Kinesio arm taping as prophylaxis against the development of Erb's Engram.
An Erb's Engram is a common debility that develops in recovering children with Erb's palsy. The purpose of this study was to investigate the effect of kinesiotaping over the deltoid and the forearm on the development of proper upper extremity function in children recovering from Erb's palsy. Thirty patients with Erb's palsy participated for 3 months in this study and were equally divided into two groups; control group A and study group B. The two groups received the same designed physical therapy program, while group B along the program, received kinesiotaping over the deltoid and the forearm. The subjects were evaluated, pre and post-treatment, and scored functionally, using the Toronto Active Motion Scale, and objectively, using an EMG device utilized to obtain the percentages of degeneration of the deltoid and the biceps muscles. Post-treatment values of six out of nine measured variables, between the two groups, revealed significant difference in favor of group B. The obtained results strongly support the introduction of kinesiotaping of the deltoid and the forearm as an adjunct to the treatment program of Erb's palsied children.


Two species of philometrid nematodes (philometridae) from marine fishes off Japan, including Philometroides branchiostegi sp. n. from Branchiostegus japonicus (malacanthidae).
Gravid females of two species of philometrid nematodes (Philometridae) were collected from marine perciform fishes in Japanese waters, mainly from the southern Sea of Japan. Based on light microscopy and scanning electron microscopy examinations, the previously described but poorly known species Philometra cryptocentri Yamaguti, 1961 is redescribed from specimens recovered from the abdominal cavity of Acanthogobius flavimanus (Temminck et Schlegel), Pterogobius elapoides (Günther) and P. zonoleucus Jordan et Snyder (all Gobiidae) (all new host records); the number (14) and arrangement of cephalic papillae in this species are described for the first time. The new species, Philometroides branchiostegi sp. n. from head tissues of Branchiostegus japonicus (Houttuyn) (Malacanthidae), based on a single specimen, is mainly characterized by the embossment of the entire body except for the cephalic end, presence of four submedian pairs of large cephalic papillae of external circle and two small lateral single papillae of internal circle, pair of large papilla-like caudal projections, the oesophagus with a distinct anterior inflation, by a markedly small body (length about 18 mm) and the larvae 306-465 microm long.


Cancer of Unknown Primary: a Cancer Registry Study of Factors Affecting Access to Diagnosis.
A potential impact of the centralisation of cancer services in the UK is difficulty in gaining access for members of the population living far from them. This could lead to delayed presentation of cancer with more advanced disease and clinical deterioration at diagnosis. A patient may be recorded in the cancer registry as having cancer of unknown primary (CUP) if the clinical state at presentation precludes investigation. Other patients may be so recorded if investigation identifies sites of metastatic tumour but the primary is not found. We hypothesised that the first group would include more patients who experienced difficulties in gaining access to health services through residing in deprived areas or through poorer geographical access to healthcare facilities. We compared the diagnosis of CUP with a comparator tumour, carcinoma of the rectum, where diagnosis is facilitated by an alarm symptom and where variations in access are lower. Records from the Northern and Yorkshire Cancer Registry from 1994 to 2002 with ICD 10 C77-C80 (CUP, including categories where investigations may have been incomplete or no primary cancer was found) and C20 (malignant neoplasm of rectum) were combined with travel time to services (primary care, secondary and tertiary services) and the Index of Multiple Deprivation. Logistic regression modelled predictors of CUP were compared with C20 and, within CUP, the odds of a histological basis of diagnosis. The registry classified 7428 patients as C80, 8849 as C77-C79, and 10 804 as C20. Compared with C20, the number of cases of C80 showed a statistically significant increasing trend with increasing travel time to primary care. Risk also increased strongly with age and deprivation. The results for C77-C79 were similar to those for C80, except that the travel time to primary care showed no effect. Considering all CUP alone, histological diagnosis significantly declined with travel time to the nearest hospital. There was no association with gender and the likelihood of histological diagnosis, but a marked decline with age, a downward trend with deprivation, and an increase when the nearest hospital was a cancer centre. These findings facilitate the understanding of factors associated with the group of patients that includes those with the least effective access to cancer services.


Localization of human monoamine oxidase-A gene to Xp11.23-11.4 by in situ hybridization: implications for Norrie disease.
A cDNA for the neurotransmitter-degrading enzyme monoamine oxidase-A (MAO-A) has been assigned by in situ hybridization to the human X chromosome and subregionally localized to Xp11.23-11.4. As restriction fragments detected by this probe are deleted in some patients with Norrie disease, this assignment provides confirmation of the localization of the disease.


Emerging technologies for hybridization based single nucleotide polymorphism detection.
Detection of single nucleotide polymorphisms (SNPs) is a crucial challenge in the development of a novel generation of diagnostic tools. Accurate detection of SNPs can prove elusive, as the impact of a single variable nucleotide on the properties of a target sequence is limited, even if this sequence consists of only a few nucleotides. New, accurate and facile strategies for the detection of point mutations are therefore absolutely necessary for the increased adoption of point-of-care molecular diagnostics. Currently, PCR and sequencing are mostly applied for diagnosing SNPs. However these methods have serious drawbacks as routine diagnostic tools because of their labour intensity and cost. Several new, more suitable methods can be applied to enable sensitive detection of mutations based on specially designed hybridization probes, mutation recognizing enzymes and thermal denaturation. Here, an overview is presented of the most recent advances in the field of fast and sensitive SNP detection assays with strong potential for integration in point-of-care tests.


Danish version of the Tilburg Frailty Indicator--translation, cross-cultural adaption and validity pretest by cognitive interviewing.
The Tilburg Frailty Indicator (TFI) is a self-administered questionnaire with a bio-psycho-social integrated approach that measures the degree of frailty in elderly persons. The TFI was developed in the Netherlands and tested in a population of elderly Dutch men and women. The aim of this study was to translate and culturally adapt the TFI to a Danish context, and to test face validity of the Danish version by cognitive interviewing. An internationally recognized procedure was applied as a basis for the translation process. The primary tasks were forward translation, reconciliation, back translation, harmonization and pretest. Pretest and review of the preliminary version by cognitive interviewing, were performed at a local community center and in an acute medical ward at the University Hospital in Aalborg, Denmark respectively. A large agreement regarding meaning of the items in the forward translation and reconciliation process was seen. Minor discrepancies were solved by consensus. Back translation revealed unclear wording in one matter. The harmonization committee agreed on a version for cognitive interviewing after revision of minor issues and thirty-four participants were interviewed. Two issues became evident and these were revised. The cognitive interviews and final lay-out resulted in minor adjustments as text type size, specific font, and lining for optimizing readability. In conclusion, we consider the TFI to be translated in such rigorous manner that the instrument can be further tested in clinical practice. The overall objective of the questionnaire being to identify frailty and improve the interventions relating to frail elderly persons in Denmark.


High performance HRM: NHS employee perspectives.
The purpose of this paper is to examine National Health Service (NHS) employee perspectives of how high performance human resource (HR) practices contribute to their performance. The paper draws on an extensive qualitative study of the NHS. A novel two-part method was used; the first part used focus group data from managers to identify high-performance HR practices specific to the NHS. Employees then conducted a card-sort exercise where they were asked how or whether the practices related to each other and how each practice affected their work. In total, 11 high performance HR practices relevant to the NHS were identified. Also identified were four reactions to a range of HR practices, which the authors developed into a typology according to anticipated beneficiaries (personal gain, organisation gain, both gain and no-one gains). Employees were able to form their own patterns (mental models) of performance contribution for a range of HR practices (60 interviewees produced 91 groupings). These groupings indicated three bundles particular to the NHS (professional development, employee contribution and NHS deal). These mental models indicate employee perceptions about how health services are organised and delivered in the NHS and illustrate the extant mental models of health care workers. As health services are rearranged and financial pressures begin to bite, these mental models will affect employee reactions to changes both positively and negatively. The novel method allows for identification of mental models that explain how NHS workers understand service delivery. It also delineates the complex and varied relationships between HR practices and individual performance.


First insights into the genetic diversity of the pinewood nematode in its native area using new polymorphic microsatellite loci.
The pinewood nematode, Bursaphelenchus xylophilus, native to North America, is the causative agent of pine wilt disease and among the most important invasive forest pests in the East-Asian countries, such as Japan and China. Since 1999, it has been found in Europe in the Iberian Peninsula, where it also causes significant damage. In a previous study, 94 pairs of microsatellite primers have been identified in silico in the pinewood nematode genome. In the present study, specific PCR amplifications and polymorphism tests to validate these loci were performed and 17 microsatellite loci that were suitable for routine analysis of B. xylophilus genetic diversity were selected. The polymorphism of these markers was evaluated on nematodes from four field origins and one laboratory collection strain, all originate from the native area. The number of alleles and the expected heterozygosity varied between 2 and 11 and between 0.039 and 0.777, respectively. First insights into the population genetic structure of B. xylophilus were obtained using clustering and multivariate methods on the genotypes obtained from the field samples. The results showed that the pinewood nematode genetic diversity is spatially structured at the scale of the pine tree and probably at larger scales. The role of dispersal by the insect vector versus human activities in shaping this structure is discussed.


Chiral Separation, X-ray Structure, and Biological Evaluation of a Potent and Reversible Dual Binding Site AChE Inhibitor.
Acetylcholinesterase (AChE) inhibitors (AChEIs) still remain the leading therapeutic options for the symptomatic treatment of cognitive deficits associated with mild-to-moderate Alzheimer's disease. The search for new AChEIs benefits from well-established knowledge of the molecular interactions of selective AChEIs, such as donepezil and related dual binding site inhibitors. Starting from a previously disclosed coumarin-based inhibitor (±)-cis-1, active as racemate in the nanomolar range toward AChE, we proceeded on a double track by (i) achieving chiral resolution of the enantiomers of 1 by HPLC and (ii) preparing two close achiral analogues of 1, i.e., compounds 4 and 6. An eudismic ratio as high as 20 was observed for the (-) enantiomer of cis-1. The X-ray crystal structure of the complex between the (-)-cis-1 eutomer (coded as MC1420) and T. californica AChE was determined at 2.8 Å, and docking calculation results suggested that the eutomer in (1R,3S) absolute configuration should be energetically more favored in binding the enzyme than the eutomer in (1S,3R) configuration. The achiral analogues 4 and 6 were less effective in inhibiting AChE compared to (±)-cis-1, but interestingly butylamide 4 emerged as a potent inhibitor of butyrylcholinesterase (BChE).


