Cardiac MR imaging: current status and future direction.
Coronary artery disease is currently a worldwide epidemic with increasing impact on healthcare systems. Magnetic resonance imaging (MRI) sequences give complementary information on LV function, regional perfusion, angiogenesis, myocardial viability and orientations of myocytes. T2-weighted short-tau inversion recovery (T2-STIR), fat suppression and black blood sequences have been frequently used for detecting edematous area at risk (AAR) of infarction. T2 mapping, however, indicated that the edematous reaction in acute myocardial infarct (AMI) is not stable and warranted the use of edematous area in evaluating therapies. On the other hand, cine MRI demonstrated reproducible data on LV function in healthy volunteers and LV remodeling in patients. Noninvasive first pass perfusion, using exogenous tracer (gadolinium-based contrast media) and arterial spin labeling MRI, using endogenous tracer (water), are sensitive and useful techniques for evaluating myocardial perfusion and angiogenesis. Recently, new strategies have been developed to quantify myocardial viability using T1-mapping and equilibrium contrast enhanced MR techniques because existing delayed contrast enhancement MRI (DE-MRI) sequences are limited in detecting patchy microinfarct and diffuse fibrosis. These new techniques were successfully used for characterizing diffuse myocardial fibrosis associated with myocarditis, amyloidosis, sarcoidosis heart failure, aortic hypertrophic cardiomyopathy, congenital heart disease, restrictive cardiomyopathy, arrhythmogenic right ventricular dysplasia and hypertension). Diffusion MRI provides information regarding microscopic tissue structure, while diffusion tensor imaging (DTI) helps to characterize the myocardium and monitor the process of LV remodeling after AMI. Novel trends in hybrid imaging, such as cardiac positron emission tomography (PET)/MRI and optical imaging/MRI, are recently under intensive investigation. With the promise of higher spatial-temporal resolution and 3D coverage in the near future, cardiac MRI will be an indispensible tool in the diagnosis of cardiac diseases, coronary intervention and myocardial therapeutic delivery.


Identification of specific carbonic anhydrase inhibitors via in situ click chemistry, phage-display and synthetic peptide libraries: comparison of the methods and structural study.
The development of highly active and selective enzyme inhibitors is one of the priorities of medicinal chemistry. Typically, various high-throughput screening methods are used to find lead compounds from a large pool of synthetic compounds, and these are further elaborated and structurally refined to achieve the desired properties. In an effort to streamline this complex and laborious process, new selection strategies based on different principles have recently emerged as an alternative. Herein, we compare three such selection strategies with the aim of identifying potent and selective inhibitors of human carbonic anhydrase II. All three approaches, in situ click chemistry, phage-display libraries and synthetic peptide libraries, led to the identification of more potent inhibitors when compared to the parent compounds. In addition, one of the inhibitor-peptide conjugates identified from the phage libraries showed greater than 100-fold selectivity for the enzyme isoform used for the compound selection. In an effort to rationalize the binding properties of the conjugates, we performed detailed crystallographic and NMR structural analysis, which revealed the structural basis of the compound affinity towards the enzyme and led to the identification of a novel exosite that could be utilized in the development of isoform specific inhibitors.


Evidence against the structural gene encoding type II collagen (COL2A1) as the mutant locus in achondroplasia.
The structure of the locus encoding the major cartilage collagen gene (COL2A1) was studied in a total of 19 cases of achondroplasia. No gross rearrangements were seen. The segregation of COL2A1 was examined in three affected kindreds using restriction site and length variants as genetic markers. In two kindreds discordant segregation between the achondroplasia and COL2A1 loci was demonstrated. Paternity/maternity was confirmed using a 'minisatellite' core sequence probe which reveals cross hybridising polymorphic loci.


Comparative sequence analysis of human minisatellites showing meiotic repeat instability.
The highly variable human minisatellites MS32 (D1S8), MS31A (D7S21), and CEB1 (D2S90) all show recombination-based repeat instability restricted to the germline. Mutation usually results in polar interallelic conversion or occasionally in crossovers, which, at MS32 at least, extend into DNA flanking the repeat array, defining a localized recombination hotspot and suggesting that cis-acting elements in flanking DNA can influence repeat instability. Therefore, comparative sequence analysis was performed to search for common flanking elements associated with these unstable loci. All three minisatellites are located in GC-rich DNA abundant in dispersed and tandem repetitive elements. There were no significant sequence similarities between different loci upstream of the unstable end of the repeat array. Only one of the three loci showed clear evidence for putative coding sequences near the minisatellite. No consistent patterns of thermal stability or DNA secondary structure were shared by DNA flanking these loci. This work extends previous data on the genomic environment of minisatellites. In addition, this work suggests that recombinational activity is not controlled by primary or secondary characteristics of the DNA sequence flanking the repeat array and is not obviously associated with gene promoters as seen in yeast.


"Essential noise" - enhancing variability of informational constraints benefits movement control: a comment on Waddington and Adams (2003).
This commentary proposes a dynamical systems perspective to re-interpret data from a group of international soccer players demonstrating that wearing textured insoles in soccer boots enhanced tactile information from the sole of the foot and increased movement discrimination capacity in ankle inversion sensitivity tests to levels similar to those in barefoot conditions. Theoretical arguments on the functional role of variability induced in the sensorimotor system by textured insoles, acting as a form of "essential noise" to enhance the accuracy of foot positioning are presented. It seems that, far from interfering with motor performance, variability can actually enhance perception of information to support motor performance. The addition of intermittent, intermediate levels of noise in a perceptual motor context may benefit performers by helping them to pick up information signals from background structure. Movement system variability is conceived as noise induced resonance benefiting the pick up of information to regulate behaviour. Variability can be functional in practical programmes to offset negative effects of losses in sensory sensitivity through ageing, disease, illness, or injury.


Where EGF receptors transmit their signals.
Excessive signaling by receptor tyrosine kinases (RTKs) can cause cancer. What molecular mechanisms normally control RTK signaling? Are they defective in tumors? If so, should therapeutics be developed to restore particular regulatory pathways to cancer cells? These questions have been approached through mechanistic studies of a prototypical RTK, the epidermal growth factor receptor (EGFR). EGFR signaling is mediated and regulated by both signaling and trafficking effectors. The amplitude of receptor-proximal signals changes as EGFRs move along the degradative trafficking pathway from the cell surface, to endosomes, and into lysosomes. To optimize therapeutic suppression of receptor oncogenicity, it may be crucial to target EGFRs that are signaling from a specific site in the trafficking pathway. Research suggests that EGFRs at the plasma membrane produce the bulk of the global transcriptional response to EGF. EGFRs localized between the internalization and early endosome fusion stages of the pathway enrich the expression of transcripts associated with cancer. EGFRs at later trafficking checkpoints controlled by the endosomal sorting complex required for transport (ESCRT) complexes II and III do not contribute substantially to the EGFR-mediated transcriptional response. These results suggest that therapeutics targeting the receptors at the earliest stages of degradative trafficking might be most effective.


Identification of miRNAs and their targets using high-throughput sequencing and degradome analysis in cytoplasmic male-sterile and its maintainer fertile lines of Brassica juncea.
Regulatory network of cytoplasmic male sterility (CMS) occurrence is still largely unknown in plants, although numerous researches have been attempted to isolate genes involved in CMS. Here, we employed high-throughput sequencing and degradome analysis to identify microRNAs and their targets using high-throughput sequencing in CMS and its maintainer fertile (MF) lines of Brassica juncea. We identified 197 known and 78 new candidate microRNAs during reproductive development of B. juncea. A total of 47 differentially expressed microRNAs between CMS and its MF lines were discovered, according to their sequencing reads number. Different expression levels of selected microRNAs were confirmed by using real-time quantitative PCR between CMS and MF lines. Furthermore, we observed that the transcriptional patterns of these microRNAs could be mimicked by artificially inhibiting mitochondrial F1F0-ATPase activity and its function in MF line by using treatment with oligomycin. Targeted genes of the microRNAs were identified by high-throughput sequencing and degradome approaches, including auxin response factor, NAC (No Apical Meristem) domain transcription factor, GRAS family transcription factor, MYB transcription factor, squamosa promoter binding protein, AP2-type transcription factor, homeobox/homeobox-leucine zipper family and TCP family transcription factors, which were observed to be differentially expressed between CMS and MF. Taken together, from these findings we suggested microRNA might participate in the regulatory network of CMS by tuning fork in gene expressions in CMS B. juncea. The differential expression of miRNAs observed between CMS and MF lines suggested that biogenesis of miRNAs could be influenced in the CMS.


CFD Modeling of Chamber Filling in a Micro-Biosensor for Protein Detection.
Tuberculosis (TB) remains one of the main causes of human death around the globe. The mortality rate for patients infected with active TB goes beyond 50% when not diagnosed. Rapid and accurate diagnostics coupled with further prompt treatment of the disease is the cornerstone for controlling TB outbreaks. To reduce this burden, the existing gap between detection and treatment must be addressed, and dedicated diagnostic tools such as biosensors should be developed. A biosensor is a sensing micro-device that consists of a biological sensing element and a transducer part to produce signals in proportion to quantitative information about the binding event. The micro-biosensor cell considered in this investigation is designed to operate based on aptamers as recognition elements against Mycobacterium tuberculosis secreted protein MPT64, combined in a microfluidic-chamber with inlet and outlet connections. The microfluidic cell is a miniaturized platform with valuable advantages such as low cost of analysis with low reagent consumption, reduced sample volume, and shortened processing time with enhanced analytical capability. The main purpose of this study is to assess the flooding characteristics of the encapsulated microfluidic cell of an existing micro-biosensor using Computational Fluid Dynamics (CFD) techniques. The main challenge in the design of the microfluidic cell lies in the extraction of entrained air bubbles, which may remain after the filling process is completed, dramatically affecting the performance of the sensing element. In this work, a CFD model was developed on the platform ANSYS-CFX using the finite volume method to discretize the domain and solving the Navier-Stokes equations for both air and water in a Eulerian framework. Second-order space discretization scheme and second-order Euler Backward time discretization were used in the numerical treatment of the equations. For a given inlet-outlet diameter and dimensions of an in-house built cell chamber, different inlet liquid flow rates were explored to determine an appropriate flow condition to guarantee an effective venting of the air while filling the chamber. The numerical model depicted free surface waves as promoters of air entrainment that ultimately may explain the significant amount of air content in the chamber observed in preliminary tests after the filling process is completed. Results demonstrated that for the present design, against the intuition, the chamber must be filled with liquid at a modest flow rate to minimize free surface waviness during the flooding stage of the chamber.


