Validation of the inflammatory bowel disease questionnaire in Swedish patients with ulcerative colitis.
The Inflammatory Bowel Disease Questionnaire (IBDQ) is a disease-specific health-related quality of life (HRQOL) questionnaire including four dimensions and a sum score. The aim of this study was to assess the internal and external validity, reliability, and sensitivity of a Swedish version of the IBDQ. Three hundred consecutive patients with ulcerative colitis completed the IBDQ and three other health-related quality of life questionnaires (the Rating Form of IBD Patient Concerns (RFIPC), the Short Form-36 (SF-36) and the Psychological General Well-Being (PGWB) index). Disease activity was evaluated using a 1-week symptom diary, blood tests and rigid sigmoidoscopy. One hundred and fourteen patients filled in the questionnaire a second time, of whom 75 had been in stable remission for over 6 months and 39 had a significant clinical change in disease activity. Factor analysis of the 32 IBDQ items did not support the four dimensional scores. The dimensional scores had sufficient convergent validity, but low discriminative validity and homogeneity. The homogeneity was also low for the sum score. The inter-dimensional correlations were high. The concurrent validity was supported by correlations between the dimensional scores and other measures of disease activity and HRQOL. Patients in relapse scored significantly less on the sum score and the four dimensions compared to patients in remission. The test-retest correlations for the dimensional scores were 0.40-0.76. Patients with a change in disease activity during the 6-month follow-up period had a significant change in IBDQ scores not found in those who remained in remission. The Swedish version of the IBDQ had external validity and was shown to be a reliable and sensitive measure of HRQOL in ulcerative colitis, though there are some concerns regarding the internal validity. The use of a sum score was not supported and the questionnaire may benefit from a redivision of items into dimensions with better homogeneity and discriminative validity.


The fragile X mental retardation protein in circadian rhythmicity and memory consolidation.
The control of new protein synthesis provides a means to locally regulate the availability of synaptic components necessary for dynamic neuronal processes. The fragile X mental retardation protein (FMRP), an RNA-binding translational regulator, is a key player mediating appropriate synaptic protein synthesis in response to neuronal activity levels. Loss of FMRP causes fragile X syndrome (FraX), the most commonly inherited form of mental retardation and autism spectrum disorders. FraX-associated translational dysregulation causes wide-ranging neurological deficits including severe impairments of biological rhythms, learning processes, and memory consolidation. Dysfunction in cytoskeletal regulation and synaptic scaffolding disrupts neuronal architecture and functional synaptic connectivity. The understanding of this devastating disease and the implementation of meaningful treatment strategies require a thorough exploration of the temporal and spatial requirements for FMRP in establishing and maintaining neural circuit function.


Representational pseudoneglect: a review.
Pseudoneglect, the tendency to be biased towards the left-hand side of space, is a robust and consistent behavioural observation best demonstrated on the task of visuospatial line bisection, where participants are asked to centrally bisect visually presented horizontal lines at the perceived centre. A number of studies have revealed that a representational form of pseudoneglect exists, occurring when participants are asked to either mentally represent a stimulus or explore a stimulus using touch in the complete absence of direct visuospatial processing. Despite the growing number of studies that have demonstrated representational pseudoneglect there exists no current and comprehensive review of these findings and no discussion of a theoretical framework into which these findings may fall. An important gap in the current representational pseudoneglect literature is a discussion of the developmental trajectory of the bias. The focus of the current review is to outline studies that have observed representational pseudoneglect in healthy participants, consider a theoretical framework for these observations, and address the impact of lifespan factors such as cognitive ageing on the phenomenon.


Immunological biomarkers of tuberculosis.
Currently there are no sufficiently validated biomarkers to aid the evaluation of new tuberculosis vaccine candidates, the improvement of tuberculosis diagnostics or the development of more effective and shorter treatment regimens. To date, the detection of Mycobacterium tuberculosis or its products has not been able to adequately address these needs. Understanding the interplay between the host immune system and M. tuberculosis may provide a platform for the identification of suitable biomarkers, through both unbiased and targeted hypothesis-driven approaches. Here, we review immunological markers, their relation to M. tuberculosis infection stages and their potential use in the fight against tuberculosis.


Examining the impact of early longitudinal patient exposure on medical students' career choices.
Medical schools include career direction experiences to help students make informed career decisions. Most experiences are short, precluding students from attaining adequate exposure to long-term encounters within medicine. We investigated the impact of the First Patient Program (FPP), which fosters longitudinal patient exposure by pairing junior medical students with chronically ill patients through their healthcare journey, in instilling career direction. Medical students who completed at least 6-months in the FPP participated in a cross-sectional survey. Students' answers were analyzed with respect to the number of FPP appointments attended. Thematic analysis was conducted to explore qualitative responses. One hundred and forty-eight students participated in the survey. Only 28 (19%) students stated that the FPP informed their career decisions. Thirty-nine percent of students who attended four or more appointments indicated that the FPP informed their career decisions, compared to 16% of students who attended less (p=0.021). Thematic analysis revealed two themes: 1) Students focused mainly on patient encounters within FPP; and 2) Students sought career directions from other experiences. The majority of students did not attain career guidance from the FPP, but rather used the program to understand the impact of chronic illness from the patient's perspective.