Abnormal P300 in people with high risk of developing psychosis.
Individuals with an "at-risk mental state" (or "prodromal" symptoms) have a 20-40% chance of developing psychosis; however it is difficult to predict which of them will become ill on the basis of their clinical symptoms alone. We examined whether neurophysiological markers could help to identify those who are particularly vulnerable. 35 cases meeting PACE criteria for the at-risk mental state (ARMS) and 57 controls performed an auditory oddball task whilst their electroencephalogram was recorded. The latency and amplitude of the P300 and N100 waves were compared between groups using linear regression. The P300 amplitude was significantly reduced in the ARMS group [8.6+/-6.4 microvolt] compared to controls [12.7+/-5.8 microvolt] (p<0.01). There were no group differences in P300 latency or in the amplitude and latency of the N100. Of the at-risk subjects that were followed up, seven (21%) developed psychosis. Reduction in the amplitude of the P300 is associated with an increased vulnerability to psychosis. Neurophysiological and other biological markers may be of use to predict clinical outcomes in populations at high risk.


Exploiting the energetic potential of 1,2,4-oxadiazole derivatives: combining the benefits of a 1,2,4-oxadiazole framework with various energetic functionalities.
A series of 1,2,4-oxadiazole-derived energetic compounds were successfully synthesized using 1,2,4-oxadiazole-3-chloroxime as a versatile starting material. These energetic compounds were fully characterized by NMR spectroscopy, IR spectroscopy, and elemental analysis. The structures of compounds 5, 6a, 6c, 8 and 8a were determined by single crystal X-ray diffraction. The physicochemical and energetic properties of all the synthesized energetic compounds, including density, thermal stability and energetic performance (e.g., detonation velocities and detonation pressures) were investigated. Among these energetic compounds, hydrazinium salts 6b and 8b and hydroxylammonium salts 6c and 8c exhibit satisfactory calculated detonation performances, which outperform the commonly used high explosive RDX. Potassium salt 5 shows good detonation performance, high density as well as high sensitivity, making it a potential primary explosive. Compound 9 is a potential candidate for melt-cast explosives due to its remarkable liquid range between melting point (Tm = 98 °C) and decomposition temperature (Td = 208 °C).


Vigorous response of human innate functioning IgM memory B cells upon infection by Neisseria gonorrhoeae.
Neisseria gonorrhoeae, the cause of the sexually transmitted infection gonorrhea, elicits low levels of specific Ig that decline rapidly after the bacteria are cleared. Reinfection with the same serovar can occur, and prior gonococcal infection does not alter the Ig response upon subsequent exposure, suggesting that protective immunity is not induced. The mucosal Ig response apparent during gonorrhea does not correlate with that observed systemically, leading to a suggestion that it is locally generated. In considering whether N. gonorrhoeae directly influences B cells, we observed that gonococcal infection prolonged viability of primary human B cells in vitro and elicited robust activation and vigorous proliferative responses in the absence of T cells. Furthermore, we observed the specific expansion of IgD(+)CD27(+) B cells in response to gonococcal infection. These cells are innate in function, conferring protection against diverse microbes by producing low-affinity, broadly reactive IgM without inducing classical immunologic memory. Although gonococcal infection of B cells produced small amounts of gonococcal-specific IgM, IgM specific for irrelevant Ags were also produced, suggesting a broad, polyspecific Ig response. The gonococci were effectively bound and engulfed by B cells. TLR9-inhibitory CpGs blocked B cell responses, indicating that intracellular bacterial degradation allows for innate immune detection within the phagolysosome. To our knowledge, this is the first report of a bacterial pathogen having specific affinity for the human IgM memory B cells, driving their potent activation and polyclonal Ig response. This unfocused T-independent response explains the localized Ig response that occurs, despite an absence of immunologic memory elicited during gonorrhea.


Complex molecular changes induced by chronic progestogens exposure in roach, Rutilus rutilus.
In our previous study, we measured 0.23-13.67ng/L progestogens (progesterone, drospirenone, levonorgestrel) in natural waters in the catchment area of the largest shallow lake of Central Europe, Lake Balaton. Progestogen contaminations act as potent steroids with mixed progestagenic, androgenic and mild estrogenic effects that is why our aim was to investigate the morphological and molecular effects of mixture of progesterone, drospirenone, and levonorgestrel in environmentally relevant (10ng/L) and higher (50 and 500ng/L) exposure concentrations in common roach, Rutilus rutilus. Steroids (e.g. progestogens) and the protein deglycase DJ-1 chaperon molecule aim the same target molecules in cells, therefore, we hypothesized that a relationship may exist between progestogens and DJ-1. Furthermore, our other aim was to follow the changes of signal molecules of different biological function due to progestogen treatment in serum and brain. Adult roaches were exposed to 10, 50 and 500ng/L of mixture of progestogen for 42 days and their somatic indices (brain-somatic, liver-somatic, gonadosomatic and kidney-somatic) were measured. Vitellogenin (VTG) expression (estrogen effect) or inhibition (androgen effect) in fish is a widely used biomarker so we measured its changes in liver by ELISA. To determine the quantity and to map the spatial distribution of DJ-1 chaperon protein the brain and liver tissues were analyzed by ELISA and immunohistochemistry. Furthermore, we also studied molecular alterations: a) in the serum by measuring cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglyceride concentrations and b) in brain homogenate using a cell stress array kit (26 protein). The somatic index of liver and kidney significantly in all the treated groups, whereas the gonadosomatic index of 500ng/L treated group showed significant decrease compared to control animals. VTG level increased significantly in 500ng/L progestogen treated group. Since the concentration of DJ-1 significantly increased in brain and liver in all progestogen treatment groups, the DJ-1 protein could be able to a more sensitive marker than VTG. Serum LDL and cholesterol levels of exposed fish were significantly decreased. DJ-1 was mediated through the stimulation of the expression of LDL-receptor which facilitates reuptake subsequently. In summary, our observations unfolded new data about molecular alterations induced by the combined action of environmental progestogens. In addition, the DJ-1 chaperon protein as a possible biomarker helped to trace the abiotic chemical environmental contaminations, like progestogens in the freshwater ecosystems.


Acute fluoride poisoning alters myocardial cytoskeletal and AMPK signaling proteins in rats.
Our previous findings revealed that increased oxidative stress, apoptosis and necrosis were implicated in acute fluoride (F-) induced cardiac dysfunction apart from hypocalcemia and hyperkalemia. Cardiac intermediate filaments (desmin and vimentin) and cytoskeleton linker molecule vinculin plays an imperative role in maintaining the architecture of cardiac cytoskeleton. In addition, AMPK is a stress activated kinase that regulates the energy homeostasis during stressed state. The present study was aimed to examine the role of cytoskeletal proteins and AMPK signaling molecules in acute F- induced cardiotoxicity in rats. In order to study this, male Wistar rats were treated with single oral doses of 45 and 90mg/kgF- for 24h. Acute F- intoxicated rats showed declined cytoskeletal protein expression of desmin, vimentin and vinculin in a dose dependent manner compared to control. A significant increase in phosphorylation of AMPKα (Thr172), AMPKß1 (Ser108) and Acetyl-coA carboxylase (ACC) (Ser79) in the myocardium and associated ATP deprivation were found in acute F- intoxicated rats. Further, ultra-structural studies confirmed myofibril lysis with interruption of Z lines, dilated sarcoplasmic reticulum and damaged mitochondrion were observed in both the groups of F- intoxicated rats. Taken together, these findings reveal that acute F- exposure causes sudden heart failure by altering the expression of cytoskeletal proteins and AMPK signaling molecules.


Genetic diversity of clinical and environmental Mucorales isolates obtained from an investigation of mucormycosis cases among solid organ transplant recipients.
Mucormycoses are invasive infections by Rhizopus species and other Mucorales. Over 10 months, four solid organ transplant (SOT) recipients at our centre developed mucormycosis due to Rhizopus microsporus (n=2), R. arrhizus (n=1) or Lichtheimia corymbifera (n=1), at a median 31.5 days (range: 13-34) post-admission. We performed whole genome sequencing (WGS) on 72 Mucorales isolates (45 R. arrhizus, 19 R. delemar, six R. microsporus, two Lichtheimia species) from these patients, from five patients with community-acquired mucormycosis, and from hospital and regional environments. Isolates were compared by core protein phylogeny and global genomic features, including genome size, guanine-cytosine percentages, shared protein families and paralogue expansions. Patient isolates fell into six core phylogenetic lineages (clades). Phylogenetic and genomic similarities of R. microsporus isolates recovered 7 months apart from two SOT recipients in adjoining hospitals suggested a potential common source exposure. However, isolates from other patients and environmental sites had unique genomes. Many isolates that were indistinguishable by core phylogeny were distinct by one or more global genomic comparisons. Certain clades were recovered throughout the study period, whereas others were found at particular time points. In conclusion, mucormycosis cases could not be genetically linked to a definitive environmental source. Comprehensive genomic analyses eliminated false associations between Mucorales isolates that would have been assigned using core phylogenetic or less extensive genomic comparisons. The genomic diversity of Mucorales mandates that multiple isolates from individual patients and environmental sites undergo WGS during epidemiological investigations. However, exhaustive surveillance of fungal populations in a hospital and surrounding community is probably infeasible.


