protein A (SP-A), and here we show how CARDS toxin uses an alternative receptor to execute its pathogenic properties. CARDS toxin binds selectively to annexin A2 (AnxA2), which exists both on the cell surface and intracellularly. Since AnxA2 regulates membrane dynamics at early stages of endocytosis and trafficking, it serves as a distinct receptor for CARDS toxin binding and internalization and enhances CARDS toxin-induced vacuolization in mammalian cells.


High recombination rates and hotspots in a Plasmodium falciparum genetic cross.
The human malaria parasite Plasmodium falciparum survives pressures from the host immune system and antimalarial drugs by modifying its genome. Genetic recombination and nucleotide substitution are the two major mechanisms that the parasite employs to generate genome diversity. A better understanding of these mechanisms may provide important information for studying parasite evolution, immune evasion and drug resistance. Here, we used a high-density tiling array to estimate the genetic recombination rate among 32 progeny of a P. falciparum genetic cross (7G8 × GB4). We detected 638 recombination events and constructed a high-resolution genetic map. Comparing genetic and physical maps, we obtained an overall recombination rate of 9.6 kb per centimorgan and identified 54 candidate recombination hotspots. Similar to centromeres in other organisms, the sequences of P. falciparum centromeres are found in chromosome regions largely devoid of recombination activity. Motifs enriched in hotspots were also identified, including a 12-bp G/C-rich motif with 3-bp periodicity that may interact with a protein containing 11 predicted zinc finger arrays. These results show that the P. falciparum genome has a high recombination rate, although it also follows the overall rule of meiosis in eukaryotes with an average of approximately one crossover per chromosome per meiosis. GC-rich repetitive motifs identified in the hotspot sequences may play a role in the high recombination rate observed. The lack of recombination activity in centromeric regions is consistent with the observations of reduced recombination near the centromeres of other organisms.


Isoforms of steroid receptor co-activator 1 differ in their ability to potentiate transcription by the oestrogen receptor.
Steroid receptor co-activator (SRC1) is one of a number of transcriptional co-activators that are capable of potentiating the activity of nuclear receptors including the oestrogen receptor (ER). Here we report that two isoforms, SRC1a and SRC1e, which diverge at their C-termini, are functionally distinct as they differ in their abilities to enhance the activity of the ER in intact cells. SRC1e enhanced the ability of the ER to stimulate transcription to a greater extent than SRC1a, which had negligible effects on certain promoters. To elucidate the basis of this functional difference, we compared the nuclear receptor-binding properties and mapped the transcriptional activation domains in the two SRC1 isoforms. Both isoforms share a triplet of nuclear receptor-binding motifs (LXXLL motifs) for binding to functional ER dimers, and an activation domain which co-localizes with the CBP-binding domain, while SRC1a contains a unique LXXLL motif in its C-terminus. Although this LXXLL motif increases the affinity for the ER in vitro, it does not appear to be responsible for the functional difference between the two isoforms. This difference is due to a second activation domain that is CBP independent and is suppressed in the SRC1a isoform. Thus, SRC1 exists as functionally distinct isoforms which are likely to play different roles in ER-mediated transcription.