Phosphorus Concentration in Water Affects the Biofilm Community and the Produced Amount of Extracellular Polymeric Substances in Reverse Osmosis Membrane Systems.
Biofouling is a problem that hinders sustainable membrane-based desalination and the stratification of bacterial populations over the biofilm's height is suggested to compromise the efficiency of cleaning strategies. Some studies reported a base biofilm layer attached to the membrane that is harder to remove. Previous research suggested limiting the concentration of phosphorus in the feed water as a biofouling control strategy. However, the existence of bacterial communities growing under phosphorus-limiting conditions and communities remaining after cleaning is unknown. This study analyzes the bacterial communities developed in biofilms grown in membrane fouling simulators (MFSs) supplied with water with three dosed phosphorus conditions at a constant biodegradable carbon concentration. After biofilm development, biofilm was removed using forward flushing (an easy-to-implement and environmentally friendly method) by increasing the crossflow velocity for one hour. We demonstrate that small changes in phosphorus concentration in the feed water led to (i) different microbial compositions and (ii) different bacterial-cells-to-EPS ratios, while (iii) similar bacterial biofilm populations remained after forward flushing, suggesting a homogenous bacterial community composition along the biofilm height. This study represents an exciting advance towards greener desalination by applying non-expensive physical cleaning methods while manipulating feed water nutrient conditions to prolong membrane system performance and enhance membrane cleanability.


Mechanism and stability of spectrally pure green up-conversion emission in Yb(3+)/Ho(3+) co-doped Ba5Gd8Zn4O21 phosphors.
A series of green-emitting up-conversion (UC) phosphors Ba5Gd8Zn4O21:Yb(3+),Ho(3+) were prepared by a modified sol-gel method, and X-ray diffraction (XRD) patterns were measured to characterize the crystal structure. The obtained UC samples emit dazzling green light and their spectra are composed of strong green emission peaking at 544 nm and negligible red emission peaking at 666 nm with the excitation of a 980 nm near-infrared (NIR) laser diode, assigned to (5)F4/(5)S2 → (5)I8 and (5)F5 → (5)I8 transitions of Ho(3+), respectively. The dependence of UC spectra on dopant contents, temperature and pumping power was employed to analyze UC emission color stability. The possible UC mechanisms and processes were proposed based on dependence of the UC emission intensity on pump power, and the lifetimes of green emission ((5)F4/(5)S2 → (5)I8) were also investigated to better comprehend the energy transfer (ET) process. The origin of spectrally pure green-emitting was discussed in detail by analyzing UC and down-conversion (DC) spectra in both the visible and NIR region by comparing that of the UC phosphor CaIn2O4:Yb(3+)/Ho(3+) with highly efficient green emission. Results suggest that Ba5Gd8Zn4O21:Yb(3+),Ho(3+) phosphors with intense green emission and high color purity have potential applications in displays and illuminating technology.


Transportation of market-weight pigs: II. effect of season and location within truck on behavior with an eight-hour transport.
Transportation of pigs to slaughter has the potential to negatively impact animal welfare, particularly in hot temperatures and over long transport durations. The objective of this experiment was to determine if season and location within vehicle influenced the behavior of market-weight pigs during loading, transit, unloading, and lairage after a long-distance trip to slaughter. On a pot-belly truck, 1,170 pigs were transported (n = 195 pigs/wk in 7 experimental compartments) for 8 h to a commercial abattoir in summer (6 wk) and winter (5 wk). Pig behavior was observed at loading, in transit, at unloading, and in lairage. Handler intervention at loading was observed, and the time to load and unload was recorded. Although season did not (P = 0.91) affect loading time, more prods (P = 0.014) were necessary to load pigs in summer than winter. Loading in winter also tended to be longer (P = 0.071) into compartments involving internal ramps. In transit, more pigs (P = 0.025) were standing in winter compared with summer. Unloading took longer (P < 0.006) in winter than in summer and from compartments where pigs had to negotiate ramps and 180° turns. Furthermore, pigs in summer experienced more slipping (P = 0.032), falling (P = 0.004), overlapping (P < 0.001), and walking backward (P < 0.001) than pigs in winter. Pigs unloading from compartments with internal ramps slipped more (P < 0.0001) than other pigs. Season influenced latency to rest in lairage, with those transported in summer resting sooner (P < 0.0001) than those in winter. In conclusion, season and location within trucks differentially affect pig behavior before, during, and after long-distance transportation. Differences in lighting and temperature between seasons and the inclusion of internal ramps within vehicles may play important roles in the welfare of pigs transported to slaughter.


Evaluation of Analysis Approaches for Latent Class Analysis with Auxiliary Linear Growth Model.
This study investigated the performance of three selected approaches to estimating a two-phase mixture model, where the first phase was a two-class latent class analysis model and the second phase was a linear growth model with four time points. The three evaluated methods were (a) one-step approach, (b) three-step approach, and (c) case-weight approach. As a result, some important results were demonstrated. First, the case-weight and three-step approaches demonstrated higher convergence rate than the one-step approach. Second, it was revealed that case-weight and three-step approaches generally did better in correct model selection than the one-step approach. Third, it was revealed that parameters were similarly recovered well by all three approaches for the larger class. However, parameter recovery for the smaller class differed between the three approaches. For example, the case-weight approach produced constantly lower empirical standard errors. However, the estimated standard errors were substantially underestimated by the case-weight and three-step approaches when class separation was low. Also, bias was substantially higher for the case-weight approach than the other two approaches.