Microfluidic stickers.
We present how to make and assemble micro-patterned stickers (microPS) to construct high performance plastic microfluidic devices in a few minutes. We take advantage of soft UV imprint techniques to tailor the geometry, the mechanical properties, and the surface chemistry of 2D and 3D microfluidic circuits. The resulting microfluidic stickers substantially overcome the actual performance of the very popular PDMS devices for a wide range of applications, while sharing their celebrated fast and easy processing. To highlight the intrinsic advantages of this method, three important applications are detailed: (i) we show that both aqueous and organic droplets can be produced and stored in stickers without any specific surface coating. (ii) We report on the outstanding pressure resistance of the microPS, which open the way to the transport of viscous complex fluids. (iii) Finally, a simple design strategy is proposed to generate complex flow patterns in interconnected stacks of microPS.


Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice.
The FDA approved drug rapamycin increases lifespan in rodents and delays age-related dysfunction in rodents and humans. Nevertheless, important questions remain regarding the optimal dose, duration, and mechanisms of action in the context of healthy aging. Here we show that 3 months of rapamycin treatment is sufficient to increase life expectancy by up to 60% and improve measures of healthspan in middle-aged mice. This transient treatment is also associated with a remodeling of the microbiome, including dramatically increased prevalence of segmented filamentous bacteria in the small intestine. We also define a dose in female mice that does not extend lifespan, but is associated with a striking shift in cancer prevalence toward aggressive hematopoietic cancers and away from non-hematopoietic malignancies. These data suggest that a short-term rapamycin treatment late in life has persistent effects that can robustly delay aging, influence cancer prevalence, and modulate the microbiome.


Development of a murine mycobacterial growth inhibition assay for evaluating vaccines against Mycobacterium tuberculosis.
The development and characterization of new tuberculosis (TB) vaccines has been impeded by the lack of reproducible and reliable in vitro assays for measuring vaccine activity. In this study, we developed a murine in vitro mycobacterial growth inhibition assay for evaluating TB vaccines that directly assesses the capacity of immune splenocytes to control the growth of Mycobacterium tuberculosis within infected macrophages. Using this in vitro assay, protective immune responses induced by immunization with five different types of TB vaccine preparations (Mycobacterium bovis BCG, an attenuated M. tuberculosis mutant strain, a DNA vaccine, a modified vaccinia virus strain Ankara [MVA] construct expressing four TB antigens, and a TB fusion protein formulated in adjuvant) can be detected. Importantly, the levels of vaccine-induced mycobacterial growth-inhibitory responses seen in vitro after 1 week of coculture correlated with the protective immune responses detected in vivo at 28 days postchallenge in a mouse model of pulmonary tuberculosis. In addition, similar patterns of cytokine expression were evoked at day 7 of the in vitro culture by immune splenocytes taken from animals immunized with the different TB vaccines. Among the consistently upregulated cytokines detected in the immune cocultures are gamma interferon, growth differentiation factor 15, interleukin-21 (IL-21), IL-27, and tumor necrosis factor alpha. Overall, we have developed an in vitro functional assay that may be useful for screening and comparing new TB vaccine preparations, investigating vaccine-induced protective mechanisms, and assessing manufacturing issues, including product potency and stability.


A mechanistic, stigmergy model of territory formation in solitary animals: Territorial behavior can dampen disease prevalence but increase persistence.
Although movement ecology has leveraged models of home range formation to explore the effects of spatial heterogeneity and social cues on movement behavior, disease ecology has yet to integrate these potential drivers and mechanisms of contact behavior into a generalizable disease modeling framework. Here we ask how dynamic territory formation and maintenance might contribute to disease dynamics in a territorial, solitary predator for an indirectly transmitted pathogen. We developed a mechanistic individual-based model where stigmergy-the deposition of signals into the environment (e.g., scent marking, scraping)-dictates local movement choices and long-term territory formation, but also the risk of pathogen transmission. Based on a variable importance analysis, the length of the infectious period was the single most important variable in predicting outbreak success, maximum prevalence, and outbreak duration. Host density and rate of pathogen decay were also key predictors. We found that territoriality best reduced maximum prevalence in conditions where we would otherwise expect outbreaks to be most successful: slower recovery rates (i.e., longer infectious periods) and higher conspecific densities. However, for slower pathogen decay rates, stigmergy-driven movement increased outbreak durations relative to random movement simulations. Our findings therefore support a limited version of the "territoriality benefits" hypothesis-where reduced home range overlap leads to reduced opportunities for pathogen transmission, but with the caveat that reduction in outbreak severity may increase the likelihood of pathogen persistence. For longer infectious periods and higher host densities, key trade-offs emerged between the strength of pathogen load, the strength of the stigmergy cue, and the rate at which those two quantities decayed; this finding raises interesting questions about the evolutionary nature of these competing processes and the role of possible feedbacks between parasitism and territoriality. This work also highlights the importance of considering social cues as part of the movement landscape in order to better understand the consequences of individual behaviors on population level outcomes.


Determinants for tuberculosis in HIV-infected adults in Northwest Ethiopia: a multicentre case-control study.
The objective of this study was to identify determinants for tuberculosis (TB) among HIV-infected adults in Northwest Ethiopia. Case-control study. Three hospitals and 10 health centres in Northwest Ethiopia. A total of 446 individuals consented to participate in the study (150 cases and 296 controls). Cases were HIV-infected adults diagnosed with active TB, and controls were HIV-infected adults without active TB. The link between TB and determinants was assessed using logistic regression. Determinants were categorised as sociodemographic, host-related, clinical and environmental. Smoking (adjusted OR (AOR) 5.47; 95% CI 2.26 to 13.22), presence of a TB patient in the family (AOR 2.66; 95% CI 1.25 to 5.66), alcohol consumption (AOR 2.49; 95% CI 1.29 to 4.80) and chewing khat (AOR 2.22; 95% CI 1.11 to 4.41) were independent determinants for increased occurrence of TB. Highly active antiretroviral therapy (HAART) (AOR 0.25; 95% CI 0.13 to 0.51), isoniazid preventive therapy (IPT) (AOR 0.22; 95% CI 0.11 to 0.41) and cotrimoxazole preventive therapy (AOR 0.32; 95% CI 0.19 to 0.55) had a protective effect against TB. HIV-infected adults with substance abuse (tobacco smoking, khat chewing and alcohol) should be prioritised for TB screening. This study reaffirmed that HAART and IPT are some of the best strategies for reducing TB occurrence in HIV-infected adults. These findings provide impetus to intensify tracing of TB household contacts.


TestSTORM: Simulator for optimizing sample labeling and image acquisition in localization based super-resolution microscopy.
Localization-based super-resolution microscopy image quality depends on several factors such as dye choice and labeling strategy, microscope quality and user-defined parameters such as frame rate and number as well as the image processing algorithm. Experimental optimization of these parameters can be time-consuming and expensive so we present TestSTORM, a simulator that can be used to optimize these steps. TestSTORM users can select from among four different structures with specific patterns, dye and acquisition parameters. Example results are shown and the results of the vesicle pattern are compared with experimental data. Moreover, image stacks can be generated for further evaluation using localization algorithms, offering a tool for further software developments.


Introducing "DoPP": A Graphical User-Friendly Application for the Rapid Species Identification of Psychoactive Plant Materials and Quantification of Psychoactive Small Molecules Using DART-MS Data.
The widespread abuse of "legal high" psychoactive plants continues to be of global concern because of their negative impacts on public health and safety. In forensic science, a major challenge in controlling these substances is the paucity of methods to rapidly identify them. We report the development of the Database of Psychoactive Plants (DoPP), a new user-friendly tool featuring an architecture for the identification of plant unknowns, and the necessary regression statistics for the development and validation of psychoactive compound quantification. The application relies on the knowledge that terrestrial plants exhibit species-specific chemical signatures that can be revealed by direct analysis in real time─high-resolution mass spectrometry (DART-HRMS). Subsequent automated machine learning processing of libraries of these spectra enables rapid discrimination and species identification. The chemical signature database includes 57 available plant species. The rapid acquisition of mass spectra and the ability to sample the materials in their native form enabled the generation of the vast amounts of spectral replicates required for database construction. For the identification of sample unknowns, a data analysis workflow was developed and implemented using the DoPP tool. It utilizes a hierarchical classification tree that integrates three machine learning methods, namely, random forest, k-nearest neighbors, and support vector machine, all of which were fused using posterior probabilities. The results show accuracies of 98 and 99% for 10-fold cross-validation and external validation, respectively, which make the classification model suitable for identity prediction of real samples.


Discrimination of speech stimuli based on neuronal response phase patterns depends on acoustics but not comprehension.
Speech stimuli give rise to neural activity in the listener that can be observed as waveforms using magnetoencephalography. Although waveforms vary greatly from trial to trial due to activity unrelated to the stimulus, it has been demonstrated that spoken sentences can be discriminated based on theta-band (3-7 Hz) phase patterns in single-trial response waveforms. Furthermore, manipulations of the speech signal envelope and fine structure that reduced intelligibility were found to produce correlated reductions in discrimination performance, suggesting a relationship between theta-band phase patterns and speech comprehension. This study investigates the nature of this relationship, hypothesizing that theta-band phase patterns primarily reflect cortical processing of low-frequency (<40 Hz) modulations present in the acoustic signal and required for intelligibility, rather than processing exclusively related to comprehension (e.g., lexical, syntactic, semantic). Using stimuli that are quite similar to normal spoken sentences in terms of low-frequency modulation characteristics but are unintelligible (i.e., their time-inverted counterparts), we find that discrimination performance based on theta-band phase patterns is equal for both types of stimuli. Consistent with earlier findings, we also observe that whereas theta-band phase patterns differ across stimuli, power patterns do not. We use a simulation model of the single-trial response to spoken sentence stimuli to demonstrate that phase-locked responses to low-frequency modulations of the acoustic signal can account not only for the phase but also for the power results. The simulation offers insight into the interpretation of the empirical results with respect to phase-resetting and power-enhancement models of the evoked response.