Pimpinella anisum L. fruit: Chemical composition and effect on rat model of nonalcoholic fatty liver disease.
Nonalcoholic fatty liver disease (NAFLD) includes a group of chronic liver disorders caused by irregular accumulation of fat in liver tissue. The current study aimed to evaluate chemical composition and the effect of fruit extract and essential oil of Pimpinella anisum in experimental model of NAFLD. Sixty rats were randomly divided into ten groups, six in each group. NAFLD was induced in rats using choline-deficient diet for 90 days, followed by 30 days of treatment with 25, 50, 100, and 200 mg/kg/day of hydroethanolic extract (AE) as well as 0.125, 0.25, and 0.5 mg/kg/day of essential oil (AO). Blood samples were collected in the final day, and lipid profile, aspartate aminotransferase (AST), alanine aminotransferase (ALT) as well as biomarkers of oxidative damage including myeloperoxidase, lipid peroxidation, total thiol molecules, and ferric-reducing ability of plasma were measured. Liver tissue sections of the sacrificed rats were also assessed histologically. AE and AO significantly reversed increase in the plasma levels of total cholesterol, low-density lipoprotein, and triacylglycerol and decrease in high-density lipoprotein level in a dose-dependent manner (P < 0.05). Serum levels of AST and ALT were also significantly modified by treatment with AE and AO (P < 0.05). Biomarkers of oxidative stress were modulated by administration of AE and AO (P < 0.05). Histological assessments also confirmed the effectiveness of treatments by reduced macrovesicular steatohepatitis. It could be concluded that P. anisum fruit extract and essential oil have beneficial effects in the treatment of NAFLD. Further studies are necessary to confirm safety and efficacy of this medicinal plant in clinical setting.


Chemiluminescence of black phosphorus quantum dots induced by hypochlorite and peroxide.
For the first time, black phosphorus quantum dots (BP QDs) were found to show chemiluminescence (CL) properties in the presence of hydrogen peroxide (H2O2) and hypochlorite (ClO-). Excited phosphorus oxides (HPO) resulting from the oxidation of BP QDs account for CL emission. Taking triacetone triperoxide (TATP) as an example, the potential application of a new CL system was evaluated. This work sheds new light on the characteristics and broader applications of black phosphorus (BP).


Measuring Frailty in Administrative Claims Data: Comparative Performance of Four Claims-Based Frailty Measures in the U.S. Medicare Data.
There has been increasing effort to measure frailty in the U.S. Medicare data. The performance of claims-based frailty measures has not been compared. This cross-sectional study included 3,097 community-dwelling fee-for-service Medicare beneficiaries (mean age 75.6 years) who participated in the 2008 Health and Retirement Study examination. Four claims-based frailty measures developed by Davidoff, Faurot, Segal, and Kim were compared against frailty phenotype, a deficit-accumulation frailty index (FI), and activities of daily living (ADL) dependence using Spearman correlation coefficients and C-statistics. Claims-based frailty measures were positively associated with frailty phenotype (prevalence in ≤10th vs >90th percentile: 8.0% vs 41.3% for Davidoff; 5.9% vs 53.1% for Faurot; 3.3% vs 48.0% for Segal; 2.9% vs 51.0% for Kim) and FI (mean in ≤10th vs >90th percentile: 0.17 vs 0.33 for Davidoff; 0.13 vs 0.37 for Faurot; 0.12 vs 0.31 for Segal; 0.10 vs 0.37 for Kim). The age and sex-adjusted C-statistics for frailty phenotype for Davidoff, Faurot, Segal, and Kim indices were 0.73, 0.74, 0.73, and 0.78, respectively, and partial correlation coefficients with FI were 0.18, 0.32, 0.26, and 0.55, respectively. The results for ADL dependence were similar (prevalence in ≤10th vs >90th percentile: 3.7% vs 50.5% for Davidoff; 2.3% vs 55.0% for Faurot; 3.0% vs 38.3% for Segal; 2.3% vs 50.8% for Kim). The age and sex-adjusted C-statistics for the indices were 0.79, 0.80, 0.74, and 0.81, respectively. The choice of a claims-based frailty measure can influence the identification of older adults with frailty and disability in Medicare data.


