Gene Expression Profiles of Two Coral Species with Varied Resistance to Ocean Acidification.
Recent studies have indicated that various corals might have different degrees of resistance to elevated CO2 levels. However, the underlying molecular mechanism accounting for these differences is still poorly understood. In this study, RNA-seq data were analyzed to identify differentially expressed genes in two coral species (Acropora austera and Acropora cerealis) in response to high CO2 levels. The calcification rates were higher in high CO2 treatment than the control in A. austera, but was not significantly different in A. cerealis. A KEGG database search revealed that in both coral species, most Ca2+ transporters were present in the calcium signaling pathway, which could be important in the CO2 regulation of coral calcification. The gene expression levels of many CO2 and HCO3- transporters were not affected by elevated CO2. Nevertheless, high CO2 levels did have an effect on the expression of certain Ca2+ transporters. The upregulation of Ca2+ transporters likely explained the higher resistance of A. austera to high CO2 than A. cerealis.


Effects of Hypercapnia and Hypercapnic Acidosis on Hospital Mortality in Mechanically Ventilated Patients.
Lung-protective ventilation is used to prevent further lung injury in patients on invasive mechanical ventilation. However, lung-protective ventilation can cause hypercapnia and hypercapnic acidosis. There are no large clinical studies evaluating the effects of hypercapnia and hypercapnic acidosis in patients requiring mechanical ventilation. Multicenter, binational, retrospective study aimed to assess the impact of compensated hypercapnia and hypercapnic acidosis in patients receiving mechanical ventilation. Data were extracted from the Australian and New Zealand Intensive Care Society Centre for Outcome and Resource Evaluation Adult Patient Database over a 14-year period where 171 ICUs contributed deidentified data. Patients were classified into three groups based on a combination of pH and carbon dioxide levels (normocapnia and normal pH, compensated hypercapnia [normal pH with elevated carbon dioxide], and hypercapnic acidosis) during the first 24 hours of ICU stay. Logistic regression analysis was used to identify the independent association of hypercapnia and hypercapnic acidosis with hospital mortality. Nil. A total of 252,812 patients (normocapnia and normal pH, 110,104; compensated hypercapnia, 20,463; and hypercapnic acidosis, 122,245) were included in analysis. Patients with compensated hypercapnia and hypercapnic acidosis had higher Acute Physiology and Chronic Health Evaluation III scores (49.2 vs 53.2 vs 68.6; p < 0.01). The mortality was higher in hypercapnic acidosis patients when compared with other groups, with the lowest mortality in patients with normocapnia and normal pH. After adjusting for severity of illness, the adjusted odds ratio for hospital mortality was higher in hypercapnic acidosis patients (odds ratio, 1.74; 95% CI, 1.62-1.88) and compensated hypercapnia (odds ratio, 1.18; 95% CI, 1.10-1.26) when compared with patients with normocapnia and normal pH (p < 0.001). In patients with hypercapnic acidosis, the mortality increased with increasing PCO2 until 65 mm Hg after which the mortality plateaued. Hypercapnic acidosis during the first 24 hours of intensive care admission is more strongly associated with increased hospital mortality than compensated hypercapnia or normocapnia.


Using scalar models for precautionary assessments of threatened species.
Scalar population models, commonly referred to as count-based models, are based on time-series data of population sizes and may be useful for screening-level ecological risk assessments when data for more complex models are not available. Appropriate use of such models for management purposes, however, requires understanding inherent biases that may exist in these models. Through a series of simulations, which compared predictions of risk of decline of scalar and matrix-based models, we examined whether discrepancies may arise from different dynamics displayed due to age structure and generation time. We also examined scalar and matrix-based population models of 18 real populations for potential patterns of bias in population viability estimates. In the simulation study, precautionary bias (i.e., overestimating risks of decline) of scalar models increased as a function of generation time. Models of real populations showed poor fit between scalar and matrix-based models, with scalar models predicting significantly higher risks of decline on average. The strength of this bias was not correlated with generation time, suggesting that additional sources of bias may be masking this relationship. Scalar models can be useful for screening-level assessments, which should in general be precautionary, but the potential shortfalls of these models should be considered before using them as a basis for management decisions.


Characterization of the Viable but Nonculturable (VBNC) State in Saccharomyces cerevisiae.
The Viable But Non Culturable (VBNC) state has been thoroughly studied in bacteria. In contrast, it has received much less attention in other microorganisms. However, it has been suggested that various yeast species occurring in wine may enter in VBNC following sulfite stress.In order to provide conclusive evidences for the existence of a VBNC state in yeast, the ability of Saccharomyces cerevisiae to enter into a VBNC state by applying sulfite stress was investigated. Viable populations were monitored by flow cytometry while culturable populations were followed by plating on culture medium. Twenty-four hours after the application of the stress, the comparison between the culturable population and the viable population demonstrated the presence of viable cells that were non culturable. In addition, removal of the stress by increasing the pH of the medium at different time intervals into the VBNC state allowed the VBNC S. cerevisiae cells to "resuscitate". The similarity between the cell cycle profiles of VBNC cells and cells exiting the VBNC state together with the generation rate of cells exiting VBNC state demonstrated the absence of cellular multiplication during the exit from the VBNC state. This provides evidence of a true VBNC state. To get further insight into the molecular mechanism pertaining to the VBNC state, we studied the involvement of the SSU1 gene, encoding a sulfite pump in S. cerevisiae. The physiological behavior of wild-type S. cerevisiae was compared to those of a recombinant strain overexpressing SSU1 and null Δssu1 mutant. Our results demonstrated that the SSU1 gene is only implicated in the first stages of sulfite resistance but not per se in the VBNC phenotype. Our study clearly demonstrated the existence of an SO2-induced VBNC state in S. cerevisiae and that the stress removal allows the "resuscitation" of VBNC cells during the VBNC state.


Tissue Specific Labeling in Proteomics.
Mass spectrometry-based proteomics is a powerful tool for identifying and quantifying proteins in biological samples. While it is routinely used for the characterization of simple cell line systems, the analysis of the cell specific proteome in multicellular organisms and tissues poses a significant challenge. Isolating a subset of cells from tissues requires mechanical and biochemical separation or sorting, a process which can alter cellular signaling, and thus, the composition of the proteome. Recently, several approaches for cell selective labeling of proteins, that include bioorthogonal amino acids, biotinylating enzymes, and genetic tools, have been developed. These tools facilitate the selective labeling of proteins, their interactome, or of specific cell types within a tissue or an organism, while avoiding the difficult and contamination-prone biochemical separation of cells from the tissue. In this review, we give an overview of existing techniques and their application in cell culture models and whole animals.


Pseudomonas urumqiensis sp. nov., isolated from rhizosphere soil of Alhagi sparsifolia.
A motile, Gram-stain-negative, fusiform-shaped bacterium, designated strain T3T, was isolated from rhizosphere soil of Alhagi sparsifolia, collected from Xinjiang, PR China. Strain T3T grew at 15-42 °C, pH 4-9 and 1-6 % (w/v) NaCl concentrations. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain T3T belonged to the genus Pseudomonas and showed highest similarity of 98.6 % to Pseudomonas azotifigens JCM 12708T, followed by Pseudomonas balearica DSM 6083T (97.8 %), Pseudomonas matsuisoli JCM 30078T (97.7 %), Pseudomonas furukawaii KF707T (97.7 %), Pseudomonas tarimensis CCTCC AB 2013065T (97.3 %) and Pseudomonas indica DSM 14015T (97.1 %). Analysis based on concatenated gene sequences of 16S rRNA, rpoB and gyrB further confirmed the phylogenetic assignment of strain T3T. The Genome-to-Genome Distance Calculator results for P. azotifigens JCM12708T and P. balearica DSM 6083T were 28.7±4.4% and 24.1±2.4 %, and the average nucleotide identity scores were 81.3 and 78.1 %. The major polar lipids of strain T3T were diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol. The predominant quinone was Q-9. The major fatty acids comprised summed feature 8 (C18 : 1ω6c/C18 : 1ω7c; 37.7 %), summed feature 3 (C16 : 1ω6c/C16 : 1ω7c; 28.2 %), C16 : 0 (15.6 %), C12 : 0 (7.8 %), C10 : 03-OH (3.0 %) and C12 : 03-OH (2.6 %). The G+C content of the genomic DNA of the type strain was 65.3 mol%. It is obvious from the phylogenetic, phenotypic and chemotaxonomic data that strain T3T represents a novel species of the genus Pseudomonas, for which the name Pseudomonasurumqiensis sp. nov., is proposed. The type strain is T3T (=ACCC 60124T=JCM 32830T).


A protocol for a discrete choice experiment: understanding patient medicine preferences for managing chronic non-cancer pain.
High rates of chronic non-cancer pain (CNCP), concerns about adverse effects including dependence among those prescribed potent pain medicines, the recent evidence supporting active rather than passive management strategies and a lack of funding for holistic programme have resulted in challenges around decision making for treatment among clinicians and their patients. Discrete choice experiments (DCEs) are one way of assessing and valuing treatment preferences. Here, we outline a protocol for a study that assesses patient preferences for CNCP treatment. A final list of attributes (and their levels) for the DCE was generated using a detailed iterative process. This included a literature review, a focus group and individual interviews with those with CNCP and clinicians who treat people with CNCP. From this process a list of attributes was obtained. Following a review by study investigators including pain and addiction specialists, pharmacists and epidemiologists, the final list of attributes was selected (number of medications, risk of addiction, side effects, pain interference, activity goals, source of information on pain, provider of pain care and out-of-pocket costs). Specialised software was used to construct an experimental design for the survey. The survey will be administered to two groups of participants, those from a longitudinal cohort of patients receiving opioids for CNCP and a convenience sample of patients recruited through Australia's leading pain advocacy body (Painaustralia) and their social media and website. The data from the two participant groups will be initially analysed separately, as their demographic and clinical characteristics may differ substantially (in terms of age, duration of pain and current treatment modality). Mixed logit and latent class analysis will be used to explore heterogeneity of responses. Ethics approval was obtained from the University of New South Wales Sydney Human Ethics committee HC16511 (for the focus group discussions, the one-on-one interviews and online survey) and HC16916 (for the cohort). A lay summary will be made available on the National Drug and Alcohol Research Centre website and Painaustralia's website. Peer review papers will be submitted, and it is expected the results will be presented at relevant pain management conferences nationally and internationally. These results will also be used to improve understanding of treatment goals between clinicians and those with CNCP.