Correction of facial asymmetry with multiplanar mandible distraction: a one-year follow-up study.
To assess the effectiveness of multiplanar mandibular distraction by evaluating the treatment effect and 1-year stability, measuring changes on the affected and nonaffected sides, and evaluating correction of the occlusal plane and oral commissure cant. Eleven patients aged 5 to 9.4 years (mean 6.7 years ) who underwent unilateral multiplanar mandibular distraction were included, 10 with hemifacial microsomia and one temporomandibular joint ankylosis. Intermaxillary elastics were applied to intraoral dental devices during and after distraction until bony consolidation and occlusal interdigitation were achieved. Radiographs were taken and measured before distraction, after vertical distraction, after completion of distraction, and 1 year after treatment. Frontal facial photographs were obtained to analyze the changes in the position of the oral commissure. The facial profile was improved by sagittal mandibular advancement. Although the facial height increased 6.6 mm during vertical distraction, with a net gain of 5.8 mm in follow-up, the mandibular plane angle was maintained. The affected mandibular length increased 8.3 mm after distraction and remained unchanged after 1 year. Ramus height increased 12.7 mm after distraction and relapsed 3.8 mm at follow-up (30%). The affected body length demonstrated postoperative growth of 3.1 mm. Correction of the chin deviation was 9.8 mm after distraction and relapsed 1.6 mm (16.3%) after 1 year. Canting of the occlusal plane and oral commissure was corrected and remained stable. Multiplanar mandibular distraction is an effective treatment for correcting facial asymmetry in young children. The 1-year follow-up revealed that the new sagittal jaw relation and mandibular body length were stable, and the achieved occlusal interdigitation was well maintained. However, the ramus height and chin deviation demonstrated some relapse.


Inhibiting pro-death NMDA receptor signaling dependent on the NR2 PDZ ligand may not affect synaptic function or synaptic NMDA receptor signaling to gene expression.
NMDA receptors (NMDARs) mediate ischemic brain damage, in part through interactions of the PDZ ligand of NR2 subunits with the PDZ domain proteins PSD-95 and neuronal nitric oxide synthase located within the NMDAR signaling complex. We have recently shown that this PDZ ligand-dependent pathway promotes neuronal death via p38 activation. A peptide mimetic of the NR2B PDZ ligand (TAT-NR2B9c) reduces p38-mediated death in vitro and p38-dependent ischemic damage in vivo. In the absence of the PDZ ligand-p38 pathway, such as in TAT-NR2B9c-treated neurons, or in NMDAR-expressing non-neuronal cells, NMDAR-dependent excitotoxicity is mediated largely by JNK and requires greater Ca2+ influx. A major reason for blocking pro-death signaling events downstream of the NMDAR as an anti-excitotoxic strategy is that it may spare physiological synaptic function and signaling. We find that neuroprotective doses of TAT-NR2B9c do not alter the frequency of spontaneous synaptic events within networks of cultured cortical neurons nor is mini-EPSC frequency altered. Furthermore, TAT-NR2B9c does not inhibit the capacity of synaptic NMDAR activity to promote neuroprotective changes in gene expression, including the upregulation of PACAP via CREB, and suppression of the pro-oxidative FOXO target gene Txnip. Thus, while the NR2 PDZ ligand does not account for all the excitotoxic effects of excessive NMDAR activity, these findings underline the value of the specific targeting of death pathways downstream of the NMDAR.


Nanoparticle tumor localization, disruption of autophagosomal trafficking, and prolonged drug delivery improve survival in peritoneal mesothelioma.
The treatment outcomes for malignant peritoneal mesothelioma are poor and associated with high co-morbidities due to suboptimal drug delivery. Thus, there is an unmet need for new approaches that concentrate drug at the tumor for a prolonged period of time yielding enhanced antitumor efficacy and improved metrics of treatment success. A paclitaxel-loaded pH-responsive expansile nanoparticle (PTX-eNP) system is described that addresses two unique challenges to improve the outcomes for peritoneal mesothelioma. First, following intraperitoneal administration, eNPs rapidly and specifically localize to tumors. The rate of eNP uptake by tumors is an order of magnitude faster than the rate of uptake in non-malignant cells; and, subsequent accumulation in autophagosomes and disruption of autophagosomal trafficking leads to prolonged intracellular retention of eNPs. The net effect of these combined mechanisms manifests as rapid localization to intraperitoneal tumors within 4 h of injection and persistent intratumoral retention for >14 days. Second, the high tumor-specificity of PTX-eNPs leads to delivery of greater than 100 times higher concentrations of drug in tumors compared to PTX alone and this is maintained for at least seven days following administration. As a result, overall survival of animals with established mesothelioma more than doubled when animals were treated with multiple doses of PTX-eNPs compared to equivalent dosing with PTX or non-responsive PTX-loaded nanoparticles.


Types of Partner Violence in Couples Affected by Incarceration: Applying Johnson's Typology to Understand the Couple-level Context for Violence.
In prior research, samples of incarcerated and reentering men and their partners report partner violence at roughly 10 times the frequency found in the general population. The relationship dynamics underlying these experiences remain poorly understood. Addressing this gap and expanding prior applications of Johnson's typology in other populations-which typically rely on survey data alone and include reports from just one member of a couple-we applied latent class analysis with dyadic survey data from 1,112 couples to identify types of partner violence in couples affected by incarceration. We assessed congruence between quantitative types and couples' qualitative accounts and compared the two major types using two-sample t-tests.In some couples, one partner used various tactics to systematically dominate and control the other, as in Johnson's coercive controlling violence. In others, physical violence arose in the context of jealousy but no other controlling behavior. This type resembled Johnson's situational couple violence. Qualitative data suggested that jealousy represented a common, situational response to periods of prolonged separation, relationship instability, status insecurity, and partnership concurrence and not a tactic of control per se. Victims of coercive controlling violence experienced more PTSD symptoms and felt less safe in their relationships than victims of jealous-only violence. Perpetrators of coercive controlling violence were more likely to use severe physical violence against their partners than perpetrators of jealous-only violence. Findings indicate that broader context is critical for interpreting the presence of jealousy (and whether it constitutes a control tactic). They indicate that prevention and response strategies tailored to these types could help couples cope safely with the extreme relationship stressors of incarceration and reentry. Finally, they suggest a need to move from an exclusive focus on individual accountability and services toward a model that also incorporates institutional accountability and change.


Control of arm movement after bilateral lesions of area 5 in the monkey (Macaca mulatta).
The effect of bilateral area 5 lesions on the analysis of proprioceptive information and the guidance of reaching movements was studied in three rhesus monkeys. In the first paradigm (Proprioceptive discrimination test) the monkeys were trained to discriminate between movements of a joystick to the right or left without visual control; they reported the direction of movement by touching or not touching a screen (go/no-go task). After area 5 had been removed, the monkeys were only mildly impaired on this test. It is concluded that such simple joint movement could be analysed in area 2, area 5 being concerned with more complex arm movements. In the second paradigm (Searching test) the monkey had to find a peanut on a board in the dark using proprioceptive information stored in memory during previous trials. After area 5 lesions, the number of correct reaches was not modified but the number of errors after an incorrect trial (correcting movement) was significantly increased. The data suggests that when visual input is not available, area 5 is involved in the guidance of arm movements on the basis of proprioceptive inputs.


Educational inequalities in cancer survival: a role for comorbidities and health behaviours?
To describe educational inequalities in cancer survival and to what extent these can be explained by comorbidity and health behaviours (smoking, physical activity and alcohol consumption). The GLOBE study sent postal questionnaires to individuals in The Netherlands in 1991 resulting in 18 973 respondents (response 70%). Questions were asked on education, health and health-related behaviours. Participants were linked for cancer diagnosis (1991-2008), comorbidity and survival (up to 2010) with the population-based Eindhoven Cancer Registry; 1127 tumours were included in the analyses. 5-year crude survival was best in highly educated patients as compared with low educated patients for all cancers combined: 49% versus 32% in male subjects (log rank: p<0.0001), 65% versus 49% in female subjects (p=0.0001). Compared with highly educated, low educated prostate cancer patients had an increased risk of death (HR 2.9 (95% CI 1.7 to 5.1), adjusted for age, stage and year). No or inconsistent associations between educational level and risk of death were seen in multivariable analyses for breast, colon and non-small cell lung cancer. Although survival in prostate cancer patients was affected by comorbidities (HR2_vs_0_comorbidities: 2.6 (1.5 to 4.4)), physical activity (HRno/little_vs__moderate_physical__activity: 2.0 (1.2 to 3.4)) and smoking (HRcurrent_vs_never_smokers: 2.6 (1.0-6.8)), these did not contribute to educational inequalities in prostate cancer survival (HRlow_vs_high_education: 3.1 (1.6 to 5.8) with adjustment for comorbidity and lifestyle). Compared with low educated, highly educated prostate cancer patients had better survival. Although presence of comorbidities, physical activity levels and smoking status affected survival from prostate cancer, these did not contribute to educational inequalities in survival. The role of other factors for inequalities in cancer survival needs to be explored.


The function of the antagonist muscle during fast limb movements in man.
We have examined fast flexion movements of the human thumb and fast extension movements of the elbow over three different distances at a variety of speeds in order to elucidate the function of the antagonist muscle in these circumstances. All movements were of such a velocity that they showed the typical bi- or triphasic pattern of muscle activation in agonist and antagonist. Slower movements, with continuous agonist activity, were not analysed. For movements made through the same angle at different velocities, there was a linear relationship between the amount of antagonist activity needed to halt the movement and the peak velocity. However, the slope of this relationship was a function of the distance moved. Movements made through large angles showed less antagonist activity than those made through small angles at the same speed. The timing of the antagonist activity also changed as a function of both distance and speed. Fast, small movements showed earlier onset of antagonist activity than slow, large ones. Movements which were halted mechanically with the subject's prior knowledge had little or no antagonist activity, since it was no longer necessary in these conditions. The complexity of these relations indicates that the triphasic pattern of muscle activity underlying these movements can no longer be regarded as a simple immutable 'programme'. The size and timing of the bursts of muscle activity are subtly adjusted to the precise nature of the task.