Identification and characterization of the RNA binding surface of the pentatricopeptide repeat protein.
The expressions of chloroplast and mitochondria genes are tightly controlled by numerous nuclear-encoded proteins, mainly at the post-transcriptional level. Recent analyses have identified a large, plant-specific family of pentatricopeptide repeat (PPR) motif-containing proteins that are exclusively involved in RNA metabolism of organelle genes via sequence-specific RNA binding. A tandem array of PPR motifs within the protein is believed to facilitate the RNA interaction, although little is known of the mechanism. Here, we describe the RNA interacting framework of a PPR protein, Arabidopsis HCF152. First, we demonstrated that a Pfam model could be relevant to the PPR motif function. A series of proteins with two PPR motifs showed significant differences in their RNA binding affinities, indicating functional differences among PPR motifs. Mutagenesis and informatics analysis putatively identified five amino acids organizing its RNA binding surface [the 1st, 4th, 8th, 12th and 'ii'(-2nd) amino acids] and their complex connections. SELEX (Systematic evolution of ligands by exponential enrichment) and nucleobase preference assays determined the nucleobases with high affinity for HCF152 and suggested several characteristic amino acids that may be involved in determining specificity and/or affinity of the PPR/RNA interaction.


Voluntary wheel running activates Akt/AMPK/eNOS signaling cascades without improving profound endothelial dysfunction in mice deficient in α-galactosidase A.
Fabry disease is caused by loss of activity of the lysosomal hydrolase α-galactosidase A (GLA). Premature life-threatening complications in Fabry patients arise from cardiovascular disease, including stroke and myocardial infarction. Exercise training has been shown to improve endothelial dysfunction in various settings including coronary artery disease. However, the effects of exercise training on endothelial dysfunction in Fabry disease have not been investigated. Gla knockout mice were single-housed in a cage equipped with a voluntary wheel (EX) or no wheel (SED) for 12 weeks. Exercised mice ran 10 km/day on average during the voluntary running intervention (VR) period. Despite significantly higher food intake in EX than SED, body weights of EX and SED remained stable during the VR period. After the completion of VR, citrate synthase activity in gastrocnemius muscle was significantly higher in EX than SED. VR resulted in greater phosphorylation of Akt (S473) and AMPK (T172) in the aorta of EX compared to SED measured by western blot. Furthermore, VR significantly enhanced eNOS protein expression and phosphorylation at S1177 by 20% and 50% in the aorta of EX when compared with SED. Similarly, plasma nitrate and nitrite levels were 77% higher in EX than SED. In contrast, measures of anti- and pro-oxidative enzymes (superoxide dismutase and p67phox subunit of NADPH oxidase) and overall oxidative stress (plasma oxidized glutathione) were not different between groups. Although the aortic endothelial relaxation to acetylcholine was slightly increased in EX, it did not reach statistical significance. This study provides the first evidence that VR improves Akt/AMPK/eNOS signaling cascades, but not endothelial function in the aorta of aged Gla deficient mice.


Design and biological characterization of hybrid compounds of curcumin and thalidomide for multiple myeloma.
In our efforts to develop effective treatment agents for human multiple myeloma (MM), a series of hybrid molecules based on the structures of thalidomide (1) and curcumin (2) were designed, synthesized, and biologically characterized in human multiple myeloma MM1S, RPMI8226, U266 cells, and human lung cancer A549 cells. The biological results showed that two hybrid compounds, 5 and 7, exhibited significantly improved lethal effects towards all three human MM cell models compared to 1 or 2 alone, as well as the combination of 1 and 2. Furthermore, mechanistic studies in U266 cells demonstrated that 5 and 7 can induce the production of reactive oxygen species (ROS) and cause G1/S arrest, thus leading to apoptosis and cell death. Additionally, they exhibited inhibitory effects on NFκB activation in A549 cells. Collectively, the results obtained from these hybrid compounds strongly encourage their further optimization as new leads to develop effective treatment agents for human MM.