Patient choice promotes adherence in preventive treatment for latent tuberculosis.
The aim of the present study was to compare the effect of patient choice on completion rates and adverse drug reactions for patients treated for latent tuberculosis infection (LTBI) using 3-month rifampicin and isoniazid treatment (3RH) or 6-month isoniazid treatment (6H). Data for all patients treated using 3RH or 6H for LTBI between 1998 and 2004 were analysed. In total, 675 patients attended for chemoprophylaxis. Of these, 314 received 3RH and 277 received 6H. From April 1, 2000, patients were offered a choice of regimen; 53.5% completed the regimen successfully, a further 10.3% potentially completed it successfully and 36.2% failed to complete treatment. Logistic regression analysis suggested that successful completion was more likely in patients who were younger (an association that was lost after removing all patients aged <16 yrs), were offered a choice of regimen and attended all clinic visits before commencing treatment. Treatment was discontinued due to adverse reactions in 16 (5.1%) patients who were prescribed 3RH and 16 (5.8%) who were prescribed 6H. Treatment failure was most likely during the first 4 weeks of treatment for both regimens. At 13 weeks of treatment, more patients taking 6H had stopped compared with those completing the 3RH regimen. Drug costs were greater using 6H compared with 3RH. In conclusion, offering a choice of regimen improves completion. Most patients chose the 3-month rifampicin and isoniazid treatment over the 6-month isoniazid treatment. Adverse drug reaction rates between the two regimens were similar.


A prediction model for sudden cardiac death in patients with heart failure and preserved ejection fraction.
Sudden cardiac death (SCD) accounts for ∼ 25% of all deaths in heart failure with preserved ejection fraction (HFpEF). However, strategies to identify HFpEF patients at a higher risk of SCD have not been developed. We studied 4128 patients with HFpEF enrolled in the Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction (I-PRESERVE) trial. All SCDs were adjudicated by a clinical endpoint committee. Cumulative incidences of SCD were estimated counting other deaths as competing risks. Cox regression analysis was used to generate a risk model for SCD. During a mean follow-up of 4.1 years, 231 (5.6%) patients died suddenly and 650 (15.7%) died non-suddenly. A multivariable model in 3480 patients including age, gender, history of diabetes and myocardial infarction, LBBB on ECG, and the natural logarithm of NT-proBNP identified a subgroup of 837 (24%) patients with ≥10% cumulative incidence of SCD over 5 years, accounting for other deaths as competing risk (Harrell's C index 0.75). The 5-year cumulative incidences of SCD in the higher and lower risk groups were 11% and 4%, respectively. In the higher risk group, 32% of deaths were SCD compared with 26% in the entire I-PRESERVE cohort. A multivariable prediction model identified patients with HFpEF who have a ≥10% risk of SCD over 5 years, similar to the risk of SCD in the Sudden Cardiac Death in Heart Failure (SCD-Heft) trial. This model may be useful for selecting patients with HFpEF for SCD prevention trials.


Potential role for magnetoencephalography in distinguishing low- and high-grade gliomas: a preliminary study with histopathological confirmation.
Gliomas are the most common form of tumor in the CNS and are exceptionally heterogeneous. Accurately characterizing gliomas, in terms of grade and type, is essential for predicting the rate of tumor progression. Histopathological grading and analysis based on biopsied tissue remains the gold standard, but non- and semi-invasive neuroimaging also plays a key role. Neuroimaging has been used to guide and optimize biopsies for several decades, but more recently molecular imaging and variants of MRI have shown promise in independently predicting glioma grade. Here we evaluated whether magnetoencephalographic (MEG) measurements of population-level physiology within the glioma space were predictive of the inherent grade of the tissue, based on definitive histopathological analyses. High-density MEG data were recorded from 11 patients who were undergoing functional mapping in preparation for resective surgery. The primary results indicated that glioma grade was positively correlated with the local amplitude of activity within the glioma space in the theta (4-7 Hz), alpha (8-14 Hz), and beta bands (14-30 Hz). Additionally, activity within the glioma was significantly elevated relative to the nonaffected homologue area in the same frequency bands. These results indicate that pathological levels of synchronization exist within the tumor space and that MEG may be a viable tool for noninvasively differentiating gliomas by their grade. Although these results should be considered preliminary and are only correlative in nature, these data suggest that MEG can potentially detect neurophysiological signatures or markers that predict the inherent grade of a glial tumor.


Evaluating the Cardiovascular Safety of Nonsteroidal Anti-Inflammatory Drugs.
Some drugs used to treat noncardiovascular conditions may adversely impact the cardiovascular status of individuals both with and without known cardiovascular disease. When the US Food and Drug Administration judges the potential cardiovascular safety signal to be of sufficient concern, it may require the pharmaceutical manufacturer of the drug in question to conduct a postmarketing (phase 4) randomized controlled trial (RCT). Although historically many phase 4 RCTs focused on efficacy (using a superiority design), contemporary phase 4 RCTs often are focused on safety and use a noninferiority design. The choices made by investigators during the planning stage of a postmarketing phase 4 RCT dedicated to the evaluation of cardiovascular safety can influence the ability to compare the standard and test agents. Multiple factors reflecting the conduct of a phase 4 RCT for a general medical condition may influence interpretation of a cardiovascular safety signal. The higher the rates of failure to adhere to the protocol and dropout from the study, the greater the risk of bias. Trials evaluating the cardiovascular safety of nonsteroidal anti-inflammatory drugs (NSAIDs) when used for arthritis are difficult to conduct and even more challenging to interpret. Concerns include the comparison of drug regimens that do not provide comparable analgesic efficacy and problems with adherence to the protocol and retention in the study. On the basis of phase 4 RCTs of NSAIDs to date, it appears that a comparatively low dose of celecoxib administered to low-risk subjects is associated with approximately the same cardiovascular risk as NSAIDs with less cyclooxygenase-2 inhibitory activity, but at the cost of not controlling arthritic pain as effectively.