Conducting Clinically Based Intimate Partner Violence Research: Safety Protocol Recommendations.
Maintaining safety is of utmost importance during research involving participants who have experienced intimate partner violence (IPV). Limited guidance on safety protocols to protect participants is available, particularly information related to technology-based approaches to informed consent, data collection, and contacting participants during the course of a study. The purpose of the article is to provide details on the safety protocol developed and utilized with women receiving care at an urban HIV clinic and who were taking part in an observational study of IPV, mental health symptoms, and substance abuse and their relationship to HIV treatment adherence. The protocol presents the technological strategies to promote safety and allow autonomy in participant decision-making throughout the research process, including Voice over Internet Protocol telephone numbers, and tablet-based eligibility screening and data collection. Protocols for management of participants at risk for suicide and/or intimate partner homicide that included automated high-risk messaging to participants and research staff and facilitated disclosure of risk to clinical staff based on participant preferences are discussed. Use of technology and partnership with clinic staff helped to provide an environment where research regarding IPV could be conducted without undue burden or risk to participants. Utilizing tablet-based survey administration provided multiple practical and safety benefits for participants. Most women who screened into high-risk categories for suicide or intimate partner homicide did not choose to have their results shared with their healthcare providers, indicating the importance of allowing participants control over information sharing whenever possible.


The National Lung Matrix Trial of personalized therapy in lung cancer.
The majority of targeted therapies for non-small-cell lung cancer (NSCLC) are directed against oncogenic drivers that are more prevalent in patients with light exposure to tobacco smoke1-3. As this group represents around 20% of all patients with lung cancer, the discovery of stratified medicine options for tobacco-associated NSCLC is a high priority. Umbrella trials seek to streamline the investigation of genotype-based treatments by screening tumours for multiple genomic alterations and triaging patients to one of several genotype-matched therapeutic agents. Here we report the current outcomes of 19 drug-biomarker cohorts from the ongoing National Lung Matrix Trial, the largest umbrella trial in NSCLC. We use next-generation sequencing to match patients to appropriate targeted therapies on the basis of their tumour genotype. The Bayesian trial design enables outcome data from open cohorts that are still recruiting to be reported alongside data from closed cohorts. Of the 5,467 patients that were screened, 2,007 were molecularly eligible for entry into the trial, and 302 entered the trial to receive genotype-matched therapy-including 14 that re-registered to the trial for a sequential trial drug. Despite pre-clinical data supporting the drug-biomarker combinations, current evidence shows that a limited number of combinations demonstrate clinically relevant benefits, which remain concentrated in patients with lung cancers that are associated with minimal exposure to tobacco smoke.


Tweet Now, See You In the ED Later? Examining the Association Between Alcohol-related Tweets and Emergency Care Visits.
Alcohol use is a major and unpredictable driver of emergency department (ED) visits. Regional Twitter activity correlates ecologically with behavioral outcomes. No such correlation has been established in real time. The objective was to examine the correlation between real-time, alcohol-related tweets and alcohol-related ED visits. We developed and piloted a set of 11 keywords that identified tweets related to alcohol use. In-state tweets were identified using self-declared profile information or geographic coordinates. Using Datasift, a third-party vendor, a random sample of 1% of eligible tweets containing the keywords and originating in state were downloaded (including tweet date/time) over 3 discrete weeks in 3 different months. In the same time frame, we examined visits to an urban, high-volume, Level I trauma center that receives > 25% of the emergency care volume in the state. Alcohol-related ED visits were defined as visits with a chief complaint of alcohol use, positive blood alcohol, or alcohol-related ICD-9 code. Spearman's correlation coefficient was used to examine the hourly correlation between alcohol-related tweets, alcohol-related ED visits, and all ED visits. A total of 7,820 tweets (representing 782,000 in-state alcohol-related tweets during the 3 weeks) were identified. Concurrently, 404 ED visits met criteria for being alcohol-related versus 2939 non-alcohol-related ED visits. There was a statistically significant relationship between hourly alcohol-related tweet volume and number of alcohol-related ED visits (rs = 0.31, p < 0.00001), but not between hourly alcohol-related tweet volume and number of non-alcohol-related ED visits (rs = -0.07, p = 0.11). In a single state, a statistically significant relationship was observed between the hourly number of alcohol-related tweets and the hourly number of alcohol-related ED visits. Real-time Twitter monitoring may help predict alcohol-related surges in ED visits. Future studies should include larger numbers of EDs and natural language processing.


Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial.
In the treatment of severe malaria, intravenous artesunate is more rapidly acting than intravenous quinine in terms of parasite clearance, is safer, and is simpler to administer, but whether it can reduce mortality is uncertain. We did an open-label randomised controlled trial in patients admitted to hospital with severe falciparum malaria in Bangladesh, India, Indonesia, and Myanmar. We assigned individuals intravenous artesunate 2.4 mg/kg bodyweight given as a bolus (n=730) at 0, 12, and 24 h, and then daily, or intravenous quinine (20 mg salt per kg loading dose infused over 4 h then 10 mg/kg infused over 2-8 h three times a day; n=731). Oral medication was substituted when possible to complete treatment. Our primary endpoint was death from severe malaria, and analysis was by intention to treat. We assessed all patients randomised for the primary endpoint. Mortality in artesunate recipients was 15% (107 of 730) compared with 22% (164 of 731) in quinine recipients; an absolute reduction of 34.7% (95% CI 18.5-47.6%; p=0.0002). Treatment with artesunate was well tolerated, whereas quinine was associated with hypoglycaemia (relative risk 3.2, 1.3-7.8; p=0.009). Artesunate should become the treatment of choice for severe falciparum malaria in adults.


Morphological decomposition of 2-D binary shapes into convex polygons: a heuristic algorithm.
In many morphological shape decomposition algorithms, either a shape can only be decomposed into shape components of extremely simple forms or a time consuming search process is employed to determine a decomposition. In this paper, we present a morphological shape decomposition algorithm that decomposes a two-dimensional (2-D) binary shape into a collection of convex polygonal components. A single convex polygonal approximation for a given image is first identified. This first component is determined incrementally by selecting a sequence of basic shape primitives. These shape primitives are chosen based on shape information extracted from the given shape at different scale levels. Additional shape components are identified recursively from the difference image between the given image and the first component. Simple operations are used to repair certain concavities caused by the set difference operation. The resulting hierarchical structure provides descriptions for the given shape at different detail levels. The experiments show that the decomposition results produced by the algorithm seem to be in good agreement with the natural structures of the given shapes. The computational cost of the algorithm is significantly lower than that of an earlier search-based convex decomposition algorithm. Compared to nonconvex decomposition algorithms, our algorithm allows accurate approximations for the given shapes at low coding costs.


Meta-analysis of selective serotonin reuptake inhibitor-associated QTc prolongation.
To evaluate the association between selective serotonin reuptake inhibitors (SSRIs) and corrected QT interval (QTc) prolongation via meta-analysis of prospective studies. PubMed/MEDLINE database (January 1, 1975-August 15, 2012), with additional reports identified using hand searches of reference lists of relevant articles. Key words searched were QT, torsades de pointes, and sudden cardiac death, combined with antidepressants, citalopram, escitalopram, fluoxetine, sertraline, paroxetine, and fluvoxamine. English-, Spanish-, and German-language articles were included. Two reviewers independently identified prospective controlled studies in adults that reported data related to QTc intervals prior to and following treatment with SSRIs. Three reviewers independently extracted study-level data including population characteristics, method of QTc measurement and treatment and outcome data. Two independent reviewers critiqued study quality. Publication bias was assessed visually using a funnel plot and quantitatively. Heterogeneity was measured using Cochran Q statistic. Sixteen articles (with 25 distinct data subsets) involving 4,292 patients were included. SSRIs were associated with a dose-dependent increase in QTc interval compared to placebo (+6.10 milliseconds; 95% CI, 3.47-8.73; P < .001). Tricyclic antidepressants (TCAs) were associated with a significantly greater QTc increase than SSRIs (TCA prolongation, 7.05 milliseconds; 95% CI, 3.84-10.27 greater than SSRIs; P < .001). With respect to specific SSRI agents, citalopram was associated with significantly greater QTc prolongation than sertraline, paroxetine, and fluvoxamine. SSRIs were associated with a modest but statistically significant increase in the QTc interval, although to a lesser extent than TCAs; this finding was not limited to any single study. Citalopram was associated with more QTc prolongation than most other SSRIs.


Childhood sexual abuse and pathogenic parenting in the childhood recollections of adult twin pairs.
We examined the relationship between childhood sexual abuse (CSA), and interviewees' recollections of pathogenic parenting, testing for possible retrospective biases in the recollections of those who have experienced CSA. Information about CSA, parental divorce and interviewees' recollections of parental rejection, parental overprotection and perceived autonomy (as assessed through a shortened version of the Parental Bonding Instrument) was obtained through telephone interviews with 3626 Australian twins who had also returned self-report questionnaires several years earlier. Recollections of parental behaviours were compared for individuals from pairs in which neither twin, at least one twin, or both twins reported CSA. Significant associations were noted between CSA and paternal alcoholism and between CSA and recollections of parental rejection. For women, individuals from CSA-discordant pairs reported levels of parental rejection that were significantly higher than those obtained from CSA-negative pairs. The levels of parental rejection observed for twins from CSA-discordant pairs did not differ significantly from those obtained from CSA-concordant pairs, regardless of respondent's abuse status. For men from CSA-discordant pairs, respondents reporting CSA displayed a tendency to report higher levels of parental rejection than did respondents not reporting CSA. Other measures of parenting behaviour (perceived autonomy and parental overprotection) failed to show a clear relationship with CSA. The relationship between CSA and respondents' recollections of parental rejection is not due solely to retrospective bias on the part of abused individuals and, consistent with other studies, may reflect a pathological family environment with serious consequences for all siblings.