Animal models of the epilepsies.
The study of mechanisms of the epilepsies requires employment of animal models. Choice of a model system depends upon several factors, including the question to be studied, the type of epilepsy to be modelled, familiarity and convenience. Over 50 models are reviewed. Major categories of models are those for simple partial seizures: topical convulsants, acute electrical stimulation, cortically implanted metals, cryogenic injury; for complex partial seizures: kainic acid, tetanus toxin, injections into area tempesta, kindling, rodent hippocampal slice, isolated cell preparations, human neurosurgical tissue; for generalized tonic-clonic seizures: genetically seizure-prone strains of mouse, rat, gerbil, fruitfly and baboon, maximal electroshock seizures, systemic chemical convulsants, metabolic derangements; and for generalized absence seizures: thalamic stimulation, bilateral cortical foci, systemic penicillin, gamma-hydroxy-butyrate, intraventricular opiates, genetic rat models. The lithium-pilocarpine, homocysteine and rapid repetitive stimulation models are most useful in studies of status epilepticus. Key findings learned from each of the models, the model's strengths and weaknesses are detailed. Interpretation of findings from each of these models can be difficult. Do results pertain to the epilepsies or to the particular model under study? How important are species differences? Which clinical seizure type is really being modelled? In a model are behavior or EEG findings only similar superficially to epilepsy, or are the mechanisms comparable? The wealth of preparations available to model the epilepsies underscores the need for unifying themes, and for better understanding of basic mechanisms of the epilepsies.


Going to work ill: A meta-analysis of the correlates of presenteeism and a dual-path model.
Interest in presenteeism, attending work while ill, has flourished in light of its consequences for individual well-being and organizational productivity. Our goal was to identify its most significant causes and correlates by quantitatively summarizing the extant research. Additionally, we built an empirical model of some key correlates and compared the etiology of presenteeism versus absenteeism. We used meta-analysis (in total, K = 109 samples, N = 175,965) to investigate the correlates of presenteeism and meta-analytic structural equation modeling to test the empirical model. Salient correlates of working while ill included general ill health, constraints on absenteeism (e.g., strict absence policies, job insecurity), elevated job demands and felt stress, lack of job and personal resources (e.g., low support and low optimism), negative relational experiences (e.g., perceived discrimination), and positive attitudes (satisfaction, engagement, and commitment). Moreover, our dual process model clarified how job demands and job and personal resources elicit presenteeism via both health impairment and motivational paths, and they explained more variation in presenteeism than absenteeism. The study sheds light on the controversial act of presenteeism, uncovering both positive and negative underlying mechanisms. The greater variance explained in presenteeism as opposed to absenteeism underlines the opportunities for researchers to meaningfully investigate the behavior and for organizations to manage it. (PsycINFO Database Record


Dietary Intake Adequacy and Food Sources of Nutrients Involved in the Methionine-Methylation Cycle in Women of Childbearing Age from the ANIBES Spanish Population.
Growing evidence confirms choline as a critical perinatal nutrient. However, intake levels of choline and betaine among the Spanish fertile population remain unknown. Given their role in one-carbon metabolism with potential epigenetic effects, the aim of the present study was to evaluate the dietary intakes, their adequacy to existing guidelines and the main food sources together with other micronutrients involved in the methylation-methionine cycle (vitamin B6, folates and vitamin B12) in women of childbearing age. The ANIBES study, a cross-sectional study of a representative sample of women of childbearing age (18-45 years, n = 641) resident in Spain, was used. The sample was divided into younger women (18-30 years, n = 251) and older women (31-45 years, n = 390). Dietary intake was assessed by a three-day dietary record by using a tablet device. Total median intakes for the total sample were 303.9 mg/d for choline; 122.6 mg/d for betaine; 1.3 mg/d for vitamin B6; 140.8 μg/d for folates, and 3.8 μg/d for vitamin B12. The older subgroup showed significantly higher choline (p < 0.05), betaine (p < 0.001) and folates (p < 0.05) intakes than younger women. Main food sources for the whole sample were meat and meat products for choline (28.3%), vitamin B6 (25.7%) and vitamin B12 (22.8%); cereals and derivatives (79.9%) for betaine; vegetables (20.0%) for folates. Overall intake adequacy was only observed for vitamin B12, with a very limited number of participants showing adequate intakes for all the other micronutrients. These results illustrate there is a relevant need to raise awareness about optimizing the status of the methionine cycle-related vitamins and cofactors in this potentially vulnerable population.