Economic evaluation of influenza vaccination in Thai chronic obstructive pulmonary disease patients.
To determine the cost-effectiveness and cost-benefit of influenza vaccination in chronic obstructive pulmonary disease (COPD) patients the authors conducted a stratified randomized, double-blind, placebo-controlled trial from June 1997 to November 1998 at a university hospital in Thailand. A total of 125 COPD patients were stratified based on their FEV1 as mild COPD (FEV1 > or = 70% predicted), moderate COPD (FEV1 50-69% predicted) and severe COPD (FEV1 < 50% predicted) and in each severity stratum they were randomized to the vaccine group (received intramuscular injection with purified trivalent split-virus vaccine containing A/Texas/36/91 (H1N1), A/Nanchang 1933/95 (H3N2) and B/Harbin 107/94) or the placebo group (received intramuscular injection with vit B1). Number of episodes of acute respiratory illness (ARI) related to influenza (clinical ARI + a serum hemagglutination inhibition antibody titre of 38 or greater and a four fold titre increase in convalescent serum compared to acute serum) as well as severity of each ARI (outpatient treatment, hospitalization or required mechanical ventilation) and costs of treatment (direct medical costs comprised real drug costs from the hospital dispensary in outpatient cases and real charges in hospitalization cases) were collected and analyzed for the cost-effectiveness and cost-benefit of influenza vaccination. The incidence of influenza-related ARI in the study year was 27 per cent in the placebo group and 6.4 per cent in the vaccine group (relative risk [RR] 0.24, vaccine effectiveness 76%). The incidence was 27.3 per cent, 23.5 per cent and 29.2 per cent in mild, moderate and severe COPD respectively in the placebo group and 4.3 per cent, 12.5 per cent, and 4.3 per cent in the mild, moderate and severe COPD respectively in the vaccine group (RR 0.16, 0.53 and 0.15; vaccine effectiveness 84%, 47%, and 85% respectively). The incremental cost-effectiveness ratios demonstrated that for every 100 patients with mild COPD whom the authors decided to vaccinate, the cost would be 24,840 baht more and would prevent 18.2 outpatients, 4.8 hospitalizations and 0 patient from mechanical ventilation due to ARI related to influenza. Likewise, the authors would have prevented 5.1 outpatients, 5.9 hospitalizations, 5.9 mechanical ventilation and 20.8 outpatients, 3.9 hospitalizations, 8.3 mechanical ventilation for every 100 moderate COPD and every 100 severe COPD patients vaccinated respectively. More than 90 per cent of the costs of treatment of influenza-related ARI were costs of hospitalization and for patients with moderate and severe airflow obstruction, more than 90 per cent of these costs were attributed to the costs of treating the patients who required mechanical ventilation. Predicted cost savings for every 100 mild COPD, 100 moderate COPD and 100 severe COPD patients vaccinated were 125,629 baht, 538,184.3 baht, and 680,647.1 baht respectively. Influenza vaccination is highly effective in the prevention of acute respiratory illness related to influenza virus infection in COPD, regardless of severity of airflow obstruction. Vaccination is more cost-effective in preventing mechanical ventilation episodes and more cost-benefit in patients with more severe airflow obstruction. Influenza vaccination should be recommended to all patients with COPD with the higher priority provided to patients with more severe airflow obstruction.


Effect of iron-limiting conditions on growth of clinical isolates of Acinetobacter baumannii.
Different clinical isolates of Acinetobacter baumannii, typed by plasmid profile, were able to grow in iron-chelated medium by secreting iron-regulated siderophores. This iron-scavenging phenotype was associated with the production of iron-repressible catechol. Siderophore utilization bioassays showed the presence of 2,3-dihydroxybenzoic acid in the growth medium, and neither enterobactin nor aerobactin was detected in culture supernatants obtained under iron-deficient conditions.