Macrophage models of Gaucher disease for evaluating disease pathogenesis and candidate drugs.
Gaucher disease is caused by an inherited deficiency of glucocerebrosidase that manifests with storage of glycolipids in lysosomes, particularly in macrophages. Available cell lines modeling Gaucher disease do not demonstrate lysosomal storage of glycolipids; therefore, we set out to develop two macrophage models of Gaucher disease that exhibit appropriate substrate accumulation. We used these cellular models both to investigate altered macrophage biology in Gaucher disease and to evaluate candidate drugs for its treatment. We generated and characterized monocyte-derived macrophages from 20 patients carrying different Gaucher disease mutations. In addition, we created induced pluripotent stem cell (iPSC)-derived macrophages from five fibroblast lines taken from patients with type 1 or type 2 Gaucher disease. Macrophages derived from patient monocytes or iPSCs showed reduced glucocerebrosidase activity and increased storage of glucocerebroside and glucosylsphingosine in lysosomes. These macrophages showed efficient phagocytosis of bacteria but reduced production of intracellular reactive oxygen species and impaired chemotaxis. The disease phenotype was reversed with a noninhibitory small-molecule chaperone drug that enhanced glucocerebrosidase activity in the macrophages, reduced glycolipid storage, and normalized chemotaxis and production of reactive oxygen species. Macrophages differentiated from patient monocytes or patient-derived iPSCs provide cellular models that can be used to investigate disease pathogenesis and facilitate drug development.


A longitudinal study of the effect of an interprofessional education curriculum on student satisfaction and attitudes towards interprofessional teamwork and education.
There has been limited research on the effect of interprofessional education (IPE) over time on the attitudes of undergraduate health and human service professional students. Previous research in this area has suggested that students from different professions report differing attitudes towards IPE and interprofessional teamwork, and such attitudes may also be influenced by other background characteristics of the students themselves (e.g., gender, age). The purpose of this study was to evaluate the longitudinal effect of the introduction of an IPE curriculum on students' attitudes towards IPE and teamwork. A time series study design was conducted to assess the attitudes of undergraduate health and human service professional students towards IPE and teamwork, and students were also asked to complete satisfaction surveys after IPE curriculum activities. Significant differences in the attitudes of students from different professions and their satisfaction with participation in IPE were reported over the duration of the study. Overall, student satisfaction with IPE participation was relatively positive; however the introduction of IPE curriculum during their undergraduate education did not appear to have a significant longitudinal effect on attitudes towards IPE or interprofessional teamwork. The findings have implications for the design and integration of IPE curriculum within existing uni-professional curriculum.


Formulation and characterization of ethylcellulose microparticles containing .L-alanyl- L-glutamine peptide.
The L-alanyl-L-glutamine peptide (AGP) has been effective to promote acute glycemia recovery during long-term insulin-induced hypoglycemia (IIH), and the oral administration of AGP is suggested to prevent prolonged hypoglycemia, such as nocturnal hypoglycemia. Considering the ability of AGP on glycemia recovery and AGP's fast metabolism, the aim of current study was to obtain and characterize ethylcellulose microparticles to deliver the drug for a prolonged time. Microparticles were prepared by simple and double emulsification/hardening method and characterized by scanning electron microscopy, thermogravimetry (TG), differential scanning calorimetry (DSC), Fourier transform infra-red (FTIR) and FT-Raman spectroscopy and in vitro release. Spherical structures with a mean diameter between 9.30 µm and 13.19 µm were formed. TG analysis showed that the thermal stability of AGP was even more increased by encapsulation with ethylcellulose. In addition, TG, DSC, FTIR and FT-Raman analyses proved that AGP was encapsulated in a molecular way. Higher values of encapsulation efficiency were observed for the microparticles prepared by double emulsification (57.83-83.67%) than for those prepared by simple emulsification (18.37%). However, the last ones could release the peptide in a quicker and more extensive manner than those prepared by double emulsification. For the first time, microparticles containing AGP were developed and exhibited prolonged in vitro release as well as protection to the drug, and it could be considered as a dosage form for patients who suffer from insulin-induced hypoglycemia and/or nocturnal hypoglycemia.


Transpecific microsatellites for hard pines.
Microsatellites are difficult to recover from large plant genomes so cross-specific utilisation is an important source of markers. Fifty microsatellites were tested for cross-specific amplification and polymorphism to two New World hard pine species, slash pine ( Pinus elliottii var. elliottii) and Caribbean pine ( P. caribaea var. hondurensis). Twenty-nine (58%) markers amplified in both hard pine species, and 23 of these 29 were polymorphic. Soft pine (subgenus Strobus) microsatellite markers did amplify, but none were polymorphic. Pinus elliottii var. elliottii and P. caribaea var. hondurensis showed mutational changes in the flanking regions and the repeat motif that were informative for Pinus spp. phylogenetic relationships. Most allele length variation could be attributed to variability in repeat unit number. There was no evidence for ascertainment bias.


The effect of Agaricus brasiliensis extract supplementation on honey bee colonies.
This study was done to discover any beneficial effect of a medicinal mushroom Agaricus brasiliensis extract on the honey bee. Firstly, a laboratory experiment was conducted on 640 bees reared in 32 single-use plastic rearing cups. A. brasiliensis extract proved safe in all doses tested (50, 100 and 150 mg/kg/day) irrespective of feeding mode (sugar syrup or candy). Secondly, a three-year field experiment was conducted on 26 colonies treated with a single dose of A. brasiliensis extract (100 mg/kg/day) added to syrup. Each year the colonies were treated once in autumn and twice in spring. The treatments significantly increased colony strength parameters: brood rearing improvement and adult population growth were noticed more often than the increase in honey production and pollen reserves. These positive effects were mainly observed in April. In conclusion, A. brasiliensis extract is safe for the bees and helps maintaining strong colonies, especially in spring.


Spatio-temporal nonrigid registration for ultrasound cardiac motion estimation.
We propose a new spatio-temporal elastic registration algorithm for motion reconstruction from a series of images. The specific application is to estimate displacement fields from two-dimensional ultrasound sequences of the heart. The basic idea is to find a spatio-temporal deformation field that effectively compensates for the motion by minimizing a difference with respect to a reference frame. The key feature of our method is the use of a semi-local spatio-temporal parametric model for the deformation using splines, and the reformulation of the registration task as a global optimization problem. The scale of the spline model controls the smoothness of the displacement field. Our algorithm uses a multiresolution optimization strategy to obtain a higher speed and robustness. We evaluated the accuracy of our algorithm using a synthetic sequence generated with an ultrasound simulation package, together with a realistic cardiac motion model. We compared our new global multiframe approach with a previous method based on pairwise registration of consecutive frames to demonstrate the benefits of introducing temporal consistency. Finally, we applied the algorithm to the regional analysis of the left ventricle. Displacement and strain parameters were evaluated showing significant differences between the normal and pathological segments, thereby illustrating the clinical applicability of our method.


Intra-articular knee temperature changes: ice versus cryotherapy device.
Cryotherapy is commonly applied without research documenting the intra-articular (IA) temperature changes or subject discomfort between ice and a cryotherapy device. The null hypothesis is that no difference would be observed in IA temperature decline or subject tolerance between ice and the cryotherapy device in normal knees. Prospective, within-subject controlled clinical trial. Twelve subjects had IA temperature in suprapatellar pouch and skin recorded bilaterally after application of cryotherapy versus ice. Subject tolerance was recorded by 10-cm visual analog scale (VAS). Statistical evaluation was by Spearman's correlation analysis and paired, nonparametric Wilcoxon's signed rank test. Both significantly lowered (P < 0.001) skin and IA temperature with median decreases (ice/cryotherapy) at 30 (3.3 degrees C/2.2 degrees C), 60 (12.8 degrees C/7.1 degrees C), and 90 (15.2 degrees C/9.7 degrees C) minutes. However, ice lowered the IA temperature significantly more than the cryotherapy device (P < 0.001) and was more painful by VAS at 30 and 60 minutes (P < 0.01). Both methods produced large declines in skin and IA temperatures. However, ice was more effective yet resulted in higher pain scores. The authors hypothesize that IA temperatures below a threshold are associated with increased perceived pain.