Polymorphisms of Interlukin-1β rs16944 confer susceptibility to myelodysplastic syndromes.
Genetic factors have been shown to be associated with Myelodysplastic syndromes (MDS) susceptibility. In recent years, the role of inflammation in the promotion of tumor growth is supported by a broad range of experimental and clinical evidence. But the relationship between polymorphisms in NOD-like receptor protein 3 (NLRP3) inflammasome and MDS is rarely reported. Thus, we conducted a case-control study, and genotyped five single nucleotide polymorphisms (SNPs) (NLRP3, IL-1β, IL-18, CARD8, and NF-κB) in MDS patients and healthy controls. The association of different genotypes with patient characteristics was analyzed. Comparing MDS patients with controls, GG genotype of IL-1β (rs16944) was observed to be associated with a significantly increased risk of MDS 78/166 (48.8%) vs 26/96 (27.0%), OR=2.1, CI (1.0-4.4). No significant association was identified regarding the rest of investigated polymorphisms and MDS susceptibility. Complex karyotypes were more frequent in patients with GG genotype of IL-1β (rs16944). Patients with IL-1β polymorphisms (rs16944) GG and GA had lower hemoglobin than those without. Patients with IL-1β polymorphisms (rs16944) GG had higher IPSS scores than those without IL-1β polymorphisms. In conclusion, our present data shows that the IL-1β polymorphisms (rs16944) GG were frequently occurred in MDS. IL-1β (rs16944) GG genotype might serve as a novel biomarker and potential targets for MDS.


Multiple heparin binding domains of respiratory syncytial virus G mediate binding to mammalian cells.
Respiratory syncytial virus (RSV) G glycoprotein mediates cell attachment through surface glycosaminoglycans (GAGs). Feldman et al. [10] suggested that specific basic amino acids in residues 184-198 of G defined a critical heparin binding domain (HBD). To further define the G HBD we made a series of truncated G proteins expressed in Escherichia coli. G88 (G residues 143-231), bound to HEp-2 cells in a dose dependent manner and binding was inhibited >99% with heparin. Cell binding of G88 was unaltered by alanine substitution mutagenesis of all basic amino acids in Feldman's region 184-198. A G88 variant truncated beyond residue 198, G58, and G58 fully alanine substituted in the region 184-198, G58A6, bound to HEp-2 cells about half as well and 100-fold less well than G88, respectively. G88 and all alanine substitution mutants of G88 inhibited RSV plaque formation by 50% (ID(50)) at concentrations of approximately 50 nM; the ID(50) of G58 was approximately 425 nM while G58A6 had an ID(50) >1600 nM. These data show that the G HBD includes as much as residues 187-231, that there is redundancy beyond the previously described HBD, and that the cell-binding and virus infectivity-blocking functions of these recombinant G proteins were closely linked and required at least one HBD.


Part-time training in general surgery: results of a web-based survey.
The recent increase in female medical school enrollment and emphasis on lifestyle considerations for both men and women pose challenges for residency recruitment and retention. This study was designed to assess interest in part-time surgical training. We hypothesized that more women than men would be interested in this option. A Web-based survey soliciting demographic information and opinions about training priorities was distributed to medical students, surgery residents, fellows, and trained surgeons. Respondents were asked to express on a 5-point Likert scale interest in (and deterrents to) substituting 1 or more years of standard residency with a shorter workweek (< 80 hours but > 40 hours) in exchange for a proportionately overall longer length of training. The survey was located on the American College of Surgeons Web site. Medical students (482), surgical residents (789), fellows (179), and fully trained surgeons (2858) affiliated with at least 1 of 4 major surgical societies. There were 4308 respondents (76% male). Of physician respondents, 9.1% had taken time out of residency for nonresearch reasons. Thirty-six percent of female and 24% of male students agreed to increased interest in surgical careers if part-time training were an option (P = .005). Twenty-five percent of female and 13% of male residents (P<.001) expressed interest in this option. Prolonged training was cited as the primary deterrent. Eleven percent to 36% of total male and female respondents expressed interest in pursuing part-time training. Significantly more women than men favored a part-time option.