Histopathological alterations of the parathyroid glands in haemodialysis patients with secondary hyperparathyroidism refractory to cinacalcet hydrochloride.
Cinacalcet treatment for secondary hyperparathyroidism (SHPT) has demonstrated parathyroid size regression and morphological changes, such as cystic degeneration and hypovascularisation, on ultrasonography. However, there have been very few reports regarding the histopathological alterations of hyperplastic parathyroid glands in patients with SHPT after administration of cinacalcet. The aim of this study was to elucidate the effects of cinacalcet for histopathological alterations on the parathyroid glands. A total of 92 hyperplastic parathyroid glands were obtained from 24 dialysis patients with severe SHPT who underwent total parathyroidectomy and were enrolled in this study. Patients were divided into those treated with and without cinacalcet (cinacalcet group and conventional group, respectively; both n=12). The areas of oxyphil cells, cystic degeneration, haemorrhagic changes and haemosiderin deposition were assessed semiquantitatively. Total maximal parathyroid gland weight and maximal-to-minimal parathyroid gland weight ratio were significantly higher in the cinacalcet group compared with the conventional group (1798.7±1658.3 mg vs 764.2±471.1 mg, p=0.018, 15.8±13.9 vs p=0.047, 6.6±4.2, respectively). Significant increases were observed in oxyphil cell area (61.7%±17.1% vs 36.7%±15.6%, p=0.001) and haemosiderosis score (1.50±1.24 vs 0.42±0.51, p=0.029) in the former rather than the latter group. These results suggest that cinacalcet may induce specific qualitative alterations of hyperplastic parathyroid glands in patients with severe SHPT.


A theoretical model of the holistic health of United Methodist clergy.
Culturally competent health interventions require an understanding of the population's beliefs and the pressures they experience. Research to date on the health-related beliefs and experiences of clergy lacks a comprehensive data-driven model of clergy health. Eleven focus groups with 59 United Methodist Church (UMC) pastors and 29 UMC District Superintendents were conducted in 2008. Participants discussed their conceptualization of health and barriers to, and facilitators of, health promotion. Audiotape transcriptions were coded by two people each and analyzed using grounded theory methodology. A model of health for UMC clergy is proposed that categorizes 42 moderators of health into each of five levels drawn from the Socioecological Framework: Intrapersonal, Interpersonal, Congregational, United Methodist Institutional, and Civic Community. Clergy health is mediated by stress and self-care and coping practices. Implications for future research and clergy health interventions are discussed.


The relation between hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression with anemia and outcome in surgically treated head and neck cancer.
Hypoxia promotes tumorigenesis through the hypoxia-inducible factor (HIF) pathway. There are 2 main homologues of the regulatory proteins, HIF-1alpha and HIF-2alpha, which have different effects in genetic knock-out experiments. Anemia may contribute to hypoxia by reducing oxygen delivery, but it is not known whether this influences HIF-alpha expression in tumors. The expression of HIF-1alpha, HIF-2alpha, carbonic anhydrase-9 (CA-9), and peripheral hemoglobin (Hb) levels in 151 patients who underwent surgery for head and neck squamous cell carcinoma (HNSCC) were analyzed and related to outcome. High HIF-1alpha was expressed in 45 of 140 tumors (30%), HIF-2alpha was expressed in 21 of 139 tumors (14%), and CA-9 was expressed in 56 of 149 tumors (62%). There was a positive correlation between HIF-1alpha expression and HIF-2alpha expression (P =.0001). HIF-1alpha alone was associated with a worse disease-specific survival (DSS) (P =.05) and disease-free survival (DFS) (P = .03) in multivariate analyses. Nine percent of tumors expressed both high HIF-1alpha and high HIF-2alpha. High HIF-1alpha/high HIF-2alpha expression was an independent prognostic factors in DSS (P = .04) and DFS (P =.005) in multivariate analyses. There was no correlation noted between Hb and HIF-1alpha, HIF-2alpha, or CA-9. HIF-1alpha alone was correlated with DSS and DFS. The additive effect of HIF-2alpha on poor prognosis suggested that different pathways may be regulated by HIF-2alph. Anemia that was not related to HIF-alpha expression suggests that tumor intrinsic factors regulate HIF-alpha therefore, anemia may be a surrogate marker for other factors that affect outcome.


The tethering arm of the EGF receptor is required for negative cooperativity and signal transduction.
The EGF receptor is a classical receptor-tyrosine kinase. In the absence of ligand, the receptor adopts a closed conformation in which the dimerization arm of subdomain II interacts with the tethering arm in subdomain IV. Following the binding of EGF, the receptor opens to form a symmetric, back-to-back dimer. Although it is clear that the dimerization arm of subdomain II is central to the formation of receptor dimers, the role of the tethering arm of subdomain IV (residues 561-585) in this configuration is not known. Here we use (125)I-EGF binding studies to assess the functional role of the tethering arm in the EGF receptor dimer. Mutation of the three major residues that contribute to tethering (D563A,H566A,K585A-EGF receptor) did not significantly alter either the ligand binding properties or the signaling properties of the EGF receptor. By contrast, breaking the Cys(558)-Cys(567) disulfide bond through double alanine replacements or deleting the loop entirely led to a decrease in the negative cooperativity in EGF binding and was associated with small changes in downstream signaling. Deletion of the Cys(571)-Cys(593) disulfide bond abrogated cooperativity, resulting in a high affinity receptor and increased sensitivity of downstream signaling pathways to EGF. Releasing the Cys(571)-Cys(593) disulfide bond resulted in extreme negative cooperativity, ligand-independent kinase activity, and impaired downstream signaling. These data demonstrate that the tethering arm plays an important role in supporting cooperativity in ligand binding. Because cooperativity implies subunit-subunit interactions, these results also suggest that the tethering arm contributes to intersubunit interactions within the EGF receptor dimer.


[Students of medicine are turning medical education on its head; from a closed to an open learning environment].
These days, students are gathering their own source materials using Google and leave the required textbooks on the shelves. This means the future of medical education lies in facilitating and freely sharing modern learning resources. This rapid shift, away from traditional textbooks, is causing unrest in academic education. The faculty is losing control and the overall picture. Existing teaching materials with strict copyrights have made it difficult for teachers and students to learn from each other. The productivity and professional curiosity of a sector that not only desires but also requires life-long learning, is being undermined by meaningless barriers and duplication of work. Free learning resources are making it easier for both students and professionals to learn, share and quickly get access to the right information. In this article, we explain what this means for medical education, what is needed and we provide a few examples.


Systematic review of reviews of risk factors for intracranial aneurysms.
Systematic reviews of systematic reviews identify good quality reviews of earlier studies of medical conditions. This article describes a systematic review of systematic reviews performed to investigate factors that might influence the risk of rupture of an intracranial aneurysm. It exemplifies the technique of this type of research and reports the finding of a specific study. The annual incidence of subarachnoid haemorrhage resulting from the rupture of intracranial aneurysms is estimated to be nine per 100,000. A large proportion of people who have this bleed, will die or remain dependent on the care of others for some time. Reliable knowledge about the risks of subarachnoid haemorrhage in different populations will help in planning, screening and prevention strategies and in predicting the prognosis of individual patients. If the necessary data were available in the identified reviews, an estimate for the numerical relationship between a particular characteristic and the risk of subarachnoid haemorrhage was included in this report. The identification of eligible systematic reviews relied mainly on the two major bibliographic databases of the biomedical literature: PubMed and EMBASE. These were searched in 2006, using specially designed search strategies. Approximately 2,000 records were retrieved and each of these was checked carefully against the eligibility criteria for this systematic review. These criteria required that the report be a systematic review of studies assessing the risk of subarachnoid haemorrhage in patients known to have an unruptured intracranial aneurysm or of studies that had investigated the characteristics of people who experienced a subarachnoid haemorrhage without previously being known to have an unruptured aneurysm. Reports which included more than one systematic review were eligible and each of these reviews was potentially eligible. The quality of each systematic review was assessed. In this review, 16 separate reports were identified, including a total of 46 eligible systematic reviews. These brought together research studies for 24 different risk factors. This has shown that the following factors appear to be associated with a higher risk of subarachnoid haemorrhage: being a woman, older age, posterior circulation aneurysms, larger aneurysms, previous symptoms, "non-white" ethnicity, hypertension, low body mass index, smoking and alcohol consumption of more than 150 g per week. The following factors appear to be associated with a lower risk of subarachnoid haemorrhage: high cholesterol, diabetes and use of hormone replacement therapy.


Short-listing of applicants from UCCA forms: the structure of pre-selection judgements.
Applicants for admission to St Mary's Hospital Medical School in 1986 were short-listed for interview by one of four assessors, who each made their assessments on a nine-item pro forma. One short-lister had also been studied in detail during 1981. Short-listers used the full range of possible judgements, in approximately the proportions requested. Only minor differences were found between them in the mean and range of their judgements, suggesting that similarity of standards can be maintained while using a number of separate short-listers. A confirmatory factor analysis of individual short-listers' judgements showed that all were extracting three separate factors, named 'Academic ability', 'Interests' and 'Contribution to community', although the less experienced short-listers differentiated these items less well than the more experienced. The short-lister assessed in 1981 and 1986 had retained an almost identical factor structure over the 5-year period.


Brain Imaging Signs and Health-Related Quality of Life after Acute Ischemic Stroke: Analysis of ENCHANTED Alteplase Dose Arm.
The influence of specific brain lesions on health-related quality of life (HRQoL) after acute ischemic stroke (AIS) is uncertain. We aimed to identify imaging predictors of poor HRQoL in alteplase-treated participants of the alteplase dose arm of the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). ENCHANTED was an international trial of low- versus standard-dose intravenous alteplase in AIS patients, with functional outcome (modified Rankin scale [mRS]) and HRQoL on the 5-dimension European Quality of Life Scale (EQ-5D) assessed at 90 days post-randomization. Brain images were analyzed centrally by trained assessors. Multivariable logistic regression was undertaken in the study population randomly divided (2:1) into training (development) and validation (performance) groups, with age (per 10-year increase), ethnicity, baseline National Institutes of Health Stroke Scale (NIHSS) score, diabetes mellitus, premorbid function (mRS score 0 or 1), and proxy respondent, forced into all models. Data are presented with odds ratios (ORs) and 95% confidence intervals (CIs). Eight prediction models were developed and validated in 2,526 AIS patients (median age 67.5 years; 38.4% female; 61.7% Asian) with complete brain imaging and 90-day EQ-5D utility score data. The best performance model included acute ischemic changes in the right (OR 1.69, 95% CI: 1.24-2.29) and deep (OR 1.50, 95% CI: 1.03-2.19) middle cerebral artery (MCA) regions. Several background features of brain frailty - atrophy, white matter change, and old infarcts - were significantly associated with adverse physical but not emotional HRQoL domains. In thrombolysed AIS patients, right-sided and deep ischemia within the MCA territory predict poor overall HRQoL, whilst features of old cerebral ischemia are associated with reduced physical HRQoL.