Relationships of intraosseous and systemic pressure waveforms in a Swine model.
Despite some focus on the use of intraosseous (IO) catheters to obtain laboratory samples, very little is known about the potential for obtaining other forms of clinical data. Largely unstudied is the relationship between IO pressures (IOPs) and systemic hemodynamic pressures such as mean arterial pressure (MAP) and central venous pressures (CVP). The objective was to explore the relationship between hemodynamic parameters (blood pressures) measured through an IO catheter and intravascular catheters placed in the arterial and central venous circulation. Eight pigs (Sus scrofa) weighing 30 to 45 kg were sedated with a short-acting agent, intubated with a cuffed endotracheal tube, and anesthetized with 2% to 3% isoflurane. Intravascular catheters were placed into the femoral or carotid artery and the femoral or jugular vein for MAP and CVP measurements. IO catheters, 15 mm for the sternum and 25 mm for the long bones, were placed percutaneously into the proximal tibia, proximal femur, proximal humerus, right proximal ulna, and/or sternum. Pressures were recorded during normotension, hypotension, and hypertension. Averaged across all eight animals, the means (ranges) for baseline systemic pressures were as follows: MAP = 66.5 (55.6 to 76.7) mm Hg, tibia IOP = 17.4 (9.3 to 34.5) mm Hg, femur IOP =18.4 (3.3 to 33.1) mm Hg, humerus IOP = 15.7 (2.8 to 28.9) mm Hg, ulna IOP = 16.0 (7.9 to 25.6) mm Hg, sternum IOP = 5.7 (-0.5 to 47.9) mm Hg, and CVP = 2.7 mm Hg (-3.3 to 7.9) mm Hg. The best median correlation occurred between femur IOP and mean MAP (r = 0.65). The four highest correlations between IOP and MAP were associated with mean femur IOP. Only one IO site had a correlation coefficient over 0.50 for CVP. The long bones tended to correlate better with the MAP and the sternum tended to correlate better with the CVP. Nonlinearity was observed in the actively rising pressure phases, which can be explained by a hysteresis model. The relationship between IOP and MAP or CVP is variable by site, with the MAP and CVP tending to be estimated by the femur and sternum, respectively. The relationship to actively rising pressures is nonlinear and a hysteresis model is proposed to explain the phase change. Further experimentation is needed to refine the IOP relationship to the MAP and CVP and assess the potential of these measurements to provide clinically relevant information.


[Effect of four doses of the Su(UR)ES gene on intercalary heterochromatin in Drosophila melanogaster].
Polytene chromosomes of salivary glands of various Drosophila melanogaster strains containing two doses of the normal Su(UR)ES allele have a constant set of intercalary heterochromatin (IHC) sites. Their DNA is underreplicated, which leads to breaks and ectopic contacts emerging at a certain rate. Almost no underreplication, breaks, or ectopic conjugation are present in mutants lacking the normal Su(UR)ES gene product. It could be expected that an increase in the number of the Su(UR)ES+ gene doses would, in turn, drastically increase ectopic conjugation and breakage. To test this hypothesis, a strain of D. melanogaster was obtained with two additional doses of Su(UR)ES+ introduced into its genome. The flies with four gene doses exhibited a considerable increase in ectopic conjugation: both the proportion of regions participating in conjugation and the number of chromosomes with numerous contact nodes were increased. As a result, chromosomes that were straight and well-stretched in homozygotes for the mutation in Su(UR)ES became twisted and wound and contained many loops or nodes. Many chromosomes were wound too tightly for cytological analysis. Four doses of Su(UR)ES+ considerably increased the number of weak "points." For example, the 2R chromosome has only 3 weak points in strains with two doses of Su(UR)ES+ and as many as 22 weak points in the strain with four doses. In the transgenic strain, the frequency of breaks in previously known weak points increased, and new breaks appeared in 19 additional sites. All new break points appeared in the regions that were earlier described as regions of late replication in the S phase.


Cost-utility analysis of adjuvant imatinib treatment in patients with high risk of recurrence after gastrointestinal stromal tumour (GIST) resection in Thailand.
Many patients develop tumour recurrence within a few years after undergoing surgical resection of gastrointestinal stromal tumours (GIST). Adjuvant imatinib treatment is recommended for patients with high risk of GIST recurrence as it can improve recurrence-free survival and overall survival of patients. This study aims to assess the cost-utility of adjuvant imatinib in patients with high risk of GIST recurrence after surgery compared with no adjuvant therapy in Thailand. A Markov model was developed to estimate lifetime costs and outcomes of using adjuvant imatinib treatment and other treatment alternatives if recurrence occurred compared with the current situation of no adjuvant therapy in high-risk patients after surgery. A 1-month cycle length was deployed in the model. Transition probabilities were derived from literature review. Costs were collected and calculated for the year 2014 from a societal perspective. Future costs and outcomes were discounted at 3% per year. One-way and probabilistic sensitivity analyses were conducted to assess parameter uncertainties. Three years of adjuvant imatinib treatment followed by imatinib treatment and best supportive care if recurrence occurred after or during adjuvant therapy, respectively, was the best option as it produced more health outcomes (1.23 life years (LYs) and 1.16 quality-adjusted life years (QALYs)) compared to no adjuvant therapy while yielding the lowest incremental cost-effectiveness ratio (ICER) of 1,648,801 Thai Baht (THB) per QALY gained. Three years of adjuvant imatinib treatment followed by sunitinib treatment if recurrence occurred had an ICER of 2,608,264 THB per QALY gained compared to the best option, while other options were dominated. A one-way sensitivity analysis showed that the utility of patients receiving adjuvant imatinib had the greatest effect on the model, followed by the discount rate and probability of GIST recurrence. Adjuvant imatinib treatment improved the health benefits of patients with high risk of GIST recurrence. However, in the Thai context, it was not cost-effective at the current price.