Using CRISPR-Cas systems as antimicrobials.
Although CRISPR-Cas systems naturally evolved to provide adaptive immunity in bacteria and archaea, Cas nucleases can be co-opted to target chromosomal sequences rather than invasive genetic elements. Although genome editing is the primary outcome of self-targeting using CRISPR-based technologies in eukaryotes, self-targeting by CRISPR is typically lethal in bacteria. Here, we discuss how DNA damage introduced by Cas nucleases in bacteria can efficiently and specifically lead to plasmid curing or drive cell death. Specifically, we discuss how various CRISPR-Cas systems can be engineered and delivered using phages or phagemids as vectors. These principles establish CRISPR-Cas systems as potent and programmable antimicrobials, and open new avenues for the development of CRISPR-based tools for selective removal of bacterial pathogens and precise microbiome composition alteration.


Factors associated with sexual activity among high-school students in Nairobi, Kenya.
The high level of HIV infection in sub-Saharan Africa has led to an increased interest in understanding the determinants of sexual activity among young people, who are at high risk of sexually transmitted infections. The present study examined sociodemographic, behavioral, and psychosocial factors associated with heterosexual activity among a sample of 3556 male and female high-school students in Nairobi, Kenya. Approximately 50% of the males and 11% of females reported having had sexual intercourse at least once in their lifetime with a significant proportion reporting multiple sexual partnerships. Sexual activity was associated with various factors including religiosity, perceived parental attitudes towards sex, living arrangements, and school characteristics. However, the pattern of association differed for males and females. Results suggest that adolescents may benefit from sex education programs addressing multiple factors that may predispose adolescents to sexual activity, and that take into account gender differences.


Development of a patient reported outcome measure for fatigue in motor neurone disease: the Neurological Fatigue Index (NFI-MND).
The objective of this research was to develop a disease-specific measure for fatigue in patients with motor neurone disease (MND) by generating data that would fit the Rasch measurement model. Fatigue was defined as reversible motor weakness and whole-body tiredness that was predominantly brought on by muscular exertion and was partially relieved by rest. Qualitative interviews were undertaken to confirm the suitability of a previously identified set of 52 neurological fatigue items as relevant to patients with MND. Patients were recruited from five U.K. MND clinics. Questionnaires were administered during clinic or by post. A sub-sample of patients completed the questionnaire again after 2-4 weeks to assess test-retest validity. Exploratory factor analyses and Rasch analysis were conducted on the item set. Qualitative interviews with ten MND patients confirmed the suitability of 52 previously identified neurological fatigue items as relevant to patients with MND. 298 patients consented to completing the initial questionnaire including this item set, with an additional 78 patients completing the questionnaire a second time after 4-6 weeks. Exploratory Factor Analysis identified five potential subscales that could be conceptualised as representing: 'Energy', 'Reversible muscular weakness' (shortened to 'Weakness'), 'Concentration', 'Effects of heat' and 'Rest'. Of the original five factors, two factors 'Energy' and 'Weakness' met the expectations of the Rasch model. A higher order fatigue summary scale, consisting of items from the 'Energy' and 'Weakness' subscales, was found to fit the Rasch model and have acceptable unidimensionality. The two scales and the higher order summary scale were shown to fulfil model expectations, including assumptions of unidimensionality, local independency and an absence of differential item functioning. The Neurological Fatigue Index for MND (NFI-MND) is a simple, easy-to-administer fatigue scale. It consists of an 8-item fatigue summary scale in addition to separate scales for measuring fatigue experienced as reversible muscular weakness and fatigue expressed as feelings of low energy and whole body tiredness. The underlying two factor structure supports the patient concept of fatigue derived from qualitative interviews in this population. All three scales were shown to be reliable and capable of interval level measurement.