Speech Processing Difficulties in Attention Deficit Hyperactivity Disorder.
The large body of research that forms the ease of language understanding (ELU) model emphasizes the important contribution of cognitive processes when listening to speech in adverse conditions; however, speech-in-noise (SIN) processing is yet to be thoroughly tested in populations with cognitive deficits. The purpose of the current study was to contribute to the field in this regard by assessing SIN performance in a sample of adolescents with attention deficit hyperactivity disorder (ADHD) and comparing results with age-matched controls. This population was chosen because core symptoms of ADHD include developmental deficits in cognitive control and working memory capacity and because these top-down processes are thought to reach maturity during adolescence in individuals with typical development. The study utilized natural language sentence materials under experimental conditions that manipulated the dependency on cognitive mechanisms in varying degrees. In addition, participants were tested on cognitive capacity measures of complex working memory-span, selective attention, and lexical access. Primary findings were in support of the ELU-model. Age was shown to significantly covary with SIN performance, and after controlling for age, ADHD participants demonstrated greater difficulty than controls with the experimental manipulations. In addition, overall SIN performance was strongly predicted by individual differences in cognitive capacity. Taken together, the results highlight the general disadvantage persons with deficient cognitive capacity have when attending to speech in typically noisy listening environments. Furthermore, the consistently poorer performance observed in the ADHD group suggests that auditory processing tasks designed to tax attention and working memory capacity may prove to be beneficial clinical instruments when diagnosing ADHD.


Pre-steady-state kinetic analysis of the incorporation of anti-HIV nucleotide analogs catalyzed by human X- and Y-family DNA polymerases.
Nucleoside reverse transcriptase inhibitors (NRTIs) are an important class of antiviral drugs used to manage infections by human immunodeficiency virus, which causes AIDS. Unfortunately, these drugs cause unwanted side effects, and the molecular basis of NRTI toxicity is not fully understood. Putative routes of NRTI toxicity include the inhibition of human nuclear and mitochondrial DNA polymerases. A strong correlation between mitochondrial toxicity and NRTI incorporation catalyzed by human mitochondrial DNA polymerase has been established both in vitro and in vivo. However, it remains to be determined whether NRTIs are substrates for the recently discovered human X- and Y-family DNA polymerases, which participate in DNA repair and DNA lesion bypass in vivo. Using pre-steady-state kinetic techniques, we measured the substrate specificity constants for human DNA polymerases β, λ, η, ι, κ, and Rev1 incorporating the active, 5'-phosphorylated forms of tenofovir, lamivudine, emtricitabine, and zidovudine. For the six enzymes, all of the drug analogs were incorporated less efficiently (40- to >110,000-fold) than the corresponding natural nucleotides, usually due to a weaker binding affinity and a slower rate of incorporation for the incoming nucleotide analog. In general, the 5'-triphosphate forms of lamivudine and zidovudine were better substrates than emtricitabine and tenofovir for the six human enzymes, although the substrate specificity profile depended on the DNA polymerase. Our kinetic results suggest NRTI insertion catalyzed by human X- and Y-family DNA polymerases is a potential mechanism of NRTI drug toxicity, and we have established a structure-function relationship for designing improved NRTIs.


Community-based participatory research (CBPR): Towards equitable involvement of community in psychology research.
Community-based participatory research (CBPR) answers the call for more patient-centered, community-driven research approaches to address growing health disparities. CBPR is a collaborative research approach that equitably involves community members, researchers, and other stakeholders in the research process and recognizes the unique strengths that each bring. The aim of CBPR is to combine knowledge and action to create positive and lasting social change. With its origins in psychology, sociology, and critical pedagogy, CBPR has become a common research approach in the fields of public health, medicine, and nursing. Although it is well aligned with psychology's ethical principles and research aims, it has not been widely implemented in psychology research. The present article introduces CBPR to a general psychology audience while considering the unique aims of and challenges in conducting psychology research. In this article, we define CBPR principles, differentiate it from a more traditional psychology research approach, retrace its historical roots, provide concrete steps for its implementation, discuss its potential benefits, and explore practical and ethical challenges for its integration into psychology research. Finally, we provide a case study of CBPR in psychology to illustrate its key constructs and implementation. In sum, CBPR is a relevant, important, and promising research framework that may guide the implementation of more effective, culturally appropriate, socially just, and sustainable community-based psychology research. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Novel IRF6 mutations in families with Van Der Woude syndrome and popliteal pterygium syndrome from sub-Saharan Africa.
Orofacial clefts (OFC) are complex genetic traits that are often classified as syndromic or nonsyndromic clefts. Currently, there are over 500 types of syndromic clefts in the Online Mendelian Inheritance in Man (OMIM) database, of which Van der Woude syndrome (VWS) is one of the most common (accounting for 2% of all OFC). Popliteal pterygium syndrome (PPS) is considered to be a more severe form of VWS. Mutations in the IRF6 gene have been reported worldwide to cause VWS and PPS. Here, we report studies of families with VWS and PPS in sub-Saharan Africa. We screened the DNA of eight families with VWS and one family with PPS from Nigeria and Ethiopia by Sanger sequencing of the most commonly affected exons in IRF6 (exons 3, 4, 7, and 9). For the VWS families, we found a novel nonsense variant in exon 4 (p.Lys66X), a novel splice-site variant in exon 4 (p.Pro126Pro), a novel missense variant in exon 4 (p.Phe230Leu), a previously reported splice-site variant in exon 7 that changes the acceptor splice site, and a known missense variant in exon 7 (p.Leu251Pro). A previously known missense variant was found in exon 4 (p.Arg84His) in the PPS family. All the mutations segregate in the families. Our data confirm the presence of IRF6-related VWS and PPS in sub-Saharan Africa and highlights the importance of screening for novel mutations in known genes when studying diverse global populations. This is important for counseling and prenatal diagnosis for high-risk families.


Biocompatibility of Subcutaneously Implanted Plant-Derived Cellulose Biomaterials.
There is intense interest in developing novel biomaterials which support the invasion and proliferation of living cells for potential applications in tissue engineering and regenerative medicine. Decellularization of existing tissues have formed the basis of one major approach to producing 3D scaffolds for such purposes. In this study, we utilize the native hypanthium tissue of apples and a simple preparation methodology to create implantable cellulose scaffolds. To examine biocompatibility, scaffolds were subcutaneously implanted in wild-type, immunocompetent mice (males and females; 6-9 weeks old). Following the implantation, the scaffolds were resected at 1, 4 and 8 weeks and processed for histological analysis (H&E, Masson's Trichrome, anti-CD31 and anti-CD45 antibodies). Histological analysis revealed a characteristic foreign body response to the scaffold 1 week post-implantation. However, the immune response was observed to gradually disappear by 8 weeks post-implantation. By 8 weeks, there was no immune response in the surrounding dermis tissue and active fibroblast migration within the cellulose scaffold was observed. This was concomitant with the deposition of a new collagen extracellular matrix. Furthermore, active blood vessel formation within the scaffold was observed throughout the period of study indicating the pro-angiogenic properties of the native scaffolds. Finally, while the scaffolds retain much of their original shape they do undergo a slow deformation over the 8-week length of the study. Taken together, our results demonstrate that native cellulose scaffolds are biocompatible and exhibit promising potential as a surgical biomaterial.


Ten years of HPV vaccination in the Netherlands: current evidence and future challenges in HPV-related disease prevention.
Girls-only vaccination against human papillomavirus (HPV) type 16 and 18 was implemented in the Netherlands in 2009. Despite the evidence of the efficacy against precancerous lesions, cross-protection induced by the vaccine and a greater potential for cancer prevention than cervical cancer only, vaccine coverage in the girls-only program has remained below target levels. In this paper, we review the literature from the Netherlands on the effectiveness and cost-effectiveness of HPV vaccination since vaccine introduction, give an account of the coverage, safety and effectiveness of HPV vaccination as has been reported in the Dutch surveillance program and discuss challenges of the current HPV vaccination program. Girls-only HPV vaccination may confer a substantial health gain in HPV-related disease prevention. However, vaccine coverage declined remarkably recently possibly related to safety concerns, limiting the benefits from girls' vaccination and increasing the potential additional benefit of sex-neutral HPV vaccination. Considering the emergence of novel vaccination and screening options and the change from cytology- to HPV-based screening in 2017, further research is required to inform decisions on the optimization of an integrated vaccination and screening program.