Are leaders still presumed white by default? Racial bias in leader categorization revisited.
In the United States, leaders of the highest valued companies, best-ranked universities, and most-consumed media outlets are more likely to be White than what would be expected based on White people's representation in the U.S. population. One explanation for this racial gap is that U.S. respondents' prototype of a leader is White by default-which is, in turn, what causes White (vs. non-White) people to be promoted up the organizational ladder more quickly. Although this explanation has empirical support, its central premise was recently challenged by experimental evidence documenting that U.S. respondents no longer associate leaders, more than nonleaders, with being White. To reconcile these contradictory findings, we conducted three preregistered experiments (N = 1,316) on the topic of whether leaders, more than nonleaders, continue to be associated with Whiteness (i.e., being categorized as White or being represented with stereotypically White qualities). Results suggest that associations between leaders and Whiteness hold up to scrutiny, but that detecting them may depend on what methods researchers employ. In particular, when researchers use direct methods of detecting racial assumptions (e.g., self-report measures), there appears to be no evidence of an association between leaders and Whiteness (Experiment 1). Yet, when researchers use more indirect methods of detecting racial assumptions (e.g., a Princeton trilogy task), an association between leaders and Whiteness readily emerges (Experiments 2 and 3). In short, although respondents refrain from freely expressing associations they may harbor between leaders and Whiteness, these associations do not appear to have dissipated with time. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


From sea to sea: Canada's three oceans of biodiversity.
Evaluating and understanding biodiversity in marine ecosystems are both necessary and challenging for conservation. This paper compiles and summarizes current knowledge of the diversity of marine taxa in Canada's three oceans while recognizing that this compilation is incomplete and will change in the future. That Canada has the longest coastline in the world and incorporates distinctly different biogeographic provinces and ecoregions (e.g., temperate through ice-covered areas) constrains this analysis. The taxonomic groups presented here include microbes, phytoplankton, macroalgae, zooplankton, benthic infauna, fishes, and marine mammals. The minimum number of species or taxa compiled here is 15,988 for the three Canadian oceans. However, this number clearly underestimates in several ways the total number of taxa present. First, there are significant gaps in the published literature. Second, the diversity of many habitats has not been compiled for all taxonomic groups (e.g., intertidal rocky shores, deep sea), and data compilations are based on short-term, directed research programs or longer-term monitoring activities with limited spatial resolution. Third, the biodiversity of large organisms is well known, but this is not true of smaller organisms. Finally, the greatest constraint on this summary is the willingness and capacity of those who collected the data to make it available to those interested in biodiversity meta-analyses. Confirmation of identities and intercomparison of studies are also constrained by the disturbing rate of decline in the number of taxonomists and systematists specializing on marine taxa in Canada. This decline is mostly the result of retirements of current specialists and to a lack of training and employment opportunities for new ones. Considering the difficulties encountered in compiling an overview of biogeographic data and the diversity of species or taxa in Canada's three oceans, this synthesis is intended to serve as a biodiversity baseline for a new program on marine biodiversity, the Canadian Healthy Ocean Network. A major effort needs to be undertaken to establish a complete baseline of Canadian marine biodiversity of all taxonomic groups, especially if we are to understand and conserve this part of Canada's natural heritage.


Spiral valve parasites of blue and common thresher sharks as indicators of shark feeding behaviour and ecology.
This study documented the parasite faunas of the spiral valves of blue sharks Prionace glauca (L. 1758) and common thresher sharks Alopias vulpinus (Bonnaterre, 1788) caught in the California Current Large Marine Ecosystem (CCLME) north of the Mexican border. The spiral valves of 18 blue and 19 thresher sharks caught in the CCLME from 2009 to 2013 were examined for parasites. Seven parasite taxa were found in blue sharks and nine in threshers. The tetraphyllidean cestode Anthobothrium sp. (78% prevalence) was the most common parasite in blue sharks, and the phyllobothriid cestode Paraorygmatobothrium sp. (90% prevalence) was the most common in threshers. An adult nematode of the genus Piscicapillaria was found in threshers for the first time and may be a new species. Adult individuals of Hysterothylacium sp. were found in both shark species. The adult acanthocephalan Rhadinorhynchus cololabis and remains of the parasitic copepod Pennella sp. - both parasites of Pacific saury, Cololabis saira - were found in the intestines of threshers, indicating recent feeding on saury. This study paves the way for a more comprehensive examination, including more samples and a wider variety of shark species, to provide a greater understanding of shark feeding behaviour and possibly provide information on shark population biology.


Seasonal Variation in Vitamin D Status among Frail Older Hospitalized Patients.
Seasonal variation in 25-hydroxyvitamin D [25(OH)D] levels is the result of sunlight dependent skin synthesis of vitamin D. However, its presence is not studied in frail older hospitalized patients. We sought to investigate whether seasonal variation in 25(OH)D levels is evident among these patients. This study investigated older participants who were consecutively admitted between February 2015 and December 2016 to the geriatric acute care ward. Results of routine measurements of 25(OH)D at hospital admission were retrospectively analyzed and stratified according to months and seasons. Previous intake of vitamin D supplementation was derived from the patients' medical records. The study group comprised 679 participants (mean age 82.1±8.2; 457 females), of which 78% had vitamin D deficiency. Older individuals not taking vitamin D supplements had a lower mean serum 25(OH)D than those receiving supplements. Of those patients with no vitamin D supplementation, 87.0% were vitamin D deficient and only 5% showing sufficient vitamin 25(OH)D. Further, there were neither monthly nor seasonal variations in vitamin 25(OH)D levels among these patients and their vitamin D levels stayed far below the recommended threshold of 20 ng/ml across the seasons. Vitamin D deficiency was very prevalent in the subgroup of older hospitalized patients without vitamin D supplementation, irrespective of season. Since no seasonal variations in mean 25(OH)D levels was observed, sunlight dependent skin synthesis is unlikely to contribute to vitamin D status in these patients. Supplementation seems to be necessary to maintain desirable vitamin D levels among this population throughout the year.


Treatment-associated polymorphisms in protease are significantly associated with higher viral load and lower CD4 count in newly diagnosed drug-naive HIV-1 infected patients.
The effect of drug resistance transmission on disease progression in the newly infected patient is not well understood. Major drug resistance mutations severely impair viral fitness in a drug free environment, and therefore are expected to revert quickly. Compensatory mutations, often already polymorphic in wild-type viruses, do not tend to revert after transmission. While compensatory mutations increase fitness during treatment, their presence may also modulate viral fitness and virulence in absence of therapy and major resistance mutations. We previously designed a modeling technique that quantifies genotypic footprints of in vivo treatment selective pressure, including both drug resistance mutations and polymorphic compensatory mutations, through the quantitative description of a fitness landscape from virus genetic sequences. Genotypic correlates of viral load and CD4 cell count were evaluated in subtype B sequences from recently diagnosed treatment-naive patients enrolled in the SPREAD programme. The association of surveillance drug resistance mutations, reported compensatory mutations and fitness estimated from drug selective pressure fitness landscapes with baseline viral load and CD4 cell count was evaluated using regression techniques. Protease genotypic variability estimated to increase fitness during treatment was associated with higher viral load and lower CD4 cell counts also in treatment-naive patients, which could primarily be attributed to well-known compensatory mutations at highly polymorphic positions. By contrast, treatment-related mutations in reverse transcriptase could not explain viral load or CD4 cell count variability. These results suggest that polymorphic compensatory mutations in protease, reported to be selected during treatment, may improve the replicative capacity of HIV-1 even in absence of drug selective pressure or major resistance mutations. The presence of this polymorphic variation may either reflect a history of drug selective pressure, i.e. transmission from a treated patient, or merely be a result of diversity in wild-type virus. Our findings suggest that transmitted drug resistance has the potential to contribute to faster disease progression in the newly infected host and to shape the HIV-1 epidemic at a population level.


Lactobacillus rhamnosus GG Attenuates Lipopolysaccharide-Induced Inflammation and Barrier Dysfunction by Regulating MAPK/NF-κB Signaling and Modulating Metabolome in the Piglet Intestine.
Probiotic Lactobacillius rhamnosus GG (LGG) shows beneficial immunomodulation on cultured cell lines in vitro and in mouse models. The aim was to investigate the effects of LGG on intestinal injury and the underlying mechanisms by elucidating inflammatory signaling pathways and metabolomic response to LPS stimulation in the piglet intestine. Piglets (Duroc × Landrace × Large White, including males and female; 8.6 ± 1.1 kg) aged 28 d were assigned to 3 groups (n = 6/group): oral inoculation with PBS for 2 wk before intraperitoneal injection of physiological saline [control (CON)] or LPS (25 μg/kg body weight; LPS) or oral inoculation with LGG for 2 wk before intraperitoneal injection of LPS (LGG+LPS). Piglets were killed 4 h after LPS injection. Systemic inflammation, intestinal integrity, inflammation signals, and metabolomic characteristics in the intestine were determined. Compared with CON, LPS stimulation significantly decreased ileal zonula occludens 1 (ZO-1; 44%), claudin-3 (44%), and occludin (41%) expression; increased serum diamineoxidase (73%), D-xylose (19%), TNF-α (43%), and IL-6 (55%) concentrations; induced p38 mitogen-activated protein kinase (p38 MAPK; 85%), extracellular signal-regulated kinase (ERK; 96%), and NF-κB p65 phosphorylation (37%) (P < 0.05). Compared with LPS stimulation alone, LGG pretreatment significantly enhanced the intestinal barrier by upregulating expressions of tight junction proteins (ZO-1, 73%; claudin-3, 55%; occludin, 67%), thereby decreasing serum diamineoxidase (26%) and D-xylose (28%) concentrations, and also reduced serum TNF-α expression (16%) and ileal p38 MAPK (79%), ERK (43%) and NF-κB p65 (37%) phosphorylation levels (P < 0.05). Metabolomic analysis showed clear separation between each group. The concentrations of caprylic acid [fold-change (FC) = 2.39], 1-mono-olein (FC = 2.68), erythritol (FC = 4.62), and ethanolamine (FC = 4.47) significantly increased in the intestine of LGG + LPS piglets compared with the LPS group (P < 0.05). These data suggest that LGG alleviates gut inflammation, improves intestinal barrier function, and modulates the metabolite profile of piglets challenged with LPS. This trial was registered at the Zhejiang University (http://www.lac.zju.edu.cn) as ZJU20170529.


Early diagnosis and management of dementia in general practice - how do Swiss GPs meet the challenge?
In general practice, the diagnosis of dementia is often delayed. Therefore, the Swiss National Dementia Strategy 2014 concluded that action was needed to improve patient care. Little is known about GPs' confidence in and approach to the diagnosis, disclosure and post-diagnostic management of individuals with dementia in Switzerland. The aim of this survey is to assess these elements of dementia care and GPs' views on the adequacy of health care services regarding dementia. Cross-sectional postal survey in Switzerland in 2017 supported by all academic institutes of general practice in Swiss universities. Members of the Swiss Association of General Practitioners (n = 4460) were asked to participate in the survey. In addition to the GPs' demographic characteristics, the survey addressed the following issues: GPs' views on the adequacy of health care services, clinical approach and confidence in the management of dementia. The survey response rate was 21%. The majority of GPs (64%) felt confident diagnosing dementia, but not in patients with a migration background (15%). For neuropsychological testing, three-quarters of GPs collaborated with memory clinics and were satisfied with the access to diagnostic services. At the time of first diagnosis, 62% of GPs diagnosed the majority of their patients with a mild stage of dementia, and 31% with a mild cognitive impairment. The most frequent actions taken by GPs after the diagnosis of mild dementia were giving advice to relatives (71%), testing fitness-to-drive (66%) and minimising cardiovascular risk factors (63%). While 65% of GPs felt confident taking care of patients with dementia, fewer (53%) felt confident in pharmacological treatment, coping with suicidal ideation (44%) or caring for patients with a migration background (16%). Half of GPs preferred to delegate the assessment of fitness-to-drive to an official authority. One in four GPs was not satisfied with the local provision of care and support facilities for patients with dementia. Overall, GPs reported confidence in establishing a diagnosis of dementia and sufficient access to diagnostic services. Post-diagnostic management primarily focused on counselling and harm reduction rather than pharmacological treatment. Future educational support for GPs should be developed, concentrating on coping with their patients' suicidal ideation and caring for patients with a migration background.