Unlocking the novel genetic diversity and population structure of synthetic Hexaploid wheat.
Synthetic hexaploid wheat (SHW) is a reconstitution of hexaploid wheat from its progenitors (Triticum turgidum ssp. durum L.; AABB x Aegilops tauschii Coss.; DD) and has novel sources of genetic diversity for broadening the genetic base of elite bread wheat (BW) germplasm (T. aestivum L). Understanding the diversity and population structure of SHWs will facilitate their use in wheat breeding programs. Our objectives were to understand the genetic diversity and population structure of SHWs and compare the genetic diversity of SHWs with elite BW cultivars and demonstrate the potential of SHWs to broaden the genetic base of modern wheat germplasm. The genotyping-by-sequencing of SHW provided 35,939 high-quality single nucleotide polymorphisms (SNPs) that were distributed across the A (33%), B (36%), and D (31%) genomes. The percentage of SNPs on the D genome was nearly same as the other two genomes, unlike in BW cultivars where the D genome polymorphism is generally much lower than the A and B genomes. This indicates the presence of high variation in the D genome in the SHWs. The D genome gene diversity of SHWs was 88.2% higher than that found in a sample of elite BW cultivars. Population structure analysis revealed that SHWs could be separated into two subgroups, mainly differentiated by geographical location of durum parents and growth habit of the crop (spring and winter type). Further population structure analysis of durum and Ae. parents separately identified two subgroups, mainly based on type of parents used. Although Ae. tauschii parents were divided into two sub-species: Ae. tauschii ssp. tauschii and ssp. strangulate, they were not clearly distinguished in the diversity analysis outcome. Population differentiation between SHWs (Spring_SHW and Winter_SHW) samples using analysis of molecular variance indicated 17.43% of genetic variance between populations and the remainder within populations. SHWs were diverse and had a clearly distinguished population structure identified through GBS-derived SNPs. The results of this study will provide valuable information for wheat genetic improvement through inclusion of novel genetic variation and is a prerequisite for association mapping and genomic selection to unravel economically important marker-trait associations and for cultivar development.


Emotional suppression and well-being in immigrants and majority group members in the Netherlands.
We were interested in interethnic differences in emotional suppression. We propose a model in which suppression of specific emotional experiences (suppressive behaviours during interactions with others) mediates the relationship between emotional suppression tendency (intention to suppress emotions) and well-being, operationalised as mood disturbance, life dissatisfaction and depressive and physical symptoms. The sample consisted of 427 majority group members and 344 non-Western and 465 Western immigrants in the Netherlands. Non-Western immigrants scored higher on emotional suppression tendency and lower on well-being than the other groups. We did not find interethnic differences in suppression of specific emotional experiences. The full mediation model was supported in all groups. Interethnic differences in well-being could not be accounted for by differences in emotional suppression.


Non-selective distribution of infectious disease prevention may outperform risk-based targeting.
Epidemic control often requires optimal distribution of available vaccines and prophylactic tools, to protect from infection those susceptible. Well-established theory recommends prioritizing those at the highest risk of exposure. But the risk is hard to estimate, especially for diseases involving stigma and marginalization. We address this conundrum by proving that one should target those at high risk only if the infection-averting efficacy of prevention is above a critical value, which we derive analytically. We apply this to the distribution of pre-exposure prophylaxis (PrEP) of the Human Immunodeficiency Virus (HIV) among men-having-sex-with-men (MSM), a population particularly vulnerable to HIV. PrEP is effective in averting infections, but its global scale-up has been slow, showing the need to revisit distribution strategies, currently risk-based. Using data from MSM communities in 58 countries, we find that non-selective PrEP distribution often outperforms risk-based, showing that a logistically simpler strategy is also more effective. Our theory may help design more feasible and successful prevention.