Noun and predicate comprehension/production and gestures in extremely preterm children at two years of age: Are they delayed?
Extremely low gestational age (ELGA, GA<28 weeks) preterm children are at high risk for linguistic impairments; however, their lexical comprehension and production as well as lexical categories in their early language acquisition have not been specifically examined via direct tools. Our study examines lexical comprehension and production as well as gestural production in ELGA children by focusing on noun and predicate acquisition. Forty monolingual ELGA children (mean GA of 26.7 weeks) and 40 full-term (FT) children were assessed at two years of corrected chronological age (CCA) using a test of noun and predicate comprehension and production (PiNG) and the Italian MB-CDI. Noun comprehension and production were delayed in ELGA compared with FT children, as documented by the low number of correct responses and the large number of errors, i.e., incorrect responses and no-response items, and by the types of incorrect responses, i.e., fewer semantically related responses, in noun production. Regarding predicate comprehension and production, a higher frequency of no responses was reported by ELGA children and these children also presented a lower frequency of bimodal spoken-gestural responses in predicate production than FT children. A delayed vocabulary size as demonstrated by the MB-CDI, was exhibited by one-fourth of the ELGA children, who were also unable to complete the predicate subtest. These findings highlight that noun comprehension and production are delayed in ELGA children at two years of CCA and are the most important indexes for the direct evaluation of their lexical abilities and delay. The types of incorrect responses and bimodal spoken-gestural responses were proven to be useful indexes for evaluating the noun and predicate level of acquisition and to plan early focused interventions. After reading this manuscript, the reader will understand (a) the differences in noun and predicate comprehension and production between ELGA and FT children and the indexes of lexical delays exhibited by ELGA children at 2;0 (CCA); (b) the relevance of evaluating errors (incorrect response and no response), the types of incorrect responses (semantically related and unrelated) and the modality of the responses (unimodal spoken and bimodal spoken-gestural) in noun and predicate production to understand the difficulties experienced by ELGA children in representing and expressing meanings; and (c) the need to plan specific interventions to support spoken and gestural modalities in lexical comprehension and production in ELGA children by focusing on noun and predicate acquisition.


Comparison of family functioning in families of depressed patients and nonclinical control families in China using the Family Assessment Device and the Family Adaptability and Cohesion Evaluation Scales II.
Family functioning influences the course and long-term outcome for patients with depression. It is important to understand the family functioning of depressed patients from the viewpoint both of patients and their family members. The objective of this study was to explore the association between family functioning and depression in a sample of Chinese families, using the Family Assessment Device (FAD) and the Family Adaptability and Cohesion Evaluation Scales II (FACES II). This study was conducted in a sample of 61 depressed patients and their family members and 61 nonclinical controls in mainland China. It compared the perception of depressed patients and their family members and evaluated agreement between family members. Results indicate that in mainland China, functioning among families with a depressed family member is poorer than that of control families. Depressed patients reported less satisfaction than did their family members. There were significant differences on 4 of the 7 FAD scales among depressed patients and their family members, whereas no discrepancies were found on the FACES II. For the FAD, low agreement between patients and family members was found on all scales except behavioral control. Moderate agreement appeared on all dimensions of FACES II except for ideal cohesion and dissatisfaction with cohesion for the families of depressed patients. Depression is associated with impaired family functioning in families in mainland China. When applying the FAD and FACES II to samples of Chinese families, clinicians should be aware that the FAD may be more sensitive to detecting problems in some areas than the FACES II.


The effect of paroxetine on 5-HT(2A) receptors in depression: an [(18)F]setoperone PET imaging study.
In the cortex of animals, serotonin (5-HT) levels increase after several weeks of treatment with selective serotonin reuptake inhibitors (SSRIs). Studies using an intrasubject design to examine the effects of SSRI treatment on 5-HT(2A) receptors in the cortex of drug-free depressed patients are needed. In theory, agonist stimulation of 5-HT(2A) receptors could be relevant to SSRI treatment by promoting neuronal growth and survival as well as direct elevation of mood. The objective of this study was to evaluate the effect of 6 weeks of paroxetine treatment on 5-HT(2A) receptors in depressed patients. After a medication-free period of at least 3 months, 19 depressed patients were treated for 6 weeks with paroxetine, 20 mg/day. The authors used [(18)F]setoperone and positron emission tomography to assess 5-HT(2A) receptor binding potential in the patients before and after treatment and in 19 age-matched healthy subjects. 5-HT(2A) binding potential declined with age in all cortical regions in the depressed and healthy subjects. There was a significant interaction between age and treatment effect on 5-HT(2A) binding potential in all cortical regions. Subjects aged 20 to 30 years had a 10% decrease in 5-HT(2A) binding potential after treatment, whereas subjects aged 30 to 40 had no change. No regional differences in 5-HT(2A) binding potential between depressed and healthy subjects were found. 5-HT(2A) receptors down-regulate in young depressed subjects after treatment with paroxetine, but this down-regulation attenuates with age. This suggests that over 6 weeks paroxetine treatment increases 5-HT agonism on 5-HT(2A) receptors in the cortex of young patients with depression.


Adenosine stimulates glycogenolysis in mouse cerebral cortex: a possible coupling mechanism between neuronal activity and energy metabolism.
Adenosine promotes a concentration-dependent hydrolysis of 3H-glycogen newly synthesized from 3H-glucose by mouse cerebral cortical slices. The EC50 for this effect is 7 microM. Theophylline antagonizes the glycogenolysis induced by adenosine with an EC50 of 80 microM. The rank-order of potencies of adenosine agonists is adenosine 5'-cyclopropyl-carboxamide greater than 2-chloroadenosine much greater than N6-cyclohexyladenosine = adenosine, suggesting that adenosine promotes glycogenolysis via receptors of the A2 type. This contention is substantiated by the weak stereospecificity observed for the glycogenolytic action of D- and L-(phenylisopropyl)-adenosine. The glycogenolysis elicited by adenosine at 10 and 100 microM is inhibited by ouabain at 10 microM, a concentration of the cardiac glycoside not significantly affecting 3H-glycogen levels per se. Interestingly, the previously demonstrated glycogenolytic action of vasoactive intestinal peptide (Magistretti et al., 1981, 1984) and of norepinephrine (Quach et al., 1978) is also antagonized by ouabain. These results demonstrate the existence of a metabolic action of adenosine, which is sensitive to ouabain and appears to be mediated by A2 receptors. The concentrations at which adenosine promotes glycogenolysis are of the same order of magnitude as those reached extracellularly by the nucleoside during neuronal depolarization (Pull and McIlwain, 1972). This set of observations therefore supports the notion that adenosine plays a modulatory role in the coupling between neuronal activity and energy metabolism in the CNS.


Video game-based coordinative training improves ataxia in children with degenerative ataxia.
Degenerative ataxias in children present a rare condition where effective treatments are lacking. Intensive coordinative training based on physiotherapeutic exercises improves degenerative ataxia in adults, but such exercises have drawbacks for children, often including a lack of motivation for high-frequent physiotherapy. Recently developed whole-body controlled video game technology might present a novel treatment strategy for highly interactive and motivational coordinative training for children with degenerative ataxias. We examined the effectiveness of an 8-week coordinative training for 10 children with progressive spinocerebellar ataxia. Training was based on 3 Microsoft Xbox Kinect video games particularly suitable to exercise whole-body coordination and dynamic balance. Training was started with a laboratory-based 2-week training phase and followed by 6 weeks training in children's home environment. Rater-blinded assessments were performed 2 weeks before laboratory-based training, immediately prior to and after the laboratory-based training period, as well as after home training. These assessments allowed for an intraindividual control design, where performance changes with and without training were compared. Ataxia symptoms were significantly reduced (decrease in Scale for the Assessment and Rating of Ataxia score, p = 0.0078) and balance capacities improved (dynamic gait index, p = 0.04) after intervention. Quantitative movement analysis revealed improvements in gait (lateral sway: p = 0.01; step length variability: p = 0.01) and in goal-directed leg placement (p = 0.03). Despite progressive cerebellar degeneration, children are able to improve motor performance by intensive coordination training. Directed training of whole-body controlled video games might present a highly motivational, cost-efficient, and home-based rehabilitation strategy to train dynamic balance and interaction with dynamic environments in a large variety of young-onset neurologic conditions. This study provides Class III evidence that directed training with Xbox Kinect video games can improve several signs of ataxia in adolescents with progressive ataxia as measured by SARA score, Dynamic Gait Index, and Activity-specific Balance Confidence Scale at 8 weeks of training.


The effect of proximity on park and beach use and physical activity among rural adolescents.
Associations between access to environments and levels of physical activity (PA) among adolescents have been established; however the influence of neighborhood design barriers (eg, major roads) on these relationships is less understood. In 2006, adolescents (n = 1304) in rural Western Australia completed the Up4it Physical Activity Survey measuring frequency and duration of organized and nonorganized physical activity by season. Geographic Information Systems (GIS) were used to objectively measure distance to nearest park and beach and busy road barriers en route to these destinations. Proximity to parks and beaches was associated with use of these environments for PA among adolescents, but this relationship attenuated after adjustment for presence of a major road. Park and beach use was positively associated with achieving recommended levels of PA. Paradoxically, proximity to these environments was not associated with achieving recommended levels of PA. Results suggest access to parks and beaches is necessary but may be insufficient to achieve recommended levels of PA. These relationships varied by season. Strategies should be put in place to encourage use of proximate supportive environments. Planning neighborhoods to reduce barriers to access and interventions to overcome seasonal variations in behavior may improve participation levels among adolescents.


Analysis of the Fusarium graminearum species complex from wheat, barley and maize in South Africa provides evidence of species-specific differences in host preference.
Species identity and trichothecene toxin potential of 560 members of the Fusarium graminearum species complex (FGSC) collected from diseased wheat, barley and maize in South Africa was determined using a microsphere-based multilocus genotyping assay. Although three trichothecene types (3-ADON, 15-ADON and NIV) were represented among these isolates, strains with the 15-ADON type predominated on all three hosts. A significant difference, however, was identified in the composition of FGSC pathogens associated with Gibberella ear rot (GER) of maize as compared to Fusarium head blight (FHB) of wheat or barley (P<0.001). F. graminearum accounted for more than 85% of the FGSC isolates associated with FHB of wheat and barley (N=425), and was also the dominant species among isolates from maize roots (N=35). However, with the exception of a single isolate identified as an interspecific hybrid between Fusariumboothii and F. graminearum, GER of maize (N=100) was exclusively associated with F. boothii. The predominance of F. graminearum among FHB isolates, and the near exclusivity of F. boothii among GER isolates, was observed across all cultivars, collection dates, and provinces sampled. Because these results suggest a difference in host preference among species of the FGSC, we hypothesize that F. graminearum may be less well adapted to infect maize ears than other members of the FGSC.