The use of ground-borne vibrations for prey localization in the Saharan sand vipers (Cerastes).
Sand vipers of the genus Cerastes are specialized semi-fossorial snakes that launch predatory strikes at rodents and lizards while partially buried in the soft sand of the Saharan desert. This study attempted to document which environmental stimuli are used by these snakes as a trigger for the ambush behavior. Denervating the olfactory and vomeronasal organs produced no changes in prey capture behavior in Cerastes cerastes. Occluding the eyes of the denervated specimens resulted in significant decreases in strike distance, diversity of strike angle and strike accuracy, demonstrating the importance of visual stimuli for target acquisition in this species. Nevertheless, every olfactory-denervated, temporarily blinded specimen succeeded in capturing free-ranging mice in every trial. Presentation of chemosensory-neutral targets to the olfactory-denervated, temporarily blinded specimens resulted in similar predatory behaviors, whether the target was isothermic to the environment or heated to mammalian body temperature. Collectively, these results provide evidence for the importance of visual stimuli during foraging in C. cerastes, the first experimental evidence for foraging by vibration detection in snakes and the strongest evidence to date that snakes are capable of 'hearing' vibrational stimuli.


Genomic Analysis of Genotype-by-Social Environment Interaction for Drosophila melanogaster Aggressive Behavior.
Human psychiatric disorders such as schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder often include adverse behaviors including increased aggressiveness. Individuals with psychiatric disorders often exhibit social withdrawal, which can further increase the probability of conducting a violent act. Here, we used the inbred, sequenced lines of the Drosophila Genetic Reference Panel (DGRP) to investigate the genetic basis of variation in male aggressive behavior for flies reared in a socialized and socially isolated environment. We identified genetic variation for aggressive behavior, as well as significant genotype-by-social environmental interaction (GSEI); i.e., variation among DGRP genotypes in the degree to which social isolation affected aggression. We performed genome-wide association (GWA) analyses to identify genetic variants associated with aggression within each environment. We used genomic prediction to partition genetic variants into gene ontology (GO) terms and constituent genes, and identified GO terms and genes with high prediction accuracies in both social environments and for GSEI. The top predictive GO terms significantly increased the proportion of variance explained, compared to prediction models based on all segregating variants. We performed genomic prediction across environments, and identified genes in common between the social environments that turned out to be enriched for genome-wide associated variants. A large proportion of the associated genes have previously been associated with aggressive behavior in Drosophila and mice. Further, many of these genes have human orthologs that have been associated with neurological disorders, indicating partially shared genetic mechanisms underlying aggression in animal models and human psychiatric disorders.


Distal tibial transphyseal osteotomy for ankle varus deformity in an operated case of clubfoot.
Ankle varus deformity arises due to a number of congenital and acquired causes leading to significant functional debility in the patients, especially children. We report a less commonly used technique, the transphyseal osteotomy of distal tibia, for the correction of varus deformity of the ankle joint in a thirteen-year-old boy. Full correction of the deformity could be achieved using this technique. The patient is fully functional with normal gait. No recurrence was detected at follow-up visit 26 months later.


Treatment of graves' disease with antithyroid drugs in the first trimester of pregnancy and the prevalence of congenital malformation.
Several reports have suggested that propylthiouracil (PTU) may be safer than methimazole (MMI) for treating thyrotoxicosis during pregnancy because congenital malformations have been associated with the use of MMI during pregnancy. We investigated whether in utero exposure to antithyroid drugs resulted in a higher rate of major malformations than among the infants born to a control group of pregnant women. We reviewed the cases of women with Graves' disease who became pregnant. The pregnancy outcomes of 6744 women were known, and there were 5967 live births. MMI alone had been used to treat 1426 of the women, and 1578 women had been treated with PTU alone. The 2065 women who had received no medication for the treatment of Graves' disease during the first trimester served as the control group. The remaining women had been treated with potassium iodide, levothyroxine, or more than one drug during the first trimester. The antithyroid drugs were evaluated for associations with congenital malformations. The overall rate of major anomalies in the MMI group was 4.1% (50 of 1231), and it was significantly higher than the 2.1% (40 of 1906) in the control group (P = 0.002), but there was no increase in the overall rate of major anomalies in the PTU group in comparison with the control group (1.9%; 21 of 1399; P = 0.709). Seven of the 1231 newborns in the MMI group had aplasia cutis congenita, six had an omphalocele, seven had a symptomatic omphalomesenteric duct anomaly, and one had esophageal atresia. Hyperthyroidism in the first trimester of pregnancy did not increase the rate of congenital malformation. In utero exposure to MMI during the first trimester of pregnancy increased the rate of congenital malformations, and it significantly increased the rate of aplasia cutis congenita, omphalocele, and a symptomatic omphalomesenteric duct anomaly.


Frequency of HER-2 positivity in rectal cancer and prognosis.
In patients with advanced rectal cancer (cUICC II and III) multimodality therapy resulted in better long-term local tumor control. Ongoing clinical trials are focusing on therapy intensification to improve disease-free (DFS) and cancer-specific survival (CSS), the integration of biomarkers for prediction of individual recurrence risk, and the identification of new targets. In this context, we investigated HER-2, a member of the epidermal growth factor receptor family, whose expression pattern and role was unclear in rectal cancer. A total of 264 patients (192 male, 72 female; median age 64 y) received standardized multidisciplinary treatment according to protocols of phase II/III trials of the German Rectal Cancer Study Group. HER-2 status was determined in pretherapeutic biopsies and resection specimens using immunohistochemistry scoring and detection of silver in situ hybridization amplification. Tumors with an immunohistochemistry score of 3 or silver in situ hybridization ratios of ≥2.0 were classified HER-2 positive; these results were correlated with clinicopathologic parameters [eg, resection (R) status, nodal status ((y)pN)], DFS, and CSS. Positive HER-2 status was found in 12.4% of biopsies and in 26.7% of resected specimens. With a median follow-up of 46.5 months, patients with HER-2 positivity showed in trend a better DFS (P=0.1) and a benefit in CSS (P=0.03). The 5-year survival rate was 96.0% (HER-2 positive) versus 80.0% (HER-2 negative). In univariate and multivariate analyses, HER-2 was an independent predictor for CSS (0.02) along with the (y)pN status (P<0.00001) and R status (P=0.011). HER-2 amplification is detectable in a relevant proportion (26.7%) of rectal cancer patients. For the development of innovative new therapies, HER-2 may represent a promising target and should be further assessed within prospective clinical trials.


Antibody-associated epilepsies: Clinical features, evidence for immunotherapies and future research questions.
The growing recognition of epilepsies and encephalopathies associated with autoantibodies against surface neuronal proteins (LGI1, NMDAR, CASPR2, GABABR, and AMPAR) means that epileptologists are increasingly asking questions about mechanisms of antibody-mediated epileptogenesis, and about the use of immunotherapies. This review summarizes clinical and paraclinical observations related to autoimmune epilepsies, examines the current evidence for the effectiveness of immunotherapy, and makes epilepsy-specific recommendations for future research. Systematic literature search with summary and review of the identified publications. Studies describing the clinical characteristics of autoantibody-associated epilepsies and treatments are detailed in tables. Literature describing the clinical manifestations and treatment of autoimmune epilepsies associated with neuronal cell-surface autoantibodies (NSAbs) is largely limited to retrospective case series. We systematically summarize the features of particular interest to epileptologists dividing patients into those with acute or subacute encephalopathies associated with epilepsy, and those with chronic epilepsy without encephalopathy. Available observational studies suggest that immunotherapies are effective in some clinical circumstances but outcome data collection methods require greater standardization. The clinical experience captured suggests that clusters of clinical features associate well with specific NSAbs. Intensive and early immunotherapy is indicated when patients present with autoantibody-associated encephalopathies. It remains unclear how patients with chronic epilepsy and the same autoantibodies should be assessed and treated. Tables in this paper provide a comprehensive resource for systematic descriptions of both clinical features and treatments, and highlight limitations of current studies.


A survey of Tennessee veterinarian and physician attitudes, knowledge, and practices regarding zoonoses prevention among animal owners with HIV infection or AIDS.
To examine the attitudes, knowledge, and practices of Tennessee veterinarians and physicians engaged in clinical practice regarding the risk for and prevention of zoonoses in people with HIV infection or AIDS. Cross-sectional survey. Licensed Tennessee veterinarians and physicians engaged in clinical practice. A survey was mailed in January 2010 to 454 licensed veterinarians and 1,737 licensed physicians. 181 of 419 (43.20%) eligible veterinarians and 201 of 1,376 (14.61%) eligible physicians responded to the survey. A majority of both veterinarians (131/179 [73.18%]) and physicians (97/192 [50.52%]) indicated that veterinarians should always or almost always be involved in advising clients with HIV infection or AIDS. The majority of veterinarians (120/173 [69.36%]) indicated they always or almost always discussed with clients the potential risk to immune-compromised persons after diagnosing a zoonosis. A high proportion (88/94 [93.62%]) of physicians indicated they never or rarely initiated discussions about zoonoses with patients with HIV infection or AIDS. All physicians (94/94 [100%]) indicated they never or rarely contacted veterinarians for advice on zoonoses. Similarly, 174 of 180 (96.76%) veterinarians had never or rarely contacted physicians for advice on zoonoses risks. Only 25.97% of veterinarians and 33.33% of physicians were correctly able to identify zoonotic pathogens of greatest concern to people with HIV infection or AIDS. We identified several implications for veterinary medical and medical practice that may reduce zoonoses transmission risks for people with HIV infection or AIDS, including increased communication between veterinarians and physicians, increased communication between people with HIV infection or AIDS and health-care providers, increased availability of client educational materials, and increased participation in zoonoses continuing education opportunities by health-care providers.