Effects of saliva contamination on dentin bond strength using all-in-one adhesives.
To evaluate the effects of saliva contamination on microtensile bond strengths of all-in-one adhesives to dentin. Flat superficial occlusal dentin surfaces of extracted human molars were used and randomly divided into 2 groups depending on two all-in-one adhesives: One-Up Bond F Plus (Tokuyama Dental) and Adper Prompt L-Pop (3M ESPE). For each adhesive, the teeth were allocated to 7 subgroups in which one group was bonded without contamination with saliva, serving as a control. The other groups, either before or after the polymerization of adhesives, were contaminated with saliva and dried; contaminated, dried, and adhesives re-applied; contaminated, rinsed, and the adhesives re-applied. Resin composite was then placed on the treated dentin surfaces. After 24 h storage in distilled water at 37 degrees C, the teeth were sectioned perpendicular to the adhesive interface in x and y directions, obtaining multiple beam-shaped specimens with a cross-sectional area of approximately 1.0 mm2. Specimens were stressed in tension at 1 mm/min until rupture of the bond. Data were analyzed using one-way ANOVA and the Games-Howell test. For both all-in-one adhesives, saliva-contaminated groups showed lower bond strengths than the controls. Re-application of the adhesives after drying or rinsing the saliva off restored the dentin bond strengths to the control levels. Saliva contamination reduced the dentin bond strengths of all-in-one adhesives. Supplementary application of the adhesive after cleaning the saliva from the dentin surface is an empirical recommendation for restoring bond strength.


Comparative assay of fluorescent antibody test results among twelve European National Reference Laboratories using various anti-rabies conjugates.
Twelve National Reference Laboratories (NRLs) for rabies have undertaken a comparative assay to assess the comparison of fluorescent antibody test (FAT) results using five coded commercial anti-rabies conjugates (Biorad, Bioveta, Fujirebio, Millipore, and SIFIN conjugates). Homogenized positive brain tissues infected with various lyssavirus species as well as negative samples were analyzed blindly using a standardized FAT procedure. Conjugates B, C, D, and E were found to be significantly more effective than conjugate A for GS7 (French RABV) diluted samples (1/8 and 1/100) while the frequency of concordant results of conjugates C and D differ significantly from conjugates A, B and E for CVS 27. For detection of EBLV-1 strains, conjugates C and D also presented a significantly lower frequency of discordant results compared to conjugates A, B and E. Conjugates B, C and D were found to be significantly more effective than conjugates E and A for EBLV-2 and ABLV samples. In view of these results, conjugates C and D set themselves apart from the others and appeared as the most effective of this 5-panel conjugates. This study clearly demonstrates that the variability of conjugates used by National Reference Laboratories can potentially lead to discordant results and influence assay sensitivity. In case of false negative results this could have a dramatic impact if the animal under investigation is responsible for human exposure. To avoid such situations, confirmatory tests should be implemented.


Talk, trust and time: a longitudinal study evaluating knowledge translation and exchange processes for research on violence against women.
Violence against women (VAW) is a major public health problem. Translation of VAW research to policy and practice is an area that remains understudied, but provides the opportunity to examine knowledge translation and exchange (KTE) processes in a complex, multi-stakeholder context. In a series of studies including two randomized trials, the McMaster University VAW Research Program studied one key research gap: evidence about the effectiveness of screening women for exposure to intimate partner violence. This project developed and evaluated KTE strategies to share research findings with policymakers, health and community service providers, and women's advocates. A longitudinal cross-sectional design, applying concurrent mixed data collection methods (surveys, interviews, and focus groups), was used to evaluate the utility of specific KTE strategies, including a series of workshops and a day-long Family Violence Knowledge Exchange Forum, on research sharing, uptake, and use. Participants valued the opportunity to meet with researchers, provide feedback on key messages, and make personal connections with other stakeholders. A number of factors specific to the knowledge itself, stakeholders' contexts, and the nature of the knowledge gap being addressed influenced the uptake, sharing, and use of the research. The types of knowledge use changed across time, and were specifically related to both the types of decisions being made, and to stage of decision making; most reported use was conceptual or symbolic, with few examples of instrumental use. Participants did report actively sharing the research findings with their own networks. Further examination of these second-order knowledge-sharing processes is required, including development of appropriate methods and measures for its assessment. Some participants reported that they would not use the research evidence in their decision making when it contradicted professional experiences, while others used it to support apparently contradictory positions. The online wiki-based 'community of interest' requested by participants was not used. Mobilizing knowledge in the area of VAW practice and policy is complex and resource-intensive, and must acknowledge and respect the values of identified knowledge users, while balancing the objectivity of the research and researchers. This paper provides important lessons learned about these processes, including attending to the potential unintended consequences of knowledge sharing.


Conjugate schema and basis representation of crossover and mutation operators.
In genetic search algorithms and optimization routines, the representation of the mutation and crossover operators are typically defaulted to the canonical basis. We show that this can be influential in the usefulness of the search algorithm. We then pose the question of how to find a basis for which the search algorithm is most useful. The conjugate schema is introduced as a general mathematical construct and is shown to separate a function into smaller dimensional functions whose sum is the original function. It is shown that conjugate schema, when used on a test suite of functions, improves the performance of the search algorithm on 10 out of 12 of these functions. Finally, a rigorous but abbreviated mathematical derivation is given in the appendices.


Investigations into the source attribution of party sparklers using trace elemental analysis and chemometrics.
In Australia, party sparklers are commonly used to initiate or prepare inorganic based homemade explosives (HMEs) as they are the most easily accessible and inexpensive pyrotechnic available on the market. As sparkler residue would be encountered in cases involving these types of devices, the characterisation and source determination of the residue would be beneficial within a forensic investigation. The aim of this study is to demonstrate the potential of using trace elemental profiling coupled with chemometric and other statistical techniques to link a variety of different sparklers to their origin. Inductively coupled plasma-mass spectrometry (ICP-MS) was used to determine the concentration of 50 elements in 48 pre-blast sparkler samples from eight sparkler brands/classes available in Australia. Extracting ground-up sparkler residue in 10% nitric acid for 24 hours was found to give the most reliable quantification. The collected data were analysed using Principal Component Analysis (PCA) to visualise the distribution of the sample data and explore whether the sparkler samples could be classified into their respective brands. ANOVA based feature selection was used to remove elements that did not largely contribute to the separation between classes. This resulted in the development of a 7-elemental profile, consisting of V, Co, Ni, Sr, Sn, Sb, W, which could be used to correctly classify the samples into eight distinct groups. Linear Discriminant Analysis (LDA) was subsequently used to construct a discriminant model using four out of six samples from each class. The model successfully classified 100% of the samples to their correct sparkler brand. The model also correctly matched 100% of the remaining samples to the correct class. This demonstrates the potential of using trace elemental analysis and chemometrics to correctly identify and discriminate between party sparklers.


The Plasmodium vivax rhoptry neck protein 5 is expressed in the apical pole of Plasmodium vivax VCG-1 strain schizonts and binds to human reticulocytes.
Different proteins derived from the membrane or the apical organelles become involved in malarial parasite invasion of host cells. Among these, the rhoptry neck proteins (RONs) interact with a protein component of the micronemes to enable the formation of a strong bond which is crucial for the parasite's successful invasion. The present study was aimed at identifying and characterizing the RON5 protein in Plasmodium vivax and evaluating its ability to bind to reticulocytes. Taking the Plasmodium falciparum and Plasmodium knowlesi RON5 amino acid sequences as template, an in-silico search was made in the P. vivax genome for identifying the orthologous gene. Different molecular tools were used for experimentally ascertaining pvron5 gene presence and transcription in P. vivax VCG-1 strain schizonts. Polyclonal antibodies against PvRON5 peptides were used for evaluating protein expression (by Western blot) and sub-cellular localization (by immunofluorescence). A 33 kDa PvRON5 fragment was expressed in Escherichia coli and used for evaluating the reactivity of sera from patients infected by P. vivax. Two assays were made for determining the RON5 recombinant fragment's ability to bind to reticulocyte-enriched human umbilical cord samples. The pvron5 gene (3,477 bp) was transcribed in VCG-1 strain schizonts and encoded a ~133 kDa protein which was expressed in the rhoptry neck of VCG-1 strain late schizonts, together with PvRON2 and PvRON4. Polyclonal sera against PvRON5 peptides specifically detected ~85 and ~30 kDa fragments in parasite lysate, thereby suggesting proteolytic processing in this protein. Comparative analysis of VCG-1 strain PvRON5 with other P. vivax strains having different geographic localizations suggested its low polymorphism regarding other malarial antigens. A recombinant fragment of the PvRON5 protein (rPvRON5) was recognized by sera from P. vivax-infected patients and bound to red blood cells, having a marked preference for human reticulocytes. The pvron5 gene is transcribed in the VCG-1 strain, the encoded protein is expressed at the parasite's apical pole and might be participating in merozoite invasion of host cells, taking into account its marked binding preference for human reticulocytes.


Development of surface chemistry for surface plasmon resonance based sensors for the detection of proteins and DNA molecules.
The immobilisation of biological recognition elements onto a sensor chip surface is a crucial step for the construction of biosensors. While some of the optical biosensors utilise silicon dioxide as the sensor surface, most of the biosensor surfaces are coated with metals for transduction of the signal. Biological recognition elements such as proteins can be adsorbed spontaneously on metal or silicon dioxide substrates but this may denature the molecule and can result in either activity reduction or loss. Self assembled monolayers (SAMs) provide an effective method to protect the biological recognition elements from the sensor surface, thereby providing ligand immobilisation that enables the repeated binding and regeneration cycles to be performed without losing the immobilised ligand, as well as additionally helping to minimise non-specific adsorption. Therefore, in this study different surface chemistries were constructed on SPR sensor chips to investigate protein and DNA immobilisation on Au surfaces. A cysteamine surface and 1%, 10% and 100% mercaptoundecanoic acid (MUDA) coatings with or without dendrimer modification were utilised to construct the various sensor surfaces used in this investigation. A higher response was obtained for NeutrAvidin immobilisation on dendrimer modified surfaces compared to MUDA and cysteamine layers, however, protein or DNA capture responses on the immobilised NeutrAvidin did not show a similar higher response when dendrimer modified surfaces were used.