Laparoscopic staging of early ovarian cancer: results of a multi-institutional cohort study.
Minimal access surgery to stage early ovarian cancer (EOC) is still regarded as investigational among many gynecologic oncologists. Reporting outcome data from large cohorts is currently the only practical way to further define the appropriateness of minimally invasive surgery for EOC patients. We sought to investigate the safety, adequacy, and outcome of laparoscopic staging of EOC by using a multi-institutional sample. Prospectively collected data in three gynecologic oncology service databases were searched for EOC patients undergoing laparoscopic staging. Surgical, pathologic, and oncologic outcome data were analyzed. The study cohort consisted of 82 women. The mean operative time was 263 ± 81 minutes. The median estimated blood loss was 100 (range 20-3000) ml. The median number of pelvic and para-aortic lymph nodes collected was 23 (3-39) and 13 (3-43), respectively. The disease was reclassified to a higher stage in 21 women (25.6%). No conversion to laparotomy occurred, and one patient had intraoperative hemorrhage requiring blood transfusion. Thirteen patients (15.8%) experienced postoperative complications. The median follow-up period was 28.5 (range 3-86) months. Overall survival and disease-free survival for the entire cohort were 98.8% and 95.1%, respectively. In the subgroup of patients who had reached or exceeded 3 years' follow-up (n = 34), 3-year overall survival and 3-year disease-free survival were 97% and 91.2%, respectively. When performed by appropriately skilled surgeons, laparoscopic comprehensive staging of EOC seems feasible and adequate, with surgicopathologic results that are reproducible in different practice settings.


The Western English Channel contains a persistent microbial seed bank.
Robust seasonal dynamics in microbial community composition have previously been observed in the English Channel L4 marine observatory. These could be explained either by seasonal changes in the taxa present at the L4 site, or by the continuous modulation of abundance of taxa within a persistent microbial community. To test these competing hypotheses, deep sequencing of 16S rRNA from one randomly selected time point to a depth of 10,729,927 reads was compared with an existing taxonomic survey data covering 6 years. When compared against the 6-year survey of 72 shallow sequenced time points, the deep sequenced time point maintained 95.4% of the combined shallow OTUs. Additionally, on average, 99.75%±0.06 (mean±s.d.) of the operational taxonomic units found in each shallow sequenced sample were also found in the single deep sequenced sample. This suggests that the vast majority of taxa identified in this ecosystem are always present, but just in different proportions that are predictable. Thus observed changes in community composition are actually variations in the relative abundance of taxa, not, as was previously believed, demonstrating extinction and recolonization of taxa in the ecosystem through time.


Searching for the physiological mechanism of density dependence: does corticosterone regulate tadpole responses to density?
Density-dependent population regulation is important in many natural populations, and in those populations, high population density is a likely stressor. In amphibians, previous laboratory studies with tadpoles suggest that corticosterone, the main glucocorticoid stress hormone, is one of the key regulators of density-dependent growth. To test this relationship in natural settings, we manipulated wood frog (Rana sylvatica) tadpole density at three levels in outdoor mesocosms and used a capture stress protocol to examine the hormonal stress response. In addition, we used the same capture protocol in six natural ponds (three high density and three low density). In the mesocosms, there was an increase in corticosterone levels in tadpoles following 1 h of confinement at weeks 1, 2, and 5. However, while tadpoles maintained at higher densities were smaller after metamorphosis, density did not alter mean levels of corticosterone obtained during confinement, and baseline levels of corticosterone did not differ between the densities. Similarly, in natural ponds, density did not correlate with baseline corticosterone or mean corticosterone levels obtained during confinement. We suggest that the physiological response to density may vary across the range of natural densities and that the role of corticosterone may be limited to periods of extreme high density, such as during pond-drying events.


Novel multi-epitope protein containing conserved epitopes from different Leishmania species as potential vaccine candidate: Integrated immunoinformatics and molecular dynamics approach.
Leishmaniosis, caused by intracellular parasites of the genus Leishmania, has become a serious public health problem around the world, and for which there are currently extensive limitations. In this work, a theoretical model was proposed for the development of a multi-epitope vaccine. The protein GP63 of the parasite was selected for epitopes prediction, due to its important biological role for the infection process and abundance. IEDB tools were used to determine epitopes B and T in Leishmania braziliensis; besides, other conserved epitopes in three species were selected. To improve immunogenicity, 50S ribosomal protein L7 / L12 (ID: P9WHE3) was used as a domain of adjuvant in the assembly process. The folding arrangement of the vaccine was obtained through homologous modeling multi-template with MODELLER v9.21, and a Ramachandran plot analysis was done. Furthermore, physicochemical properties were described with the ProtParam tool and secondary structure prediction combining GOR-IV and SOPMA tools. Finally, a molecular dynamics simulation (50 ns) was performed to establish flexibility and conformational changes. The analysis of the results indicates high conservancy in the epitopes predicted among the four species. Moreover, Ramachandran plot, physicochemical parameters, and secondary structure prediction suggest a stable conformation of the vaccine, after a minimum conformational change that was evaluated with the free energy landscape. The conformational change does not drive any substantial change for epitope exposition on the surface. The vaccine proposed could be tested experimentally to guide new approaches in the development of pan-vaccines; vaccines with regions conserved in multiple species.


The reduction of surface plasmon losses in quasi-suspended graphene.
Highly confined surface plasmons on graphene attract substantial interest as potential information carriers for highly integrated photonic data processing circuits. However, plasmon losses remain the main obstacle for implementation of such devices. In near-field microscopic experiments performed at the wavelength of 10 μm we show that a substantial reduction of plasmon damping can be achieved by placing a nanometric polymer nano-dots spacer between the graphene layer and the supporting silicon oxide slab making graphene quasi-suspended. We argue that reduction of plasmon losses is attributed to weaker coupling with substrate phonons in the quasi-suspended graphene.


Detailed analysis and follow-up studies of a high-throughput screening for indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors.
Indoleamine 2,3-dioxygenase 1 (IDO1) is a key regulator of immune responses and therefore an important therapeutic target for the treatment of diseases that involve pathological immune escape, such as cancer. Here, we describe a robust and sensitive high-throughput screen (HTS) for IDO1 inhibitors using the Prestwick Chemical Library of 1200 FDA-approved drugs and the Maybridge HitFinder Collection of 14,000 small molecules. Of the 60 hits selected for follow-up studies, 14 displayed IC50 values below 20 μM under the secondary assay conditions, and 4 showed an activity in cellular tests. In view of the high attrition rate we used both experimental and computational techniques to identify and to characterize compounds inhibiting IDO1 through unspecific inhibition mechanisms such as chemical reactivity, redox cycling, or aggregation. One specific IDO1 inhibitor scaffold, the imidazole antifungal agents, was chosen for rational structure-based lead optimization, which led to more soluble and smaller compounds with micromolar activity.


Diagnostic accuracy of a LAMP kit for diagnosis of imported malaria in Switzerland.
The diagnosis of acute malaria in non-endemic countries is still carried out largely by microscopic examination of thick and thin smears or rapid diagnostic tests. Low-density infections might be missed, however, but the more sensitive PCR is more expensive, complex and requires considerable more time. We examined the suitability of a new loop-mediated isothermal DNA-amplification kit (LAMP) for malaria diagnosis in febrile returning travellers in comparison to qPCR and microscopic examination in a prospective study in a non-endemic setting at the Swiss TPH. Among 205 complete datasets, 43 samples were positive for malaria by microscopy, with Plasmodium falciparum (35 cases) being the most frequent species. All these samples were positive by both LAMP and qPCR, too. An additional 4 samples negative by microscopy were positive by both LAMP and qPCR. Three of these samples were follow-up samples taken after start of treatment in patients originally identified as positive by microscopy. The LAMP performed exactly as did the qPCR and is a very valuable diagnostic alternative with a potential of being used also in endemic settings.


Time trends for risk of severe age-related diseases in individuals with and without HIV infection in Denmark: a nationwide population-based cohort study.
Whether the reported high risk of age-related diseases in HIV-infected people is caused by biological ageing or HIV-associated risk factors such as chronic immune activation and low-grade inflammation is unknown. We assessed time trends in age-standardised and relative risks of nine serious age-related diseases in a nationwide cohort study of HIV-infected individuals and population controls. We identified all HIV-infected individuals in the Danish HIV Cohort Study who had received HIV care in Denmark between Jan 1, 1995, and June 1, 2014. Population controls were identified from the Danish Civil Registration System and individually matched in a ratio of nine to one to the HIV-infected individuals for year of birth, sex, and date of study inclusion. Individuals were included in the study if they had a Danish personal identification number, were aged 16 years or older, and were living in Denmark at the time of study inclusion. Data for study outcomes were obtained from the Danish National Hospital Registry and the Danish National Registry of Causes of Death and were cardiovascular diseases (myocardial infarction and stroke), cancers (virus associated, smoking related, and other), severe neurocognitive disease, chronic kidney disease, chronic liver disease, and osteoporotic fractures. We calculated excess and age-standardised incidence rates and adjusted incidence rate ratios of outcomes for time after HIV diagnosis, highly active antiretroviral therapy (ART) initiation, and calendar time. The regression analyses were adjusted for age, sex, calendar time, and origin. We identified 5897 HIV-infected individuals and 53,073 population controls; median age was 36·8 years (IQR 30·6-44·4), and 76% were men in both cohorts. Dependent on disease, the HIV cohort had 55,050-57,631 person-years of follow-up and the population controls had 638,204-659,237 person-years of follow-up. Compared with the population controls, people with HIV had high excess and relative risk of all age-related diseases except other cancers. Overall, the age-standardised and relative risks of cardiovascular diseases, cancers, and severe neurocognitive disease did not increase substantially with time after HIV diagnosis or ART initiation. Except for chronic kidney diseases, the age-standardised and relative risks of age-related diseases did not increase with calendar time. Severe age-related diseases are highly prevalent in people with HIV, and continued attention and strategies for risk reduction are needed. The findings from our study do not suggest that accelerated ageing is a major problem in the HIV-infected population. Preben og Anna Simonsens Fond, Novo Nordisk Foundation, Danish AIDS Foundation, Augustinus Foundation, and Odense University Hospitals Frie Fonds Midler.