Response behavior of diblock copolymer brushes in explicit solvent.
The understanding of phase behavior of copolymer brushes is of fundamental importance for the design of smart materials. In this paper, we have performed classical density functional theory calculations to study diblock copolymer brushes (A-B) in an explicit solvent which prefers the A block to B block. With increasing B-block length (N(B)), we find a structural transition of the copolymer brush from mixed to collapsed, partial-exposed, and exposed structure, which is qualitatively consistent with experiments. The phase transitions are attributed to the interplay between entropic cost of folding copolymer brushes and enthalpic effect of contact between unlike components. In addition, we examine the effect of different parameters, such as grafting density (ρ(g)), the bottom block length (N(A)), and the chain length of solvent (N(S)) on the solvent response of copolymer brushes. The transition chain length (N(B)) increases with decreasing ρ(g) and N(A), and a smaller solvent molecule makes the collapsed structure less stable due to its lower penetration cost. Our results provide the insight to phase behavior of copolymer brushes in selective solvents from a molecular view.


Quantification of right to left shunt at rest and during exercise in patients with pulmonary arteriovenous malformations.
Current treatment of patients with pulmonary arteriovenous malformations requires serial embolisations by means of steel coils or balloons. Measurement of right to left shunt is the most specific index of response to treatment. A new method of measuring shunt has been developed that is less invasive than traditional methods. Right to left pulmonary shunt (expressed as percentage of cardiac output) was measured at rest in 19 patients with pulmonary arteriovenous malformations and six normal subjects by using intravenously injected albumin microspheres labelled with technetium-99m. The technique was compared with a simultaneous shunt measurement in subjects breathing 100% oxygen while they rested. The microsphere technique was adapted to measure the right to left shunt during exercise in 12 patients and five normal subjects with a new method of quantification. The mean (SD) shunt at rest as measured by the microsphere method was 23.2% (15.6%) in the patients and 2.7% (1.2%) in the normal subjects. When these values were compared with those of the 100% oxygen method the difference in mean values was 1% and the limits of agreement between the two methods -32% to +45%. The microsphere method is less invasive (arterial blood gas sampling is not required), quicker, and more comfortable for patients than the 100% oxygen method. In five of the normal subjects the mean (SD) 99mTc microsphere shunt increased from 2.9% (1.3%) at rest to 5.1% (2.9%) during exercise. In the 12 patients studied during exercise the shunt increased from 33.7% (12.7%) at rest to 41.7% (13.3%) during exercise in eight but decreased from 22.6% (2.4%) at rest to 17.6% (2.2%) during exercise in four. Arterial desaturation during exercise correlated with change in the size of the right to left shunt during exercise (r = +0.80). The microsphere method allows measurement of right to left shunt at rest and during exercise. Serial measurements at rest provide a simple, safe assessment of the physiological response to embolisation in patients with pulmonary arteriovenous malformations.


Assessment of Palatal Plane and Occlusal Plane for Determining Anteroposterior Jaw Relation.
Sagittal jaw relationship is an important parameter for orthodontic treatment planning. Angular and linear measurements both have been proposed and used in orthodontic cephalometrics to assess the sagittal jaw relationships. However, angular measurement has been questioned over the years for its reliability as a result of changes in facial height, jaw inclination and the variable positions of Nasion. So, the objective of our study was to assess the linear anteroposterior jaw relation in a sample of Nepali population using occlusal (Wits appraisal) and palatal planes as reference lines. A descriptive cross-sectional study was conducted using the lateral cephalogram of 101 individuals visiting the Department of Orthodontics, Kantipur Dental College, Kathmandu, Nepal. Individuals with Class I skeletal relation were selected using convenience sampling method. Radiographs were standardised and traced. Occlusal and palatal planes were drawn that were bisected by the perpendicular lines from Point A and Point B. The linear distances between the intersections were measured to determine sagittal jaw relations. In Nepali individuals with normal ANB angle (3.05°±2.511°), the sagittal jaw relation with reference to occlusal (Wits appraisal) and palatal planes were found to be 0.203±3.343mm and 3.574±4.074mm respectively. Various methods has been proposed and used to assess the sagittal jaw relation and each method has its own strength and limitations. So, it is well advised to use additional cephalometric analysis whenever possible before arriving at any diagnosis and treatment plans.


Dynamical genetic programming in XCSF.
A number of representation schemes have been presented for use within learning classifier systems, ranging from binary encodings to artificial neural networks. This paper presents results from an investigation into using a temporally dynamic symbolic representation within the XCSF learning classifier system. In particular, dynamical arithmetic networks are used to represent the traditional condition-action production system rules to solve continuous-valued reinforcement learning problems and to perform symbolic regression, finding competitive performance with traditional genetic programming on a number of composite polynomial tasks. In addition, the network outputs are later repeatedly sampled at varying temporal intervals to perform multistep-ahead predictions of a financial time series.


Optimizing accu time-of-flight/direct analysis in real time for explosive residue analysis.
The use of a direct analysis in real time (DART) mass spectrometer (MS) instrument was optimized for 22 compounds of organic explosive residues to provide a guide for DART-MS users in rapid screening of explosive compounds. Samples were introduced as neat solutions and sequential dilutions to determine optimal instrument conditions and lowest concentration detectable. Most compounds were optimized to 250°C in the negative ion mode, and several compounds benefited from the addition of a chloride dopant from methylene chloride (amino-dinitrotoluenes, RDX, EGDN, and PETN). Few compounds were more sensitive in the positive ion mode (TEGDN, DEGDN, HNS, and DMNB). Mixtures of compounds were detected using clean room wipes, directly from their surfaces and from subsequent extractions. Compounds from the mixtures were also successfully detected in soil and from swipes of spiked surfaces. The instrument showed merit in detection of pg/μL solutions for most of the compounds and among the substrates tested.


Ultrastructural investigations of the bone and fibrous connective tissue interface with endosteal dental implants.
The interface between the tissues of the oral cavity and ceramic and titanium cylindrical endosteal dental implants was investigated with correlated light microscopy, transmission electron microscopy and scanning electron microscopy. This study suggested that mandibular bone can directly interface and form an intimate association with one-stage endosteal dental implants. This potential attachment matrix is composed of a composite of calcified bone, and an osteoid unmineralized matrix in association with an apparent osteogenic connective tissue. Further, results from this study suggested that at a level inferior to the junctional epithelium, and superior to the level of crestal bone, fibrous connective tissue can attach to the dental implant. This non-loadbearing attachment of gingival connective tissue could, by contact inhibition, prevent apical epithelial migration. In association with previously documented epithelial attachment, such apical support and connective tissue attachment appears to suggest that endosteal dental implants can be adequately maintained in the oral cavity.


New telomere to telomere assembly of human chromosome 8 reveals a previous underestimation of G-quadruplex forming sequences and inverted repeats.
Taking advantage of evolving and improving sequencing methods, human chromosome 8 is now available as a gapless, end-to-end assembly. Thanks to advances in long-read sequencing technologies, its centromere, telomeres, duplicated gene families and repeat-rich regions are now fully sequenced. We were interested to assess if the new assembly altered our understanding of the potential impact of non-B DNA structures within this completed chromosome sequence. It has been shown that non-B secondary structures, such as G-quadruplexes, hairpins and cruciforms, have important regulatory functions and potential as targeted therapeutics. Therefore, we analysed the presence of putative G-quadruplex forming sequences and inverted repeats in the current human reference genome (GRCh38) and in the new end-to-end assembly of chromosome 8. The comparison revealed that the new assembly contains significantly more inverted repeats and G-quadruplex forming sequences compared to the current reference sequence. This observation can be explained by improved accuracy of the new sequencing methods, particularly in regions that contain extensive repeats of bases, as is preferred by many non-B DNA structures. These results show a significant underestimation of the prevalence of non-B DNA secondary structure in previous assembly versions of the human genome and point to their importance being not fully appreciated. We anticipate that similar observations will occur as the improved sequencing technologies fill in gaps across the genomes of humans and other organisms.


Neuroepithelial bodies as mechanotransducers in the intrapulmonary airway epithelium: involvement of TRPC5.
In rodent lungs, a major part of the myelinated vagal airway afferents selectively contacts pulmonary neuroepithelial bodies (NEBs). Because most myelinated vagal airway afferents concern physiologically characterized mechanoreceptors, the present study aimed at unraveling the potential involvement of NEB cells in transducing mechanosensory information from the airways to the central nervous system. Physiological studies were performed using confocal Ca(2+) imaging of airway epithelium in murine lung slices. Mechanical stimulation by short-term application of a mild hypoosmotic solution (230 mosmol) resulted in a selective, fast, reversible, and reproducible Ca(2+) rise in NEB cells. Other airway epithelial cells could only be activated using more severe hypoosmotic stimuli (< 200 mosmol). NEB cells selectively expressed the Ca(2+)-permeable osmo- and mechanosensitive transient receptor potential canonical channel 5 (TRPC5) in their apical membranes, whereas immunoreactivity for TRP vanilloid-4 and TRP melastatin-3 was abundant in virtually all other airway epithelial cells. Hypoosmotic activation of NEB cells was prevented by GsMTx-4, an inhibitor of mechanosensitive ion channels, and by SKF96365, an inhibitor of TRPC channels. Short application of gadolinium, reported to activate TRPC5 channels, evoked a transient Ca(2+) rise in NEB cells. Osmomechanical activation of NEB cells gave rise to a typical delayed activation of Clara-like cells due to the release of ATP from NEB cells. Because ATP may activate the NEB-associated P2X(2/3) ATP receptor expressing myelinated vagal afferents, the current observations strongly suggest that pulmonary NEB cells are fully equipped to initiate mechanosensory signal transduction to the central nervous system via a purinergic signaling pathway.