Effects of patchouli and cinnamon essential oils on biofilm and hyphae formation by Candida species.
The prevalence and fatality rates with biofilm-associated candidal infections have remained a challenge to the medical fraternity despite major advances in the field of antifungal therapy. Traditionally, essential oils (EOs) from the aromatic plants have been found to be excellent therapeutic agents to treat fungal ailments. The present study explores the antivirulent and antibiofilm effects of under explored leaf EOs of Indian patchouli EO extracted from Pogostemon heyneanus (PH), Indian cassia from Cinnamomum tamala (CT) and camphor EO from C. camphora (CC) against Candida species. The EOs were investigated for its efficacy to disrupt the young and preformed Candida spp. biofilms and to inhibit the yeast to hyphal transition, a hallmark virulent trait of C. albicans. The ability of these EOs to inhibit metabolically active cells was assessed through XTT assay. Of these three EOs, CT EO showed enhanced biofilm inhibition than others and hence it was further selected to study its biomass inhibition potential and exopolysaccharide layer disruption ability. The CT EO reduced the biomass of the preformed biofilms of all three Candida strains, which was supported by confocal microscopy. It also disrupted the exopolysaccharide layer of the Candida strains as shown by scanning electron microscopy. The present findings validate the effectiveness of EOs against the virulence of Candida spp. and emphasize the pharmaceutical potential of several native but yet unexplored wild aromatic plants in the prospect of therapeutic application.


Cytogenetics and Blast Count Determine Transplant Outcomes in Patients with Active Acute Myeloid Leukemia.
Acute myeloid leukemia (AML) patients not in remission and beyond first or second complete remission are considered allogeneic stem cell transplant (SCT) candidates. We present 361 patients who underwent SCT from matched related or unrelated donors between 2005 and 2013. The purpose was to identify a subgroup of patients with active disease at the time of transplant that benefit. Cox proportional hazards regression analysis was used for univariate and multivariate analyses to predict overall survival (OS). Variables considered were age, sex, SWOG cytogenetic risk group, bone marrow (BM) and peripheral blood (PB) blast percentage, regimen intensity, and type of AML. At a median of 26 months after transplantation, OS, progression-free survival (PFS), non-relapse mortality, and relapse rates were 26, 24, 23, and 48%, respectively. In a univariate analysis, risk cytogenetics (p < 0.001) and BM blasts >4% (p = 0.006) or any blasts in PB (p < 0.001) indicated worse OS. In a multivariate analysis, patients with <5% BM blasts or absence of circulating blasts and good or intermediate risk cytogenetics had significantly superior OS (46%), PFS (44%), and disease progression at 3 years. Based on these findings, patients not in remission with good or intermediate risk cytogenetics and low blast counts should be considered for SCT.


Learning disability and epilepsy. 1, towards common outcome measures.
A major component of the population of people who have epilepsy are people with a learning disability. As a group, such individuals often have complex epilepsy which is refractory to treatment. Current available measures to assess the outcomes of therapeutic interventions in epilepsy are based on seizure frequency, seizure severity and quality-of-life measures, but have not been validated in people with a learning disability. Thus, we do not know if such measures of outcome serve the needs of this group. This review examines how able we are to assess the efficacy of our interventions to control epilepsy in people with learning disability. It is suggested that a standard data set is necessary as the basis of the assessment of any therapeutic intervention. Central components of this data set would encompass a definition of important characteristics of an individual, a description of their epilepsy and an assessment of the impact of their condition on both their own and their carer's health. The approach to obtaining this information should employ a methodology which can allow for environmental influences.


Periodontal status in smokers and never-smokers: clinical findings and real-time polymerase chain reaction quantification of putative periodontal pathogens.
Smoking is a well-known risk factor for destructive periodontal disease, but its relationship with periodontal status and subgingival microbiota remains unclear. Inherent limitations of microbiological methods previously used may partly explain these mixed results, and real-time polymerase chain reaction (PCR) has been presented as a valid alternative. The aim of the present study was to investigate the clinical condition and microbiological profile of patients with chronic periodontitis as related to the habit of smoking. Fifty patients (33 to 59 years old), 25 smokers and 25 never-smokers, constituted the sample. The visible plaque index (VPI), gingival bleeding index (GBI), bleeding on probing (BOP), periodontal probing depth (PD), clinical attachment loss (CAL), and gingival crevicular fluid (GCF) volume were recorded. Real-time PCR quantified Porphyromonas gingivalis, Micromonas micros, Dialister pneumosintes, Actinobacillus actinomycetemcomitans and total bacteria in subgingival samples. Smokers and never-smokers showed similar values for VPI, GBI, and BOP. Smokers had deeper PD in buccal/lingual sites and higher CAL independently of the tooth surface. The GCF volume was smaller in smokers, independent of the PD. Similar amounts of total bacteria and P. gingivalis were observed for both groups. Significantly higher numbers of D. pneumosintes and M. micros were present in smokers and associated with moderate and deep pockets. When heavy smokers were considered, higher counts of total bacteria, M. micros, and D. pneumosintes were observed. Smoking seems to have a detrimental impact on the periodontal status and microbiological profile of patients with periodontitis. Compared to never-smokers, smokers had deeper pockets, greater periodontal destruction, and higher counts of some putative periodontal pathogens.


PD-L1 blockade synergizes with IL-2 therapy in reinvigorating exhausted T cells.
The inhibitory receptor programmed cell death 1 (PD-1) plays a major role in functional exhaustion of T cells during chronic infections and cancer, and recent clinical data suggest that blockade of the PD-1 pathway is an effective immunotherapy in treating certain cancers. Thus, it is important to define combinatorial approaches that increase the efficacy of PD-1 blockade. To address this issue, we examined the effect of IL-2 and PD-1 ligand 1 (PD-L1) blockade in the mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection. We found that low-dose IL-2 administration alone enhanced CD8+ T cell responses in chronically infected mice. IL-2 treatment also decreased inhibitory receptor levels on virus-specific CD8+ T cells and increased expression of CD127 and CD44, resulting in a phenotype resembling that of memory T cells. Surprisingly, IL-2 therapy had only a minimal effect on reducing viral load. However, combining IL-2 treatment with blockade of the PD-1 inhibitory pathway had striking synergistic effects in enhancing virus-specific CD8+ T cell responses and decreasing viral load. Interestingly, this reduction in viral load occurred despite increased numbers of Tregs. These results suggest that combined IL-2 therapy and PD-L1 blockade merits consideration as a regimen for treating human chronic infections and cancer.


Changes in skeletal muscle oxygenation during exercise measured by near-infrared spectroscopy on ascent to altitude.
We sought to quantify changes in skeletal muscle oxygenation during exercise using near-infrared spectroscopy (NIRS) in healthy volunteers ascending to high altitude. Using NIRS, skeletal muscle tissue oxygen saturation (StO2) was measured in the vastus lateralis of 24 subjects. Measurements were performed at sea level (SL; 75 m), at 3,500 m, on arrival at 5,300 m (5,300 m-a; days 15 to 17) and at 5,300 m again (5,300 m-b; days 69 to 71). Amongst the subjects, nine remained at 5,300 m whilst 14 climbed to a maximum of 8,848 m. Exercise was 3 minutes of unloaded cycling followed by an incremental ramp protocol to exhaustion. The absolute StO2 at different stages of exercise along with the difference between StO2 at stages and the rate of change in StO2 were compared between altitudes. Resting peripheral oxygen saturation was recorded. NIRS data achieving predefined quality criteria were available for 18 subjects at 75 m, 16 subjects at 3,500 m, 16 subjects on arrival at 5,300 m and 16 subjects on departure from 5,300 m. At SL, mean StO2 declined from 74.4% at rest to 36.4% at maximal oxygen consumption (P < 0.0001) and then rose to 82.3% (P < 0.0001) 60 seconds after exercise had ceased. At 3,500 m-a and 5,300 m-b, the pattern was similar to SL but absolute values were approximately 15% lower at all stages. At 5,300 m-a, the resting StO2 was similar to SL and the change in StO2 at each exercise stage less marked. At 5,300 m-b, the rate of decline in StO2 during exercise was more rapid than SL (P = 0.008); here the climbers had a smaller decline in StO2 during exercise (41.0%) and a slower rate of desaturation (0.086%/second) than those who had remained at 5,300 m (62.9% and 0.127%/second) (P = 0.031 and P = 0.047, respectively). In most individuals, NIRS can be used to measure exercising skeletal muscle oxygenation in the field. During exercise the patterns of absolute oxygenation are broadly similar at altitude and SL. Following prolonged adaptation to altitude, the rate of muscle desaturation is more rapid than observed at SL but less so in those exposed to extreme hypoxia above 5,300 m.


Caring for patients with rabies in developing countries - the neglected importance of palliative care.
Although limited publications address clinical management of symptomatic patients with rabies in intensive care units, the overwhelming majority of human rabies cases occur in the rural setting of developing countries where healthcare workers are few, lack training and drugs. Based on our experience, we suggest how clinicians in resource-limited settings can make best use of essential drugs to provide assistance to patients with rabies and their families, at no risk to themselves. Comprehensive and compassionate patient management of furious rabies should aim to alleviate thirst, anxiety and epileptic fits using infusions, diazepam or midazolam and antipyretic drugs via intravenous or intrarectal routes. Although the patient is dying, respiratory failure must be avoided especially if the family, after being informed, wish to take the patient home alive for funereal rites to be observed. Healthcare staff should be trained and clinical guidelines should be updated to include palliative care for rabies in endemic countries.