Selenite protects Caenorhabditis elegans from oxidative stress via DAF-16 and TRXR-1.
Selenium is an essential micronutrient. In the present study, trace amount of selenite (0.01 μM) was evaluated for oxidative stress resistance and potential associated factors in Caenorhabditis elegans. Selenite-treated C. elegans showed an increased survival under oxidative stress and thermal stress compared to untreated controls. Further studies demonstrated that the significant stress resistance of selenite on C. elegans could be attributed to its in vivo free radical-scavenging ability. We also found that the oxidative and thermal stress resistance phenotypes by selenite were absent from the forkhead transcription factor daf-16 mutant worms. Moreover, selenite influenced the subcellular distribution of DAF-16 in C. elegans. Furthermore, selenite increased mRNA levels of stress-resistance-related proteins, including superoxide dismutase-3 and heat shock protein-16.2. Additionally, selenite (0.01 μM) upregulated expressions of transgenic C. elegans carrying sod-3::green fluorescent protein (GFP) and hsp-16.2::GFP, whereas this effect was abolished by feeding daf-16 RNA interference in C. elegans. Finally, unlike the wild-type N2 worms, the oxidative stress resistance phenotypes by selenite were both absent from the C. elegans selenoprotein trxr-1 mutant worms and trxr-1 mutants feeding with daf-16 RNA interference. These findings suggest that the antioxidant effects of selenite in C. elegans are mediated via DAF-16 and TRXR-1.


3D beam reconstruction by fluorescence imaging.
We present a technique for mapping the complete 3D spatial intensity profile of a laser beam from its fluorescence in an atomic vapour. We propagate shaped light through a rubidium vapour cell and record the resonant scattering from the side. From a single measurement we obtain a camera limited resolution of 200 × 200 transverse points and 659 longitudinal points. In constrast to invasive methods in which the camera is placed in the beam path, our method is capable of measuring patterns formed by counterpropagating laser beams. It has high resolution in all 3 dimensions, is fast and can be completely automated. The technique has applications in areas which require complex beam shapes, such as optical tweezers, atom trapping and pattern formation.


Optimization of Pharmacokinetic and In Vitro Safety Profile of a Series of Pyridine Diamide Indirect AMPK Activators.
A set of focused analogues have been generated around a lead indirect adenosine monophosphate-activated kinase (AMPK) activator to improve the rat clearance of the molecule. Analogues were focused on inhibiting amide hydrolysis by the strategic placement of substituents that increased the steric environment about the secondary amide bond between 4-aminopiperidine and pyridine-5-carboxylic acid. It was found that placing substituents at position 3 of the piperidine ring and position 4 of the pyridine could all improve clearance without significantly impacting on-target potency. Notably, trans-3-fluoropiperidine 32 reduced rat clearance from above liver blood flow to 19 mL/min/kg and improved the hERG profile by attenuating the basicity of the piperidine moiety. Oral dosing of 32 activated AMPK in mouse liver and after 2 weeks of dosing improved glucose handling in a db/db mouse model of Type II diabetes as well as lowering fasted glucose and insulin levels.


Screen time and metabolic risk factors among adolescents.
To examine the association between screen time (ST) (ie, television/DVD/video and computer use) guidelines and risk factors for cardiovascular disease, type 2 diabetes mellitus, and fatty liver diseases in mid-adolescence. Cross-sectional. High schools in Sydney, Australia. Grade 10 students (N = 496; 58% boys; mean [SD] age, 15.4 [0.4] years). Body mass index, waist circumference, cardiorespiratory endurance, dietary factors, socioeconomic status, and pubertal status. Screen time was categorized as less than 2 hours per day or 2 or more hours per day and calculated for weekday, weekend, and the entire week. Fasting blood samples were analyzed for levels of high-density lipoprotein and low-density lipoprotein cholesterol, triglycerides, insulin, and glucose; homeostasis model assessment of insulin resistance (HOMA-IR); levels of alanine aminotransferase, gamma-glutamyltransferase, and high-sensitivity C-reactive protein; and blood pressure. Abnormal results were categorized according to published guidelines. Mean ST for all students was 3.1 hours per day and for weekdays and weekend days, 2.6 hours per day and 4.4 hours per day, respectively. Boys were more likely to exceed ST guidelines than girls (odds ratio [OR], 2.71; 95% confidence interval [CI], 1.67-4.38). There were no significant associations between ST guidelines and metabolic risk factors among girls. After adjusting for potential confounders, boys who exceeded ST guidelines on weekdays were more likely to have elevated HOMA-IR (adjusted OR, 2.42; 95% CI, 1.11-5.28) and insulin levels (adjusted OR, 2.73; 95% CI, 1.43-5.23). Adolescent boys with ST of 2 or more hours per day on weekdays have twice the risk of abnormal levels of insulin and HOMA-IR compared with peers with ST less than 2 hours per day on weekdays. These results suggest there is an increased risk of insulin resistance among adolescent boys who do not meet ST guidelines on weekdays.