Exploring the impact of house screening intervention on entomological indices and incidence of malaria in Arba Minch town, southwest Ethiopia: A randomized control trial.
House is the major site for malaria infection where most human-vector contact takes place. Hence, improving housing might reduce the risk of malaria infection by limiting house entry of vectors. This study aimed to explore the impact of screening doors and windows with wire meshes on density and entomological inoculation rate (EIR) of malaria vector, and malaria incidence, and assess the acceptability, durability, and cost of the intervention. The susceptibility status of malaria vector was also assessed. A two-arm randomized trial was done in Arba Minch Town, southwest Ethiopia. 92 houses were randomly included in the trial. The baseline entomological and malaria prevalence data were collected. The mosquito sampling was done twice per household per month by Centers for Diseases Control and Prevention (CDC) light traps for six months. The baseline prevalence of malaria was assessed by testing 396 (83% of the 447 study participants) household members in all the eligible houses. The 92 houses were then randomized into control and intervention groups using mosquito and malaria prevalence baseline data to make the two groups comparable except the intervention. Then, we put wire-mesh on doors and windows of 46 houses. Post-screening mosquito collection was done in each household twice per month for three months. Each household member was visited twice per month for six months to assess malaria episodes. The frequency of damage to different structure of screening was measured twice. In-depth interview was conducted with 24 purposely selected household heads from intervention group. Speciation of Anopheles mosquito was done by morphological key, and the circum-sporozoite proteins (CSPs) analysis was done using enzyme-linked immunosorbent assay. A generalized estimating equation with a negative binomial distribution was used to assess the impact of the intervention on the indoor density of vectors. Clinical malaria case data were analyzed using Poisson regression with generalized linear model. Screening doors and windows reduced the indoor density of An. arabiensis by 48% (mean ratio of intervention to control = 0.85/1.65; 0.52) (P = .001). Plasmodium falciparum CSP rate was 1.6% (3/190) in the intervention houses, while it was 2.7% (10/372) in the control houses. The protective efficacy of screening intervention from CSP positive An. arabiensis was 41% (mean ratio of intervention to control = 1.6/2.7; 0.59), but was not statistically significant (P = .6). The EIR of An. arabiensis was 1.91 in the intervention group, whereas it was 6.45 in the control group. 477 participants were followed for clinical malaria (50.1% from intervention and 49.9% from the control group). Of 49 RDT positive cases, 45 were confirmed to be positive with microscopy. 80% (n = 36) cases were due to P. falciparum and the rest 20% (n = 9) were due to P. vivax. The incidence of P. falciparum in the intervention group was lower (IRR: 0.39, 95% CI: 0.2-0.80; P = .01) than in the control group. Using incidence of P. falciparum infection, the protective efficacy of intervention was 61% (95% CI: 18-83; P = .007). 97.9% of screened windows and 63.8% of screened doors were intact after eleven months of installation. Malaria mosquito was resistance (mortality rate of 75%) to the insecticide used for bed nets treatment. Almost all participants of intervention arm were willing to continue using screened doors and windows. Screening doors and windows reduced the indoor exposure to malaria vectors. The intervention is effective, durable and well-accepted. Hence, the existing interventions can be supplemented with house screening intervention for further reduction and ultimately elimination of malaria by reducing insecticide pressure on malaria vectors. However, further research could be considered in broad setting on different housing improvement and in the way how to scale-up for wider community.


Cathodal Cerebellar tDCS Combined with Visual Feedback Improves Balance Control.
Balance control is essential to maintain a stable body position and to prevent falls. The aim of this study was to determine whether balance control could be improved by using cerebellar transcranial direct current stimulation (tDCS) and visual feedback in a combined approach. A total of 90 healthy volunteers were randomly assigned to six groups defined by the delivery of tDCS (cathodal or anodal or sham) and the provision or not of visual feedback on balance during the acquisition phase. tDCS was delivered over the cerebellar hemisphere ipsilateral to the dominant leg for 20 min at 2 mA during a unipedal stance task. Body sway (i.e., ankle angle and hip position) was measured as an overall maximal unit in anteroposterior and mediolateral direction, together with participant rating of perception of stability, before (baseline), during (acquisition), and after (final) the intervention. We found a reduction in body sway during the acquisition session when visual feedback alone was provided. When the visual feedback was removed (final session), however, body sway increased above baseline. Differently, the reduction in overall maximal body sway was maintained during the final session when the delivery of cathodal tDCS and visual feedback was combined. These findings suggest that cathodal tDCS may support the short-term maintenance of the positive effects of visual feedback on balance and provide the basis for a new approach to optimize balance control, with potential translational implications for the elderly and patients with impaired posture control.


Aging and infectious diseases: workshop on HIV infection and aging: what is known and future research directions.
Highly active antiretroviral treatment has resulted in dramatically increased life expectancy among patients with HIV infection who are now aging while receiving treatment and are at risk of developing chronic diseases associated with advanced age. Similarities between aging and the courses of human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome suggest that HIV infection compresses the aging process, perhaps accelerating comorbidities and frailty. In a workshop organized by the Association of Specialty Professors, the Infectious Diseases Society of America, the HIV Medical Association, the National Institute on Aging, and the National Institute on Allergy and Infectious Diseases, researchers in infectious diseases, geriatrics, immunology, and gerontology met to review what is known about HIV infection and aging, to identify research gaps, and to suggest high priority topics for future research. Answers to the questions posed are likely to help prioritize and balance strategies to slow the progression of HIV infection, to address comorbidities and drug toxicity, and to enhance understanding about both HIV infection and aging.


A comparative content analysis of media reporting of sports betting in Australia: lessons for public health media advocacy approaches.
Harmful gambling is a significant public health issue. There has been widespread discussion in the Australian media about the extent and impact of sports betting on the Australian community, particularly relating to young men and children. Given the role that the media plays in influencing policy change and political agendas, and the acknowledgement that media based advocacy is a fundamental component of successful advocacy campaigns, this research aimed to investigate how different stakeholder groups discuss sports betting within the Australian print media. The study uses this information to provide recommendations to guide public health media advocacy approaches. A quantitative content analysis of print media articles was conducted during two significant Parliamentary Inquiries about sports betting - (1) The Joint Select Committee Inquiry into the Advertising and Promotion of Gambling Services in Sport (2012/2013), and (2) 'The Review of Illegal Offshore Wagering (2015/2016). A total of 241 articles from 12 daily Australian newspapers were analysed. Statistical analysis was used to compare frequency of, and changes in, themes, voices and perspectives over time. Discussions about the marketing and communication of sports betting was a main theme in media reporting (n = 165, 68.5%), while discussions about gambling reform decreased significantly across the two time periods (p < 0.0001). The presence of sports betting industry (p < 0.0001), sporting code (p < 0.0001) and public health expert (p = 0.001) voices all increased significantly across the two time periods. There were very few (n = 11, 4.6%) voices from those who had experienced gambling harm. Finally, while there were significantly fewer articles taking the perspective that regulation changes were needed to protect vulnerable sub-populations (p < 0.0001), articles that had a neutral perspective about the need for regulation change increased significantly across the two time periods (p < 0.0001). Mapping the media reporting of sports betting is important in developing effective public health advocacy approaches. This study indicates that discussions about the marketing strategies utilised by the sports betting industry was still a main theme in media articles. However, discussions relating to sports betting reforms, in particular to protect individuals who may be vulnerable to the harm associated with these products and their promotional strategies (for example children and young men) decreased during the time periods. Public health advocates may seek to address the decrease in media reports about reform by developing clear evidence-based messages about why regulatory reform is needed, as well as the potential consequences of not implementing reforms. Working with organisations to build capacity for people who have experienced gambling harm may help ensure that individuals with a lived experience of harm have an increased voice in the media.


Effect of caffeine on quadriceps muscle pain during acute cycling exercise in low versus high caffeine consumers.
This experiment examined the effect of a moderate dose of caffeine on quadriceps muscle pain during a bout of high-intensity cycling in low- versus high-caffeine-consuming males. College-age men who were low (< or =100 mg/day; n = 12) or high (> or =400 mg/day; n = 13) habitual caffeine consumers ingested caffeine (5 mg/kg body weight) or a placebo in a counterbalanced order and 1 hr later completed 30 min of cycle ergometry at 75-77% of peak oxygen consumption. Perceptions of quadriceps muscle pain, as well as oxygen consumption, heart rate, and work rate, were recorded during both bouts of exercise. Caffeine ingestion resulted in a statistically significant and moderate reduction in quadriceps muscle-pain-intensity ratings during the 30-min bout of high-intensity cycle ergometry compared with placebo ingestion in both low (d = -0.42) and high (d = -0.55) caffeine consumers. The results suggest that caffeine ingestion is associated with a moderate hypoalgesic effect during high-intensity cycling in college-age men who are low or high habitual caffeine consumers, but future work should consider better defining and differentiating pain and effort when examining the effects of caffeine during acute exercise.


Viral load and physical status of human papillomavirus (HPV) 18 in cervical samples from female sex workers infected with HPV 18 in Burkina Faso.
Viral DNA load and physical status might be predictive of either high-grade cervical lesions or disease progression among women infected by human papillomavirus (HPV) 16, but these virological markers have rarely been studied in HPV 18 infections. The relationships between HPV 18 DNA load, viral genome physical status and cervical squamous intraepithelial lesions were analyzed among female sex workers infected with HPV18 in Burkina Faso. HPV 18 E2 and E6 genes were quantitated by real-time PCR. Among 21 women infected with HPV 18, 67% of whom were HIV-1-seropositive, 11 (52.4%) had a normal cytology, 8 (38.1%) had low-grade squamous intraepithelial lesions, and 2 (9.5%) had high-grade squamous intraepithelial lesions. Total viral load and integrated viral load were higher in women with squamous intraepithelial lesions than in women with normal cytology (P = 0.01 for both parameters). Total viral load and integrated viral load were higher in HIV-1-seropositive women than in those who were not infected with HIV (P = 0.01, and P, 0.01, respectively). Total viral load or integrated viral load >1,000 copies/ng of DNA were more frequent in women with squamous intraepithelial lesions than in women with normal cytology (7/10 vs. 1/11; P = 0.007) and in HIV-1-seropositive women (8/14 vs. 0/7 in HIV-uninfected women; P = 0.02). Both HPV 18 DNA and integrated DNA loads might represent markers of cervical lesions. Prospective evaluations are needed to establish the value of these parameters to predict high-grade lesion or lesion progression.