Utility of B-type natriuretic peptides in the assessment of patients with systemic sclerosis-associated pulmonary hypertension in the PHAROS registry.
To assess the utility of B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) in detecting and monitoring pulmonary hypertension (PH) in systemic sclerosis (SSc). PHAROS is a multicenter prospective cohort of SSc patients at high risk for developing pulmonary arterial hypertension (SSc-AR-PAH) or with a definitive diagnosis of SSc-PH. We evaluated 1) the sensitivity and specificity of BNP≥64 and NT-proBNP≥210 pg/mL for the detection of SSc-PAH and/ or SSc-PH in the SSc-AR-PAH population; 2) baseline and longitudinal BNP and NT-proBNP levels as predictors of progression to SSc-PAH and/or SSc-PH; 3) baseline BNP≥180, NT-proBNP≥553 pg/mL, and longitudinal changes in BNP and NT-proBNP as predictors of mortality in SSc-PH diagnosed patients. 172 SSc-PH and 157 SSc-AR- PAH patients had natriuretic peptide levels available. Median BNP and NT-proBNP were significantly higher in the SSc-PH versus SSc-AR-PAH group. The sensitivity and specificity for SSc-PAH detection using baseline BNP≥64 pg/mL was 71% and 59%; and for NT-proBNP≥210 pg/mL, 73% and 78%. NT-proBNP showed stronger correlations with haemodynamic indicators of right ventricular dysfunction than BNP. Baseline creatinine, RVSP > 40 mmHg, and FVC%:DLco% ratio ≥1.8 were associated with progression from SSc-AR-PAH to SSc-PH but no association with individual or combined baseline BNP and NT-proBNP levels was observed. Baseline and follow-up BNP or NT-proBNP levels were not predictive of death, however, a composite BNP/NT-proBNP group predicted mortality (HR 3.81 (2.08-6.99), p<.0001). NT-proBNP may be more useful than BNP in the detection and monitoring of PAH in SSc patients, but additional studies are necessary.


Absence of allogeneic restriction in human T-cell-mediated cytotoxicity to Epstein-Barr virus-infected target cells. Demonstration of an HLA-linked control at the effector level.
Peripheral T lymphocytes from patients with infectious mononucleosis (IM) are sensitized in vivo against the Epstein-Barr virus (EBV). The expression of HLA-A, B, or C molecules at the target cell surface is necessary for the cytotoxic reaction because (a) EBV-positive Daudi cells lacking HLA-A, B, and C determinants are resistant to anti-EBV T-cell lysis, (b) cytolysis of EBV-positive target cells can be consistently inhibited by anti-HLA-A, B, and C and anti-beta 2 microglobulin antibodies. However, no evidence for allogeneic restriction in this system was apparent as (a) cytotoxic T lymphocytes (CTL) from one given individual could exert a cytotoxicity of a similar magnitude on different EBV-positive target cells, regardless of the number of HLA-A or B specificities shared by the effectors and targets; (b) CTL from IM patients were able to kill target cells without any HLA-A or B antigen in common; and (c) T5-1 variants lacking one or two HLA antigens at the A, B, or D locus are killed to the same extent as the parental cells. 7 of the 9 IM patients with detectable circulating anti-EBV CTL carried the HLA-A1 antigen, whereas none of the 16 IM patients lacking detectable peripheral CTL were HLA-A1 positive (mean specific lysis of T5-1 target cells by T cells from HLA-A1 positive patients: 29.3 vs. 0.6% in HLA-A1-negative patients) (P less than 10(-9)). These data suggest an HLA-A1-linked gene control of the magnitude of the anti-EBV CTL response. Thus, the HLA region appears to act at two different level sin the T-cell-mediated lysis of EBV-infected cells by controlling first, the development of anti-EBV and second, the expression of HLA-A, B, and C molecules involved as recognition structures at the target cell surface.


The rubber manufacturing industry: a case report and review of cutaneous exposure and sequelae.
Exposure to chemical carcinogens in rubber manufacturing remains a serious occupational health concern. Workers are exposed to these carcinogens via skin or inhalation. Rubber manufacturing work is associated with a high prevalence of dermatologic diseases such as eczema, allergic contact dermatitis and atopic dermatitis. The role that epidermal exposure plays in the development of malignancies historically associated with the rubber industry is less certain. We present a case relevant to this discussion and review the role of skin exposure in the rubber industry, providing an overview of the cutaneous and systemic manifestations of occupational exposures in modern day rubber workers.


PGC-1 coactivators: inducible regulators of energy metabolism in health and disease.
Members of the PPARgamma coactivator-1 (PGC-1) family of transcriptional coactivators serve as inducible coregulators of nuclear receptors in the control of cellular energy metabolic pathways. This Review focuses on the biologic and physiologic functions of the PGC-1 coactivators, with particular emphasis on striated muscle, liver, and other organ systems relevant to common diseases such as diabetes and heart failure.


The impact of cohort substance use upon likelihood of transitioning through stages of alcohol and cannabis use and use disorder: Findings from the Australian National Survey on Mental Health and Wellbeing.
We used population-level Australian data to estimate prevalence, age of onset and speed of transitions across stages of alcohol and cannabis use, abuse and dependence, and remission from disorder, and consider the potential impacts that an individual's age cohort's level of substance use predicted transitions into and out of substance use. Data on use, DSM-IV use disorders, and remission from these disorders were collected from participants (n = 8463) in the 2007 Australian National Survey of Mental Health and Wellbeing using the Composite International Diagnostic Interview. Lifetime prevalence (95% confidence interval) of alcohol use, regular use, abuse and dependence were 94.1% (93.3-94.8%), 64.5% (62.9-66.2%), 18.7% (17.4-19.9%) and 4.0% (3.4-4.6%). Lifetime prevalence of cannabis use, abuse and dependence were 19.8% (18.6-20.9%), 4.4% (3.8-5.0%) and 1.9% (1.5-2.4%). Among those with the disorder, rates of remission from cannabis abuse, alcohol abuse, cannabis dependence and alcohol dependence were 90.5% (87.4-93.6%), 86.2% (83.8-88.7%), 79.6% (71.1-88.1%) and 53.8% (46.6-61.0%). Increases in the estimated proportion of people in the respondent's age cohort who used alcohol/cannabis as of a given age were significantly associated with most transitions from use through to remission beginning at the same age. Clear associations were documented between cohort-level prevalence of substance use and personal risk of subsequent transitions of individuals in the cohort from use to greater substance involvement. This relationship remained significant over and above associations involving the individual's age of initiation. These findings have important implications for our understanding of the causal pathways into and out of problematic substance use.


The visual white matter connecting human area prostriata and the thalamus is retinotopically organized.
The human visual system is capable of processing visual information from fovea to the far peripheral visual field. Recent fMRI studies have shown a full and detailed retinotopic map in area prostriata, located ventro-dorsally and anterior to the calcarine sulcus along the parieto-occipital sulcus with strong preference for peripheral and wide-field stimulation. Here, we report the anatomical pattern of white matter connections between area prostriata and the thalamus encompassing the lateral geniculate nucleus (LGN). To this end, we developed and utilized an automated pipeline comprising a series of Apps that run openly on the cloud computing platform brainlife.io to analyse 139 subjects of the Human Connectome Project (HCP). We observe a continuous and extended bundle of white matter fibers from which two subcomponents can be extracted: one passing ventrally parallel to the optic radiations (OR) and another passing dorsally circumventing the lateral ventricle. Interestingly, the loop travelling dorsally connects the thalamus with the central visual field representation of prostriata located anteriorly, while the other loop travelling more ventrally connects the LGN with the more peripheral visual field representation located posteriorly. We then analyse an additional cohort of 10 HCP subjects using a manual plane extraction method outside brainlife.io to study the relationship between the two extracted white matter subcomponents and eccentricity, myelin and cortical thickness gradients within prostriata. Our results are consistent with a retinotopic segregation recently demonstrated in the OR, connecting the LGN and V1 in humans and reveal for the first time a retinotopic segregation regarding the trajectory of a fiber bundle between the thalamus and an associative visual area.


Platelet thrombospondin forms a trimolecular complex with plasminogen and histidine-rich glycoprotein.
Thrombospondin (TSP), a multifunctional alpha-granule glycoprotein of human platelets binds fibrinogen, fibronectin, heparin, histidine-rich glycoprotein (HRGP), and plasminogen (Plg), and thus, may play an important role in regulating thrombotic influences at vessel surfaces. In this study we have demonstrated that purified human platelet TSP formed a trimolecular complex with human Plg and HRGP. Complex formation was detected by a specific binding enzyme-linked immunosorbent assay (ELISA) which demonstrated simultaneous binding of fluid-phase Plg and HRGP to TSP adsorbed to microtitration wells. While neither ligand inhibited complex formation of the other with TSP, 10 mM epsilon-amino-n-caproic acid selectively blocked incorporation of Plg into the complex, suggesting that TSP contains independent binding sites for Plg and HRGP. Comparable extent of trimolecular complex formation was also detected when TSP monomer was substituted for whole TSP in the ELISA. HRGP covalently cross-linked to Sepharose 4B simultaneously bound both 125I-TSP and 131I-Plg, confirming trimolecular complex formation. Rocket immunoelectrophoresis of mixtures of the purified radiolabeled proteins into anti-Plg containing agarose also confirmed trimolecular complex formation. The TSP-HRGP-Plg complex bound a similar amount of heparin as the TSP-HRGP complex, demonstrating that the HRGP within the trimolecular complex maintained functional capability. Similarly, using a fluorometric plasmin substrate, the trimolecular complex was shown to be an effective substrate for tissue plasminogen activator. Significant amounts of plasmin were generated from the TSP-HRGP-Plg complex (equivalent to that from the TSP-Plg complex), but the rate of plasmin generation from the trimolecular complex was greater than from the bimolecular complex, suggesting an important interaction of HRGP with Plg when both are complexed to TSP. The macromolecular assembly of these three proteins on cellular surfaces, such as the platelet, may serve important regulatory functions, both prothrombotic at sites of active fibrin deposition and proteolytic in nonfibrin-containing microenvironments.


Post-traumatic cluster headache: from the periphery to the central nervous system?
A correlation between head trauma and cluster headache is believed to exist. We report a case of post-traumatic episodic cluster headache that fulfills the criteria of the International Classification of Headache Disorders, 2nd edition. The distinctive features of this case are: a close temporal relation between head trauma and headache onset; pain ipsilateral to the side of trauma; mild severity of trauma; episodic course well-responsive to low doses of verapamil. Given the close temporal relation between the 2 events, multiple hypotheses can be advanced about a possible role of head trauma in the pathogenesis of cluster headache.