Effect of Electrical Myostimulation on the Function of Lower Leg Muscles.
Electrical myostimulation (EMS) method is applied to improve skeletal muscle function. The aim of this study was to evaluate the efficacy of EMS applied to the sole and calf muscles on their strength and on maximal sprint performance. Each of 10 training sessions involved 10 seconds of stimulation and 50 seconds of rest for a total of 10 minutes. After the 10 training sessions, the maximal voluntary contraction (MVC) of right calf muscles increased by 6.0% from 830.0 ± 47.0 N to 878.0 ± 45.3 N (p ≤ 0.05). When EMS was applied to trained athletes, their 10-m sprint performance improved by 2.1% (p ≤ 0.05). In the second part of the study, a 3-week training program with EMS was applied to athletes, which significantly improved their 10-m sprint performance from a standing start by 5.3% and from a running start by 4.7% (p ≤ 0.05). Thus, 10 EMS cycles up to the maximal tolerated intensity applied every other day improved the MVC of foot flexion muscles and 10-m sprint performance from both standing and running starts. Three weeks of EMS training did not affect the intensity of calf muscle blood flow and oxygen saturation at rest. The training program supplemented with 10 EMS sessions produced significantly greater effects on the 10-m sprint performance from both a standing and a running start.


Smoking Pattern and Associated Sociodemographic Factors: Findings from a Nationwide STEPS Survey in Iran.
Smoking is a modifiable risk factor for noncommunicable diseases with a wide range of harmful health outcomes. Identification of sociodemographic characteristics of smokers can be a guideline to development of effective intervention proportional to target population. This study aimed to determine smoking pattern and its associated sociodemographic factors in Iran. This cross-sectional study was conducted based on data from the sixth round of nationwide STEPwise approach to Surveillance (STEPS) survey in the 31 provinces of Iran. A total of 10,834 participants aged ≥15 years were selected through a multistage cluster sampling method. Collecting data was performed via three-step questionnaire (ecological, behavioral risk factors, and physical and biochemical measurements). Data analysis was performed via Epi Info and then SPSS version 21 softwares using descriptive methods and analytical tests. Of all participants, 9.6% were current cigarette smokers, which was significantly more frequent among men than women (21.5% vs. 1.1%, respectively, P < 0.001). Smoking was significantly associated with being self-employed and having under diploma education level (P < 0.05). Of all current cigarette smokers, 8.7% were daily smokers. The mean ± standard deviation of systolic blood pressure and history of cardiovascular symptoms in current smokers were higher than nonsmokers (P = 0.005 and P < 0.001, respectively). Coughing for >4 weeks, frequent wheezing, and shortness of breath were significantly more frequent in current smokers than nonsmokers (P < 0.001, P < 0.001, and P = 0.02, respectively). Our results draw a picture of sociodemographic distribution of smoking pattern to determine the specific characteristics of the target population affecting cigarette smoking and identified specific demographic strategies for preventive and control action plan.


Fourth-generation endovascular stent-graft: the concept of laminar flow.
The stent graft is a noncompliant system inserted in a semi-compliant structure. This generates a mismatch. The media also shows a composite movement and is oriented 45° resulting in an arterial spiral movement that contributes to maintaining the clockwise orientation of laminar flow with an 80° deflection. Our multilayer stent is constituted by a single Nitinol thread, worked on 3 surfaces in order to realize a proper exoskeleton that reproduces the architecture of the tunica media, in particular its flexo-torsional forces, thus restoring the energy transmission and the match between the wall and the blood flow. A first in vivo implantation was performed by using an experimental pig model in our veterinary department. The pig underwent general anesthesia and the right femoral artery was surgically exposed in order to accommodate a 12F long introducer sheath. Under fluoroscopy three multilayer stents were consecutively implanted from the aortic isthmus to the iliac bifurcation in an overlap fashion. All the intercostal artery and visceral branches were covered by the overlapped stents. The final control angiography revealed an optimal sealing of the implanted stent with an evident flexotorsional oscillatory movement, which follows the conical architecture of the thoracic aorta and the complete patency of all the branches that arise from the aorta. After two months, the multilayer showed a normal endothelialization process with an optimal adhesion to the aortic wall both proximally and distally without provoking any inflammatory response or thickness wall alterations. The perfect and homogenous endothelialization preserved the patency of all the collateral branches arising from the treated aorta, in particular all the intercostal arteries, celiac trunk, and renal arteries. The disease of the aorta essentially concerns the tunica media as it causes disruption of the media components. This exoskeleton works like a neo-tunica media, is perfectly endothelialized, and seems to optimally transmit the flexotorsional forces, restoring the match between wall and flow that represents the primary condition for laminar flow and branch perfusion.


[Making sense of the narratives of chronically ill persons].
Understand how chronically ill persons reframe life through their discursive practices. Six interviews were selected from the original seventeen made with chronically ill persons from a public hospital in the metropolitan region of Porto Alegre. Recorded and transcribed interviews produced narratives concerning the existential situation in the face of disease, perspectives for the future, a comprehension of diagnosis and of therapy as well as the role of professionals for the reframing. Talks were divided in linguistic repertoires concerning diagnosis and therapy. In the first, the narratives of meaning are structured around cause of the disease from a genetic background (destiny) or due to the style of life (fault). In the repertoires about therapy, narratives of the self identity reconfiguration depend on the autonomy or heteronomy in relation to the physician's words as mediator of salvation, on perception of the body as a factor of relation, on the social representation of medication and on emotional situation. Self-satisfaction relies on finding the thread to bring together the elements of existence based on a new model permitting a new identity. The professional must be involved in the narratives of identity reconstruction enabling therapy to produce the expected effect and for the patient to feel as a participant of the process, assuming with autonomy the necessary changes in life.