Spatio-temporal distribution of Plasmodium falciparum and p. Vivax malaria in Thailand.
Malaria incidence data at the district level from 1997 to 2002 and total malaria case data from 1965 to 2002 in Thailand were analyzed to determine the spatial and temporal dynamics of Plasmodium falciparum and P. vivax malaria incidence. Over the 37-year period, there was a 35-fold reduction in the incidence rates of P. falciparum malaria (11.86% in 1965 versus 0.34% in 2002) and a 7-fold reduction in P. vivax malaria (2.89% in 1965 versus 0.40% in 2002). The incidence ratio of P. falciparum to P. vivax malaria was reduced from 4.1 to 0.8 during this period. Malaria incidence rate exhibited the most rapid reduction between 1975 and 1985, coinciding with the introduction of a combination of antifolate drugs (sulfadoxine-pyrimethamine). The distribution maps of P. falciparum and P. vivax malaria incidence rates indicated a high spatial heterogeneity. The Thailand-Myanmar and Thailand-Cambodia border areas, where migration of foreign workers was pronounced, had the highest incidence rates for P. falciparum, P. vivax, and mixed-species infections. Transition probability analysis based on the malaria incidence rate among Thai residents indicated that there was an overall trend of decrease in the number of malaria cases and the number of high incidence districts between 1997 and 2002. High spatial variation in malaria incidence and local human migration patterns suggest that malaria control measures need to be adjusted according to local environmental and demographic settings.


The long-term effects of a self-management program for inner-city primary care patients with acute low back pain.
We evaluated the effect of a self-management program for low-income primary care patients with acute low back pain (ALBP) from inner-city neighborhood health centers. We conducted a randomized controlled trial of a self-management program compared with usual care at university-affiliated neighborhood health centers and an emergency department of an inner-city public teaching hospital. We enrolled 211 patients who visited a physician for ALBP (<90 days' duration). The self-management program consisted of 3 group sessions and telephone follow-up that focused on understanding back pain, increasing physical activity, and dealing with fears and frustrations. At baseline, 4 months, and 12 months, blinded interviewers assessed back pain physical function (Roland Disability Questionnaire), health status (Arthritis Impact Measurement Scales), self-efficacy, and time spent in physical activity. Compared with patients receiving usual care, intervention patients reported significantly better scores on the Roland Disability Questionnaire (P =.009), mental functioning (P =.009), self-efficacy to manage ALBP (P =.03), time spent in physical activity (P =.047), and reduced fears of movement/reinjury (P =.005) after 12 months. A self-management program can improve and maintain functional status, mental functioning, and self-efficacy to manage future symptoms for 1 year among primary care patients with ALBP living in the urban, inner city.


The Effects of Cell Phone and Text Message Conversations on Simulated Street Crossing.
A fully immersive, high-fidelity street-crossing simulator was used to examine the effects of texting on pedestrian street-crossing performance. Research suggests that street-crossing performance is impaired when pedestrians engage in cell phone conversations. Less is known about the impact of texting on street-crossing performance. Thirty-two young adults completed three distraction conditions in a simulated street-crossing task: no distraction, phone conversation, and texting. A hands-free headset and a mounted tablet were used to conduct the phone and texting conversations, respectively. Participants moved through the virtual environment via a manual treadmill, allowing them to select crossing gaps and change their gait. During the phone conversation and texting conditions, participants had fewer successful crossings and took longer to initiate crossing. Furthermore, in the texting condition, smaller percentage of time with head orientation toward the tablet, fewer number of head orientations toward the tablet, and greater percentage of total characters typed before initiating crossing predicted greater crossing success. Our results suggest that (a) texting is as unsafe as phone conversations for street-crossing performance and (b) when subjects completed most of the texting task before initiating crossing, they were more likely to make it safely across the street. Sending and receiving text messages negatively impact a range of real-world behaviors. These results may inform personal and policy decisions.


Environmental influences on physical activity in rural adults: the relative contributions of home, church and work settings.
This study examines the relative contribution of social (eg, social support) and physical (eg, programs and facilities) aspects of worksite, church, and home settings to physical activity levels among adults in rural communities. Data are from a cross-sectional survey of 268 African American and Caucasian adults, ages 40-70, living in southwest Georgia. Separate regression models were developed for walking, moderate, vigorous, and total physical activity as measured in METs-minutes-per-week. Social support for physical activity was modest in all 3 settings (mean scores 1.5-1.9 on a 4-point scale). Participants reported limited (<1) programs and facilities for physical activity at their worksites and churches. An interaction of physical and social aspects of the home setting was observed for vigorous and moderate physical activity and total METs. There were also interactions between gender and social support at church for vigorous activity among women, and between race and the physical environment at church for moderate physical activity. A cross-over interaction was found between home and church settings for vigorous physical activity. Social support at church was associated with walking and total METs. Homes and churches may be important behavioral settings for physical activity among adults in rural communities.


Speech recognition in fluctuating and continuous maskers: effects of hearing loss and presentation level.
Listeners with normal-hearing sensitivity recognize speech more accurately in the presence of fluctuating background sounds, such as a single competing voice, than in unmodulated noise at the same overall level. These performance differences are greatly reduced in listeners with hearing impairment, who generally receive little benefit from fluctuations in masker envelopes. If this lack of benefit is entirely due to elevated quiet thresholds and the resulting inaudibility of low-amplitude portions of signal + masker, then listeners with hearing impairment should derive increasing benefit from masker fluctuations as presentation levels increase. Listeners with normal-hearing (NH) sensitivity and listeners with hearing impairment (HI) were tested for sentence recognition at moderate and high presentation levels in competing speech-shaped noise, in competing speech by a single talker, and in competing time-reversed speech by the same talker. NH listeners showed more accurate recognition at moderate than at high presentation levels and better performance in fluctuating maskers than in unmodulated noise. For these listeners, modulated versus unmodulated performance differences tended to decrease at high presentation levels. Listeners with HI, as a group, showed performance that was more similar across maskers and presentation levels. Considered individually, only 2 out of 6 listeners with HI showed better overall performance and increasing benefit from masker fluctuations as presentation level increased. These results suggest that audibility alone does not completely account for the group differences in performance with fluctuating maskers; suprathreshold processing differences between groups also appear to play an important role. Competing speech frequently provided more effective masking than time-reversed speech containing temporal fluctuations of equal magnitude. This finding is consistent with "informational" masking resulting from competitive processing of words and phrases within the speech masker that would notoccur for time-reversed sentences.


Learning to live on a Mars day: fatigue countermeasures during the Phoenix Mars Lander mission.
To interact with the robotic Phoenix Mars Lander (PML) spacecraft, mission personnel were required to work on a Mars day (24.65 h) for 78 days. This alien schedule presents a challenge to Earth-bound circadian physiology and a potential risk to workplace performance and safety. We evaluated the acceptability, feasibility, and effectiveness of a fatigue management program to facilitate synchronization with the Mars day and alleviate circadian misalignment, sleep loss, and fatigue. Operational field study. PML Science Operations Center. Scientific and technical personnel supporting PML mission. Sleep and fatigue education was offered to all support personnel. A subset (n = 19) were offered a short-wavelength (blue) light panel to aid alertness and mitigate/reduce circadian desynchrony. They were assessed using a daily sleep/work diary, continuous wrist actigraphy, and regular performance tests. Subjects also completed 48-h urine collections biweekly for assessment of the circadian 6-sulphatoxymelatonin rhythm. Most participants (87%) exhibited a circadian period consistent with adaptation to a Mars day. When synchronized, main sleep duration was 5.98 ± 0.94 h, but fell to 4.91 ± 1.22 h when misaligned (P < 0.001). Self-reported levels of fatigue and sleepiness also significantly increased when work was scheduled at an inappropriate circadian phase (P < 0.001). Prolonged wakefulness (≥ 21 h) was associated with a decline in performance and alertness (P < 0.03 and P < 0.0001, respectively). The ability of the participants to adapt successfully to the Mars day suggests that future missions should utilize a similar circadian rhythm and fatigue management program to reduce the risk of sleepiness-related errors that jeopardize personnel safety and health during critical missions.


Effectiveness of Two Topical Anaesthetic Agents used along with Audio Visual Aids in Paediatric Dental Patients.
Topical anaesthetic agents enable pain free intraoral procedures, symptomatic pain relief for toothache, superficial mucosal lesions and pain related to post extraction time. Most common anxiety provoking and fearful experience for children in dental operatory is administration of local anaesthesia because on seeing the needle, children usually become uncooperative. One of recent trend of behaviour management technique is using non-aversive techniques out of which audiovisual distraction has emerged as a very successful technique for managing children in dental settings. Audio visual distraction could decrease the procedure related anxiety of patients undergoing dental treatment and can be very relaxing for highly anxious patients. The aim of the present study was to compare the efficacy of topical anaesthetics EMLA (Eutectic Mixture of Local Anaesthetics) cream and benzocaine (20%) gel in reducing the pain during the needle insertion with and without the use of Audio Visual (AV) aids. The study was conducted on 120 children, the age range of 3-14 years attending the outpatient department for their treatment. EMLA and benzocaine gel (20%) were assessed for their effectiveness in reducing the pain on needle insertion during local anaesthesia administration. Based on the inclusion and the exclusion criteria, children requiring local anaesthesia for the dental treatment were randomly divided into four equal groups of 30 children based upon whether AV aids were used or not. AV aids were given using Sony Vaio laptop with earphones with nursery rhymes and cartoon movies DVD. The pain assessment was done by using the Visual Analogue Scale (VAS) scale and measurement of the physiological responses of pulse rate and oxygen saturation were done by pulse oximeter. There was a statistically significant difference in the mean pain score, pulse rate and mean oxygen saturation rate when it was compared between the four groups. EMLA with AV aids was found to be a better topical anaesthestic agent as compared to other three groups. EMLA with AV aids was better when compared with EMLA without AV aids followed by benzocaine with AV aids. Benzocaine topical anaesthetic agent without AV aids was least effective in reducing the pain scores and improving the oxygen saturation rate.