Macrostructural brain changes in patients with longstanding type 1 diabetes mellitus - a cortical thickness analysis study.
Longstanding diabetes mellitus (DM) is associated with the risk of complications affecting the central nervous system. The aims were to study brain volume and cortical thickness in regional brain areas in DM patients and to correlate the findings with relevant clinical data.15 patients with longstanding (average 24.6 years) type 1 DM and 20 healthy controls were studied in a 3T magnetic resonance scanner. Using an automated surface based cortical segmentation method, cortical thickness was assessed in anatomical regions including total and lobe-wise grey and white matter volumes. Also morphological changes were evaluated.No differences between patients and controls were found in regard to number of white matter lesions (P=0.50), grey and white matter volumes (P=0.25) and overall cortical thickness (P=0.64). Subanalysis revealed exclusively reduced cortical thickness of the postcentral (P=0.03) and superior parietal gyrus (P=0.008) in patients. The cortical thickness of these regions was not associated with diabetes duration, age at diabetes onset or to HbA1c (all P>0.08). Patients with peripheral neuropathy showed reduced right postcentral gyrus cortical thickness compared to patients without peripheral neuropathy (P=0.02).Patients with longstanding type 1 diabetes showed cortical thinning involving sensory related areas, even though no overall macrostructural brain alterations were detected. This could possibly have underlying functional significance since cortical thinning was associated to presence of peripheral neuropathy. The absence of universal macrostructural changes might illustrate that more pronounced brain pathology is likely to be preceded by more subtle microstructural changes as reported in other studies.


Crystal structures of two camelid nanobodies raised against GldL, a component of the type IX secretion system from Flavobacterium johnsoniae.
GldL is an inner-membrane protein that is essential for the function of the type IX secretion system (T9SS) in Flavobacterium johnsoniae. The complex that it forms with GldM is supposed to act as a new rotary motor involved in the gliding motility of the bacterium. In the context of structural studies of GldL to gain information on the assembly and function of the T9SS, two camelid nanobodies were selected, produced and purified. Their interaction with the cytoplasmic domain of GldL was characterized and their crystal structures were solved. These nanobodies will be used as crystallization chaperones to help in the crystallization of the cytoplasmic domain of GldL and could also help to solve the structure of the complex using molecular replacement.


2-Aminoadipic acid protects against obesity and diabetes.
Obesity and type 2 diabetes (T2D) are both complicated endocrine disorders resulting from an interaction between multiple predisposing genes and environmental triggers, while diet and exercise have key influence on metabolic disorders. Previous reports demonstrated that 2-aminoadipic acid (2-AAA), an intermediate metabolite of lysine metabolism, could modulate insulin secretion and predict T2D, suggesting the role of 2-AAA in glycolipid metabolism. Here, we showed that treatment of diet-induced obesity (DIO) mice with 2-AAA significantly reduced body weight, decreased fat accumulation and lowered fasting glucose. Furthermore, Dhtkd1-/- mice, in which the substrate of DHTKD1 2-AAA increased to a significant high level, were resistant to DIO and obesity-related insulin resistance. Further study showed that 2-AAA induced higher energy expenditure due to increased adipocyte thermogenesis via upregulating PGC1α and UCP1 mediated by β3AR activation, and stimulated lipolysis depending on enhanced expression of hormone-sensitive lipase (HSL) through activating β3AR signaling. Moreover, 2-AAA could alleviate the diabetic symptoms of db/db mice. Our data showed that 2-AAA played an important role in regulating glycolipid metabolism independent of diet and exercise, implying that improving the level of 2-AAA in vivo could be developed as a strategy in the treatment of obesity or diabetes.


Item generation and pilot testing of the Comprehensive Professional Behaviours Development Log.
The purpose of this project was to generate and refine criteria for professional behaviors previously identified to be important for physical therapy practice and to develop and pilot test a new instrument, which we have called the Comprehensive Professional Behaviours Development Log (CPBDL). Items were generated from our previous work, the work of Warren May and his colleagues, a competency profile for entry-level physical therapists, our regulatory code of ethics, and an evaluation of clinical performance. A group of eight people, including recent graduates, clinical instructors and professional practice leaders, and faculty members, refined the items in two iterations using the Delphi process. The CPBDL contains nine key professional behaviors with a range of nine to 23 specific behavioral criteria for individuals to reflect on and to indicate the consistency of performance from a selection of "not at all," "sometimes," and "always" response options. Pilot testing with a group of 42 students in the final year of our entry-to-practice curriculum indicated that the criteria were clear, the measure was feasible to complete in a reasonable time frame, and there were no ceiling or floor effects. We believe that others, including health care educators and practicing professionals, might be interested in adapting the CPBDL in their own settings to enhance the professional behaviors of either students in preparation for entry to practice or clinicians wishing to demonstrate continuing competency to professional regulatory bodies.


A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity.
The relevance of many BRCA2 variants of uncertain significance (VUS) to breast cancer has not been determined due to limited genetic information from families carrying these alterations. Here, we classified six new variants as pathogenic or nonpathogenic by analysis of genetic information from families carrying 64 individual BRCA2 DNA binding domain (DBD) missense mutations using a multifactorial likelihood model of cancer causality. Next, we evaluated the use of a homology-directed DNA break repair (HDR) functional assay as a method for inferring the clinical relevance of VUS in the DBD of BRCA2 using 18 established nonpathogenic missense variants and all 13 established pathogenic missense mutations from the BRCA2 DBD. Compared with the known status of these variants based on the multifactorial likelihood model, the sensitivity of the HDR assay for pathogenic mutations was estimated at 100% [95% confidence interval (CI): 75.3%-100%] and specificity was estimated at 100% (95% CI: 81.5%-100%). A statistical classifier for predicting the probability of pathogenicity of BRCA2 DBD variants was developed using these functional results. When applied to 33 additional VUS, the classifier identified eight with 99% or more probability of nonpathogenicity and 18 with 99% or more probability of pathogenicity. Thus, in the absence of genetic evidence, a cell-based HDR assay can provide a probability of pathogenicity for all VUS in the BRCA2 DBD, suggesting that the assay can be used in combination with other information to determine the cancer relevance of BRCA2 VUS.


Structure, function and diversity of the healthy human microbiome.
Studies of the human microbiome have revealed that even healthy individuals differ remarkably in the microbes that occupy habitats such as the gut, skin and vagina. Much of this diversity remains unexplained, although diet, environment, host genetics and early microbial exposure have all been implicated. Accordingly, to characterize the ecology of human-associated microbial communities, the Human Microbiome Project has analysed the largest cohort and set of distinct, clinically relevant body habitats so far. We found the diversity and abundance of each habitat's signature microbes to vary widely even among healthy subjects, with strong niche specialization both within and among individuals. The project encountered an estimated 81-99% of the genera, enzyme families and community configurations occupied by the healthy Western microbiome. Metagenomic carriage of metabolic pathways was stable among individuals despite variation in community structure, and ethnic/racial background proved to be one of the strongest associations of both pathways and microbes with clinical metadata. These results thus delineate the range of structural and functional configurations normal in the microbial communities of a healthy population, enabling future characterization of the epidemiology, ecology and translational applications of the human microbiome.


Pharmacodynamic interactions of ciprofloxacin, piperacillin, and piperacillin/tazobactam in healthy volunteers.
Mathematical modeling methods were used to study pharmacokinetic and pharmacodynamic interactions of the antimicrobial combinations piperacillin plus ciprofloxacin and piperacillin plus tazobactam. Twelve healthy volunteers received the following treatments: piperacillin (4 g), ciprofloxacin (400 mg), piperacillin (4 g) plus ciprofloxacin (400 mg), and piperacillin (4 g) plus tazobactam (0.5 g), via intravenous infusion in a four-period crossover design. Serum drug concentrations were analyzed by means of high-performance liquid chromatography (HPLC), and inhibitory titers were performed against eight organisms. The pharmacodynamic response (growth or no growth) was modeled for each of the monotherapy courses using a Hill-type model where Emax was 1 (100% probability of no growth [P(NG)]), and EC50 was the concentration associated with a 50% P(NG). For piperacillin plus ciprofloxacin, P(NG) was a function of 1) plasma concentrations for both drugs; 2) EC50 values from the monotherapy courses; and 3) theta, an interaction term that accommodates synergy, additivity, or antagonism. For piperacillin/tazobactam, the serum ultrafiltrate area under the inhibitory curve was compared with that of piperacillin alone to determine the benefit of tazobactam. The interaction between piperacillin and ciprofloxacin was additive. The addition of tazobactam to piperacillin was beneficial against certain organisms. The model developed can be used to evaluate the activity of combination regimens against representative pathogens.


Enhanced itaconic acid production in Aspergillus niger using genetic modification and medium optimization.
Aspergillus niger was selected as a host for producing itaconic acid due to its versatile and tolerant character in various growth environments, and its extremely high capacity of accumulating the precursor of itaconic acid: citric acid. Expressing the CAD gene from Aspergillus terreus opened the metabolic pathway towards itaconic acid in A. niger. In order to increase the production level, we continued by modifying its genome and optimizing cultivation media. Based on the results of previous transcriptomics studies and research from other groups, two genes : gpdA encoding the glyceraldehyde -3-dehydrogenase (GPD) and hbd1 encoding a flavohemoglobin domain (HBD) were overexpressed in A. niger. Besides, new media were designed based on a reference medium for A. terreus. To analyze large numbers of cultures, we developed an approach for screening both fungal transformants and various media in 96-well micro-titer plates. The hbd1 transformants (HBD 2.2/2.5) did not improve itaconic acid titer while the gpdA transformant (GPD 4.3) decreased the itaconic acid production. Using 20 different media, copper was discovered to have a positive influence on itaconic acid production. Effects observed in the micro-titer plate screening were confirmed in controlled batch fermentation. The performance of gpdA and hbd1 transformants was found not to be beneficial for itaconic acid production using the tested cultivation conditions. Medium optimization showed that, copper was positively correlated with improved itaconic acid production. Interestingly, the optimal conditions for itaconic acid clearly differ from conditions optimal for citric- and oxalic acid production.


Prestimulus cortical activity is correlated with speed of visuomotor processing.
Response time (RT) is an important behavioral measure of the overall efficacy of sensorimotor processing and is known to vary significantly from trial to trial. Past work on how stimulus evoked cortical responses contribute to RT variability has helped delineate the stages of neuronal information processing. Much less is known about how the state of the brain immediately preceding the stimulus onset (prestimulus) affects RT. We addressed this problem by analyzing data from three macaque monkeys trained to perform a visuomotor pattern discrimination task. Local field potentials were recorded from up to 16 bipolar surface-to-depth electrodes widely distributed over one cerebral hemisphere in each monkey. The degree of linear correlation between RT and prestimulus spectral power was determined over a wide range of frequencies. In the prefrontal cortex, prestimulus power in the beta range (14-30 Hz) was negatively correlated with RT in two monkeys, suggesting a possible role of activity in this frequency range in the mediation of top-down control of visuomotor processing. In the sensorimotor cortex, prestimulus power in the beta range was positively correlated with RT in two monkeys, consistent with the hypothesis that oscillations in this range support the maintenance of steady-state motor output. In visual occipital and temporal lobe areas, prestimulus power in the alpha/low beta range (8-20 Hz) showed positive correlations with RT in three monkeys, possibly reflecting a spatially specific disengagement of visual anticipatory attention. Through measurement of prestimulus spectral coherence, it was further determined that sites showing similar patterns of correlation between spectral power and RT were also linked together in synchronized networks.


Constrictive Bronchiolitis Attributable to Inhalation of Toxic Agents: Considerations for a Case Definition.
We identified cases of constrictive bronchiolitis (CB), an inflammatory injury obliterating the small airways, in adults caused by inhalational exposure to determine an appropriate case definition. We performed a systematic review with meta-analysis for these cases from 1990 to 2017. Publications were included if there was 1) inhalational exposure; 2) respiratory symptoms/signs; 3) pulmonary function test results; and 4) computerized tomographic chest imaging. Many had a lung biopsy. Two hundred seventy-four articles were retrieved; 22 manuscripts comprising 102 cases were included. Diagnostic criteria from cases associated with military deployment to southwest Asia were statistically different from criteria of other etiologies. In three cases, the scan was consistent with CB, the biopsy nondiagnostic, yet the diagnosis was made. CB associated with military deployment presented with diagnostic features statistically different from features in the other cases.


Gene expression profiling changes induced by a novel Gemini Vitamin D derivative during the progression of breast cancer.
We investigated gene expression changes induced by a novel Gemini Vitamin D(3) analog, RO-438-3582 (1alpha,25-dihydroxy-20S-21(3-hydroxy-3-methyl-butyl)-23-yne-26,27-hexafluoro-cholecalciferol, Ro3582), in a unique human breast MCF10 model. We used two breast epithelial cell lines from this model, namely MCF10AT1 (Ha-ras oncogene transfected MCF10A, early premalignant) and MCF10CA1a (fully malignant and metastatic derived from the MCF10AT1 line). We analyzed gene expression changes induced by Ro3582 using GeneChip technology, quantitative RT-PCR, Western blot analysis, or a gene transcription assay. Interestingly, we found distinct gene expression profile differences between Ro3582-induced response of the early premalignant MCF10AT1 and the malignant and metastatic MCF10CA1a cell lines. Moreover, while the Gemini Vitamin D(3) analog Ro3582 modulated the expression of several Vitamin D target genes such as the 24-hydroxylase, CD14, osteocalcin, and osteopontin in both cell lines, Ro3582 regulated many genes involved in cell proliferation and apoptosis, cell adhesion, invasion, angiogenesis as well as cell signaling pathways, such as the BMP and TGF-beta systems, differently in the two cell lines. The Gemini Vitamin D(3) analog Ro3582 induced more significant gene changes in the early premalignant MCF10AT1 cells than in the malignant metastatic MCF10CA1a cells, suggesting that Gemini Vitamin D(3) analogs may be more effective in preventing the progression of an early stage of breast carcinogenesis than in treating late stage breast cancer.


The 6-year migration characteristics of a hydroxyapatite-coated femoral stem: a radiostereometric analysis study.
A prospective cohort of 30 patients undergoing primary total hip arthroplasty for treatment of osteoarthritis was enrolled in a study to characterize the migration behavior of a clinically successful cementless stem. At 6 years, the mean subsidence of the stem was 0.63 mm (range, -0.33 to 3.68 mm); the mean rotation into retroversion was 1.41° (range, -1.33° to 7.48°). No stems had additional subsidence of more than 0.25 mm between 6 months and 6 years. The resultant mean subsidence between 2 and 6 years was 0.03 mm, which is below the limit measurable by radiostereometric analysis. The data demonstrate that subsidence of this cementless stem occurs within the first 6 months, after which there is persistent stabilization.


Future Costs in Cost-Effectiveness Analyses: Past, Present, Future.
There has been considerable debate on the extent to which future costs should be included in cost-effectiveness analyses of health technologies. In this article, we summarize the theoretical debates and empirical research in this area and highlight the conclusions that can be drawn for current practice. For future related and future unrelated medical costs, the literature suggests that inclusion is required to obtain optimal outcomes from available resources. This conclusion does not depend on the perspective adopted by the decision maker. Future non-medical costs are only relevant when adopting a societal perspective; these should be included if the benefits of non-medical consumption and production are also included in the evaluation. Whether this is the case currently remains unclear, given that benefits are typically quantified in quality-adjusted life-years and only limited research has been performed on the extent to which these (implicitly) capture benefits beyond health. Empirical research has shown that the impact of including future costs can be large, and that estimation of such costs is feasible. In practice, however, future unrelated medical costs and future unrelated non-medical consumption costs are typically excluded from economic evaluations. This is explicitly prescribed in some pharmacoeconomic guidelines. Further research is warranted on the development and improvement of methods for the estimation of future costs. Standardization of methods is needed to enhance the practical applicability of inclusion for the analyst and the comparability of the outcomes of different studies. For future non-medical costs, further research is also needed on the extent to which benefits related to this spending are captured in the measurement and valuation of health benefits, and how to broaden the scope of the evaluation if they are not sufficiently captured.


Dry transfer method for suspended graphene on lift-off-resist: simple ballistic devices with Fabry-Pérot interference.
We demonstrate a fabrication scheme for clean suspended structures using chemical-vapor-deposition-grown graphene and a dry transfer method on lift-off-resist-coated substrates to facilitate suspended graphene nanoelectronic devices for technological applications. It encompasses the demands for scalable fabrication as well as for ultra-fast response due to weak coupling to environment. The fabricated devices exhibited initially a weak field-effect response with substantial positive (p) doping which transformed into weak negative (n) doping upon current annealing at the temperature of 4 K. With increased annealing current, n-doping gradually decreased while the Dirac peak position approached zero in gate voltage. An ultra-low residual charge density of 9 × 108 cm-2 and a mobility of 1.9 × 105 cm2 V-1 s-1 were observed. Our samples display clear Fabry-Pérot (FP) conductance oscillation which indicates ballistic electron transport. The spacings of the FP oscillations are found to depend on the charge density in a manner that agrees with theoretical modeling based on Klein tunneling of Dirac particles. The ultra-low residual charge, the FP oscillations with density dependent period, and the high mobility prove the excellent quality of our suspended graphene devices. Owing to its simplicity, scalability and robustness, this fabrication scheme enhances possibilities for production of suspended, high-quality, two-dimensional-material structures for novel electronic applications.


Takayasu's arteritis.
Takayasu's arteritis, an inflammatory and obliterative disease of medium and large arteries, is classified as a giant cell arteritis. It has a predilection for the aortic arch and its branches and the pulmonary arteries. Unlike atherosclerotic vascular diseases, Takayasu's arteritis affects young women primarily. Early symptoms may be mainly systemic and may resemble polymyalgia rheumatica. The etiology is unknown, but infectious agents and autoimmunity have been suggested to play a role. Diagnosis is based on symptoms, physical findings, and angiographic findings, because tissue diagnosis rarely is feasible. The two cases reported here represent contrasting phases of Takayasu's arteritis.


I ain't no fortunate one: On the motivated denial of class privilege.
[Correction Notice: An Erratum for this article was reported in Vol 119(6) of Journal of Personality and Social Psychology (see record 2021-01144-001). In the article, in the Independent variables subsection of Experiment 6, the second paragraph is duplicated here in error. The correct location appears as the fourth paragraph of this subsection. All versions of this article have been corrected.] Invisibility makes privilege powerful. Especially when it remains unexposed, privilege perpetuates inequity by giving unearned advantages to certain groups over others. However, recent social movements (e.g., Occupy) attempt to expose class-based privilege, threatening its invisibility. Across 8 experiments, we show that beneficiaries of class privilege respond to such exposure by increasing their claims of personal hardships and hard work, to cover privilege in a veneer of meritocracy. Experiments 1a-c show that when people are provided evidence of their own class privilege, they claim to have suffered more personal life hardships. Experiment 2 suggests that these claims are driven in part by threats to self-regard. Experiment 3 finds that such self-defense is motivated specifically by a desire to attribute positive outcomes to the self (i.e., sense of personal merit). When given the chance to first bolster their sense of personal merit, those benefitting from privilege no longer claim hardships in response to evidence of privilege. Experiments 4 and 5 further suggest self-concerns are at play: only self-relevant privilege evokes defensive responses, and self-affirmation reduces hardship claims more than does system-affirmation. Finally, Experiment 6 suggests that people claim hardships because they believe these imply personal merit on their part. Preventing the privileged from claiming hardship leads them to claim increased effort in the workplace and to increase effort on a difficult task. Overall, results suggest that even when those benefitting from class privileges are confronted with evidence of their "invisible knapsack," ideologies of personal merit help them cover the privileges of class once again. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Anti-immigrant prejudice: Understanding the roles of (perceived) values and value dissimilarity.
Although human values and value dissimilarity play pivotal roles in the prejudice literature, there remain important gaps in our understanding. To address these gaps, we recruited three British samples (N = 350) and presented Muslim immigrants, refugees, and economic migrants as target groups. Using polynomial regression analyses, we simultaneously tested effects of individuals' own values, their perceptions of immigrant values, and self-immigrant value dissimilarities on prejudice. Results indicated that favorability toward immigrants is higher when individuals hold higher self-transcendence values (e.g., equality) and lower self-enhancement values (e.g., power), and when they perceive immigrants to hold higher self-transcendence values and lower self-enhancement values. In addition, prejudice toward immigrants is higher when individuals who hold higher conservation values (e.g., security) perceive immigrants to value openness (e.g., freedom) more, suggesting a value dissimilarity effect. No value dissimilarity effects emerged when immigrants were perceived to be higher in conservation, self-transcendence, or self-enhancement values. Overall, these results showed that effects of values and value dissimilarity differ depending on which value dimension is considered. Additionally, the results revealed support for a novel mechanism with the motivation to be nonprejudiced underpinning the links between individuals' values and prejudice. Our discussion highlights the multifaceted manner in which values are linked to prejudice. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Implications of extubation failure and prolonged mechanical ventilation in the postoperative period following elective intracranial surgery.
Patients undergoing neurosurgery are predisposed to a variety of complications related to mechanical ventilation (MV). There is an increased incidence of extubation failure, pneumonia, and prolonged MV among such patients. The aim of the present study was to assess the influence of extubation failure and prolonged MV on the following variables: postoperative pulmonary complications (PPC), mortality, reoperation, tracheostomy, and duration of postoperative hospitalization following elective intra-cranial surgery. The study involved a prospective observational cohort of 317 patients submitted to elective intracranial surgery for tumors, aneurysms and arteriovenous malformation. Preoperative assessment was performed and patients were followed up for the determination of extubation failure and prolonged MV (>48 h) until discharge from the hospital or death. The occurrence of PPC, incidence of death, the need for reoperation and tracheostomy, and the length of hospitalization were assessed during the postoperative period. Twenty-six patients (8.2%) experienced extubation failure and 30 (9.5%) needed prolonged MV after surgery. Multivariate analysis showed that extubation failure was significant for the occurrence of death (OR = 8.05 [1.88; 34.36]), PPC (OR = 11.18 [2.27; 55.02]) and tracheostomy (OR = 7.8 [1.12; 55.07]). Prolonged MV was significant only for the occurrence of PPC (OR = 4.87 [1.3; 18.18]). Elective intracranial surgery patients who experienced extubation failure or required prolonged MV had a higher incidence of PPC, reoperation and tracheostomy and required a longer period of time in the ICU. Level of consciousness and extubation failure were associated with death and PPC. Patients who required prolonged MV had a higher incidence of extubation failure.