The socio-economic transition and health professions education in Mongolia: a qualitative study.
Former socialist countries have undergone a socio-economic transition in recent decades. New challenges for the healthcare system have arisen in the transition economy, leading to demands for better management and development of the health professions. However, few studies have explored the effects of this transition on health professions education. Thus, we investigated the effects of the socio-economic transition on the health professions education system in Mongolia, a transition economy country, and to identify changes in requirements. We used a multi-level perspective to explore the effects of the transition, including the input, process, and output levels of the health professions education system. The input level refers to planning and management, the process level refers to the actual delivery of educational services, and the output level refers to issues related to the health professionals, produced by the system. This study utilized a qualitative research design, including document review and interviews with local representatives. Content analysis and the constant comparative method were used for data analysis. We explored tensions in the three levels of the health professions education system. First, medical schools attained academic authority for planning and management without proper regulation and financial support. The government sets tuition fees, which are the only financial resource of medical schools; thus, medical schools attempt to enroll more students in order to adapt to the market environment. Second, the quality of educational services varies across institutions due to the absence of a core curriculum and differences in the learning environment. After the transition, the number of private medical schools rapidly increased without quality control, while hospitals started their own specialized training programs. Third, health professionals are struggling to maintain their professional values and development in the market environment. Fixed salaries lead to a lack of motivation, and quality evaluation measures more likely reflect government control than quality improvement. Mongolia continues to face the consequences of the socio-economic transition. Medical schools' lack of financial authority, the varying quality of educational services, and poor professional development are the major adverse effects. Finding external financial support, developing a core curriculum, and reforming a payment system are recommended.


Biosynthesis of vitamin B12: the preparative multi-enzyme synthesis of precorrin-3A and 20-methylsirohydrochlorin (a 2,7,20-trimethylisobacteriochlorin).
The Bacillus subtilis genes hemB, hemC and hemD, encoding respectively the enzymes porphobilinogen synthase, hydroxymethylbilane synthase and uroporphyrinogen III synthase, have been expressed in Escherichia coli using a single plasmid construct. An enzyme preparation from this source converts 5-aminolaevulinic acid (ALA) preparatively and in high yield into uroporphyrinogen III. The Pseudomonas denitrificans genes cobA and cobI, encoding respectively the enzymes S-adenosyl-L-methionine:uroporphyrinogen III methyltransferase (SUMT) and S-adenosyl-L-methionine:precorrin-2 methyltransferase (SP2MT), were also expressed in E. coli. When SUMT was combined with the coupled-enzyme system that produces uroporphyrinogen III, precorrin-2 was synthesized from ALA, and when SP2MT was also added the product from the coupling of five enzymes was precorrin-3A. Both of these products are precursors of vitamin B12, and they can be used directly for biosynthetic experiments or isolated as their didehydro octamethyl esters in > 40% overall yield. The enzyme system which produces precorrin-3A is sufficiently stable to allow long incubations on a large scale, affording substantial quantities (15-20 mg) of product.


Individualized Glycemic Goals and an Expanded Classification of Severe Hypoglycemia in Diabetes.
The view that a hemoglobin A1c (A1C) level <7% (55 mmol/mol) is the accepted glycemic goal for most people with diabetes sometimes conflicts with the view that glycemic goals should be individualized and, thus, that somewhat higher A1C levels are appropriate for some, particularly many at risk for iatrogenic hypoglycemia because of treatment with insulin, a sulfonylurea, or a glinide. The relationship between A1C and chronic complications of diabetes is curvilinear, A1C is a relatively weak predictor of cardiovascular disease, and minor elevations of A1C above 7% have not been found to be associated with increased mortality. Iatrogenic hypoglycemia causes recurrent morbidity in diabetes and is sometimes fatal. In those at risk for hypoglycemia, a reasonable individualized glycemic goal is the lowest A1C that does not cause severe hypoglycemia and preserves awareness of hypoglycemia, preferably with little or no symptomatic or even asymptomatic hypoglycemia, at a given stage in the evolution of the individual's diabetes. A somewhat higher A1C level is appropriate in those who have previously experienced hypoglycemia or have potential high risk for hypoglycemia, have a long duration of diabetes, and have a short life expectancy, among other traits. Given the importance of severe hypoglycemia in selecting glycemic goals, it is proposed to expand the classification of severe hypoglycemia beyond a hypoglycemic event requiring assistance from another person to include a measured glucose concentration <50 mg/dL (2.8 mmol/L), a level associated with sudden death.


Visual sensitivity and cortical response to the temporal envelope of amplitude-modulated flicker.
To investigate the perception of a temporal envelope of flickering light is important for understanding nonlinear temporal processing in the visual system. The influence of the frequency components of a flickering light on the perception of the envelope remains unclear, with few studies having investigated the cortical activities for the envelope. We investigated the detection thresholds, brightness, and magnetoencephalographic responses related to amplitude-modulated (AM) flickering lights. The results showed that the sensitivity to flicker at the envelope periodicity of the AM flickering light was lower for a high-frequency carrier (40 Hz) than for a lower-frequency one (10, 20, or 30 Hz). Also, the primary visual cortex responded at the frequency corresponding to the envelope periodicity of the AM flickering light, and the strength of the cortical response reflected the brightness of the flicker at the envelope periodicity.


The fuzzy sphere morphology is responsible for the increase in light scattering during the shrinkage of thermoresponsive microgels.
Thermoresponsive microgels undergo a volume phase transition from a swollen state under good solvent conditions to a collapsed state under poor solvent conditions. The most prominent examples of such responsive systems are based on poly-(N-isopropylacrylamide). When cross-linked with N,N'-methylenebisacrylamide, such microgels typically possess a fuzzy-spherelike morphology with a higher cross-linked core and a loosely cross-linked fuzzy shell. Despite the efforts devoted to understanding the internal structure of microgels and their kinetics during collapse/swelling, the origins of the accompanying changes in light scattering intensity have barely been addressed. In this work, we study core-shell microgels that contain small gold nanoparticle cores with microgel shells of different thicknesses and cross-linker densities. All microgels are small enough to fulfill the Rayleigh-Debye-Gans criterion at all stages of swelling. Due to the high X-ray contrast of the gold cores, we can use absolute intensity small-angle X-ray scattering to determine the number density in the dilute dispersions. This allows us to extract polymer volume fractions of the microgels at different stages of swelling from form factor analysis of small-angle neutron scattering data. We match our findings to results from temperature-dependent absorbance measurements. The increase in absorbance during the shrinkage of the microgels is related to the transition from fuzzy spheres to hard sphere-like scattering objects with a rather homogeneous density profile. We provide a first attempt to model experimental spectra using finite difference time domain simulations that take into account the structural changes during the volume phase transition. Our findings significantly contribute to the understanding of the optical properties of thermoresponsive microgels. Further, we provide polymer volume fractions and microgel refractive indices as a function of the swelling state.


Stable changes in mesenchymal stromal cells from multiple myeloma patients revealed through their responses to Toll-like receptor ligands and epidermal growth factor.
In human multiple myeloma (MM), the tumor cells exhibit strict dependence on bone marrow (BM) stromal elements. It has been suggested that, in turn, MM cells modify multipotent stromal cells (MSCs), diverting them to support the myeloma. We investigated MM-derived MSCs by comparing their toll-like receptor (TLR) responses to those of MSCs derived from healthy controls. We now report that MM-derived MSCs manifested intact proliferation responses and IL-6 secretion and their adipose and osteogenic differentiation responses to TLR ligands were also similar to those of healthy controls, ranging from augmentation to inhibition. However, MM-derived MSCs were found to be defective in IL-8 secretion and ERK1/2 phosphorylation following TLR-2 activation. Moreover, MM-derived MSCs failed to respond to EGF by elevation of ERK1/2 phosphorylation. The persistence of these changes in extensively cultured MM-derived MSCs, suggests that these cells are stably, if not irreversibly modified.


Spatial Distribution of Noninvasive Break Up Times and Clinical Relevance in Healthy Participants and Mild Dry Eye.
Noninvasive keratograph break up times (NIKBUTs) are preferred to dye-based methods to evaluate tear stability in translational medicine. We analyzed the NIKBUTs in different regions of the precorneal tear by using a common imaging technology and explored potential correlations with clinical parameters. We tested NIKBUTs of 120 participants (62.5% females, aged 61.0 ± 13.8 years) with the Keratograph 5M, with standardized symptoms, ocular surface evaluation, and tear lipid layer interferometry. NIKBUTs were obtained from color maps in up to 165 spatial zones corresponding to 7 concentric rings. The lowest NIKBUT of tested zones averaged 7.8 ± 7.4 seconds (median, 4.5; range, 1.5-24 seconds), with the lowest NIKBUT measuring <2 seconds in many inferior zones. A mean of 5 zones had broken up by 2 seconds compared to a mean of about 50 zones by 10 seconds. NIKBUTs in specific inferior peripheral zones were significantly directly correlated to tear lipid thicknesses. The receiver operating characteristics for detecting reduced tear lipid thickness were better than overall NIKBUTs for participants with readings in these zones. Weaker correlations of NIKBUTs with symptoms were observed in two other zones. Overall, the NIKBUT displayed by keratograph was not significantly associated with any clinical parameters. Decreased NIKBUTs in specific peripheral locations may be associated with lower lipid thicknesses. Future measurements of NIKBUTs should ideally be determined in smaller defined zones than current maps. An understanding of how to evaluate tear stability allows a more robust clinical evaluation of new drugs and medical devices for dry eye.