Adder bites in Britain.
Ninety-five cases of adder bite that have occurred in Britain over the past 100 years are reviewed. Most bites occurred in men who foolishly picked up the adder. Three-quarters of the victims reached hospital within two hours of the bite. When venom is injected the early symptoms include local swelling and discoloration, vomiting, diarrhoea, and early collapse, which often resolves spontaneously. In severe poisoning persistent or recurrent shock is the main feature. Children recover quickly but adults may take weeks or months to recover, during which there may be considerable disability in the bitten limb. Deaths are rare: only 14 deaths from poisoning were recorded in the past 100 years. In England and Wales only one death from adder bite was recorded in 1950-72, but there were 61 deaths from bee or wasp stings. In most cases simple symptomatic treatment is enough, but all patients should be carefully monitored. With persistent or recurrent shock Zagreb antivenom is indicated; and it should also be considered in adults seen within two hours of the bite to minimise morbidity from local effects.


Future challenges for occupational health services can be prevented by proactive collaboration with the companies using the services: a participatory and reflection project.
There is clearly a need for research in the field of occupational health service (OHS) for applying new perspectives. Proactive collaboration is needed between the OHSs and the companies. The customers of the companies using the services should be able to safeguard themselves from the health problems caused by the work environment through proactive collaboration with the OHSs. The main purpose of this interdisciplinary study was to explore how the stakeholders reflected to create and agree on core values for future challenges in OHS, as seen from the perspectives of OHS professionals and customer companies. An action research process was conducted. This study was divided into three phases. In phase I, the data were collected from interviews and diaries of interdisciplinary occupational health professionals (n=12). A focus group that sampled the eight managers of the customer companies was also included. In phase II, a questionnaire was developed with 24 questions focusing on examining the future challenges for OHS. The questionnaire was sent to customer companies (n=116). In phase III, a scoping review was undertaken. Three categories emerged from the analysis: "Balancing complex situations" clarified the complexity regarding senior employees; "Working with a proactive approach" indicated the need for working with a new proactive approach supporting sustainable health; and "Collaborate internally and externally" showed good relationships between the customer and the OHS, which is a mutual responsibility to both the partners. The results outlined that it is necessary to take action to apply new proactive health promotions, with a focus on workplace health promotion. The results also indicated that interventions for senior employees are of importance. This study was done in collaboration with the stakeholders from the occupational health care service center and the managers from the customer companies. The use of a participatory research design, including close collaboration with the participants, allows the researchers to see the challenges.


Prevalence and molecular characterization of Staphylococcus aureus from human stool samples.
To determine the prevalence of intestinal S. aureus colonization of patients at a large teaching hospital and determine the molecular characteristics of the identified strains. The second objective of this research was to determine risk factors associated with S. aureus intestinal colonization. A cross-sectional study of 781 specimens from inpatients and outpatients at the University of Iowa Hospitals and Clinics Clinical Microbiology Laboratory was conducted. S. aureus was identified using traditional culture methodologies. Methicillin-resistance was determined via PCR of the mecA gene. PVL PCR, spa typing, and antimicrobial sensitivity testing were also done. A nested case-control study was done on a subset of patients with all colonized patients defined as cases and non-colonized controls. Medical record abstractions were done to identify risk factors for intestinal colonization in the nested study. Out of 625 patients included in the final study, 58 were positive for S. aureus (9.3%). One isolate was positive for the PVL gene. A high number of isolates were resistant to multiple antibiotics including oxacillin (43.1%), erythromycin (51.7%), and levofloxacin (41.4%). All isolates were susceptible to vancomycin, daptomycin, linezolid, and quinupristin-dalfopristin. In the nested study, having a disease or condition of the gastrointestinal tract significantly increased the odds of intestinal colonization (OR: 1.96, 95% CI: 1.04-3.7; aOR: 13.9, 95% CI: 1.67-115.7). No other variables were significantly associated with increased odds of colonization. S. aureus was identified from the stool of patients at the University of Iowa Hospitals and Clinics, with a large number of those isolates being resistant to antibiotics and may serve a reservoir for subsequent infections as well as asymptomatic transmission.


An Aluminum-Inducible IREG Gene is Required for Internal Detoxification of Aluminum in Buckwheat.
Buckwheat (Fagopyrum esculentum Moench) is able to detoxify aluminum (Al) both externally and internally, but the molecular mechanisms underlying its high Al tolerance are not understood. We functionally characterized a gene (FeIREG1) belonging to IRON REGULATED/ferroportin in buckwheat, which showed high expression in our previous genome-wide transcriptome analysis. FeIREG1 was mainly expressed in the roots, and its expression was up-regulated by Al, but not by other metals and low pH. Furthermore, in contrast to AtIREG1 and AtIREG2 in Arabidopsis, the expression of FeIREG1 was not induced by Fe deficiency. Spatial expression analysis showed that the Al-induced expression of FeIREG1 was found in the root tips and higher expression was detected in the outer layers of this part. Immunostaining also showed that FeIREG1 was localized at the outer cell layers in the root tip. A FeIREG1-green fluorescent protein (GFP) fusion protein was localized to the tonoplast when transiently expressed in onion epidermal cells. Overexpression of FeIREG1 in Arabidopsis resulted in increased Al tolerance, but did not alter the tolerance to Cd, Co and Fe. The tolerance to Ni was slightly enhanced in the overexpression lines. Mineral analysis showed that the accumulation of total root Al and other essential mineral elements was hardly altered in the overexpression lines. Taken together, our results suggest that FeIREG1 localized at the tonoplast plays an important role in internal Al detoxification by sequestering Al into the root vacuoles in buckwheat.


Chocolate Consumption and Risk of Heart Failure: A Meta-Analysis of Prospective Studies.
Epidemiological studies have shown inconsistent findings on the association between chocolate consumption and risk of heart failure (HF). We, therefore, performed a meta-analysis of prospective studies to determine the role of chocolate intake in the prevention of HF. We searched databases of PubMed, Web of Science, and Scopus through December 2016 and scrutinized the reference lists of relevant literatures to identify eligible studies. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) were aggregated using random effect models. The dose-response relationship between chocolate consumption and incident HF was also assessed. This meta-analysis is registered with PROSPERO, number CRD42017054230. Five prospective studies with 106,109 participants were finally included. Compared to no consumption of chocolate, the pooled HRs (95% CIs) of HF were 0.86 (0.82-0.91) for low-to-moderate consumption (<7 servings/week) and 0.94 (0.80-1.09) for high consumption (≥7 servings/week). In dose-response meta-analysis, we detected a curve linear relationship between chocolate consumption and risk of HF (p for nonlinearity = 0.005). Compared with non-consumption, the HRs (95% CIs) of HF across chocolate consumption levels were 0.92 (0.88-0.97), 0.86 (0.78-0.94), 0.93 (0.85-1.03), and 1.07 (0.92-1.23) for 1, 3, 7, and 10 servings/week, respectively. In conclusion, chocolate consumption in moderation may be associated with a decreased risk of HF.


Weight bearing after tibial fracture as a guide to healing.
Judging when it is safe to remove an external fixator or plaster cast requires clinical and radiological assessment, both of which are subjective. Weight bearing has been shown to increase with time post-fracture and we hypothesised that it could be used as an objective measure of fracture healing. Ground reaction force (and hence weight bearing) and fracture stiffness were measured serially in a group of 12 patients with tibial fractures treated by external fixation. Ground reaction force was measured for both fractured and non-fractured limbs using a force plate and the fracture stiffness was measured using the Orthometer, a commercially produced device for measuring the stiffness of fractures treated by external fixation. In 10 patients who made good recoveries, prior to fixator removal, weight bearing though the injured leg was seen to approach 90% of that through the uninjured leg and the fracture stiffness exceeded 15 Nm/deg. Two patients with delayed union achieved weight bearing of 40% of normal and a fracture stiffness of less than 5 Nm/deg at 20 weeks. Weight bearing correlates reasonably well with fracture stiffness. It is quicker and easier to measure than fracture stiffness and potentially has relevance to other fracture fixation methods.