Moving forward with the neuromuscular junction.
The neuromuscular junction (NMJ) is indispensable for survival. This synapse between motoneurons and skeletal muscle fibers allows posture, movement and respiration. Therefore, its dysfunction creates pathologies than can be lethal. The molecular mechanisms of NMJ development and maintenance are the subject of intensive studies. This mini-review focuses on some of the most recent discoveries. An unexpected role for a protein, rapsyn, which has been known for 40 years to aggregate acetylcholine receptors has emerged. A new cell partner at NMJ has been unmasked and is challenging our understanding of the functioning of this synapse. Toxins are now used as new tools to study degeneration/regeneration. The possibility of creating human NMJ in vitro is within reach with major consequences for drug screening. Wnts are secreted neurogenic factors that have been involved in vitro in acetylcholine receptor clustering, but their precise role in vivo remains to be clarified. All these data are raising new and exciting perspectives in the field and are discussed in this Review. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms.


The future of clinical trials and drug development: 2050.
A workshop held at the 18th Annual Conference of the Pharmaceutical Contract Management Group in Krakow on 9 September 2022 asked over 200 delegates what the clinical trial landscape would look like in 2050. Issues considered included who will be running the pharmaceutical industry in 2050; how 'health chips', wearables and diagnostics will impact on finding the right patients to study; how will artificial intelligence be designing and controlling clinical trials; and what will the role of the Clinical Research Associate, the critical observer, documenter and conductor of a clinical trial need to look like by 2050. The consensus was that, by 2050, if you are working in clinical trials, you will be a data scientist. We can expect to see an increasing role of new technologies and a new three-phase registration model for novel therapies. The first phase will involve an aspect of quality evaluation and biological proof-of-concept probably involving more preclinical modelling and engineered human cell lines and fewer animal studies than currently used. Once registered, new products will enter a period of adaptive clinical development (delivered as a single study) intended to establish safety. This phase will most likely take around 1-2 years and explore tailored options for administration. Investigations will most likely be conducted in patients, possibly in a 'patient-in-a-box' setting (hospital or healthcare centre, virtual or microsite). On completion of safety licencing, drugs will begin an assessment of efficacy in partnership with those responsible for reimbursement - testing will be performed in patients, possibly where individual patient involvement in safety testing will offer some reimbursement deal for future treatment. Change is coming, though its precise form will likely depend on the creativity and vision of sponsors, regulators and payers.


Dynamic regulation of pancreatic β cell function and gene expression by the SND1 coregulator in vitro.
The pancreatic β cell synthesizes, packages, and secretes insulin in response to glucose-stimulation to maintain blood glucose homeostasis. Under diabetic conditions, a subset of β cells fail and lose expression of key transcription factors (TFs) required for insulin secretion. Among these TFs is Pancreatic and duodenal homeobox 1 (PDX1), which recruits a unique subset of transcriptional coregulators to modulate its activity. Here we describe a novel interacting partner of PDX1, the Staphylococcal Nuclease and Tudor domain-containing protein (SND1), which has been shown to facilitate protein-protein interactions and transcriptional control through diverse mechanisms in a variety of tissues. PDX1:SND1 interactions were confirmed in rodent β cell lines, mouse islets, and human islets. Utilizing CRISPR-Cas9 gene editing technology, we deleted Snd1 from the mouse β cell lines, which revealed numerous differentially expressed genes linked to insulin secretion and cell proliferation, including limited expression of Glp1r. We observed Snd1 deficient β cell lines had reduced cell expansion rates, GLP1R protein levels, and limited cAMP accumulation under stimulatory conditions, and further show that acute ablation of Snd1 impaired insulin secretion in rodent and human β cell lines. Lastly, we discovered that PDX1:SND1 interactions were profoundly reduced in human β cells from donors with type 2 diabetes (T2D). These observations suggest the PDX1:SND1 complex formation is critical for controlling a subset of genes important for β cell function and is targeted in diabetes pathogenesis.


Haemophilus b disease after vaccination with Haemophilus b polysaccharide or conjugate vaccine.
The reported frequency of invasive Haemophilus influenzae type b disease occurring within 1 year after immunization was compared in American children who received either Praxis Biologics' Haemophilus b polysaccharide vaccine or Connaught Laboratories' Haemophilus b conjugate vaccine during the first year of distribution. All domestic cases reported to the Food and Drug Administration or the Centers for Disease Control were included in the study. An estimated 4.5 million and 2.0 million doses of polysaccharide and conjugate vaccines were administered, respectively. Approximately three cases of early-onset disease (disease developing less than 15 days after vaccination) per million doses were reported for the polysaccharide compared with four cases per million doses for the conjugate vaccine. There were 30.7 reported vaccine failures per million doses of the polysaccharide vaccine compared with 9.0 per million doses of the conjugate vaccine, a 3.4-fold difference. The reporting rate ratios (cases of vaccine failure to cases of early-onset disease) for the polysaccharide and conjugate were 11.5 and 2.3, respectively, a fivefold difference. Thus, compared with recipients of the polysaccharide vaccine, vaccine failures reported among recipients of the conjugate vaccine were 80% fewer than expected.


Transcriptome-Wide Profiling of Protein-RNA Interactions by Cross-Linking and Immunoprecipitation Mediated by FLAG-Biotin Tandem Purification.
RNA and RNA-binding proteins (RBPs) control multiple biological processes. The spatial and temporal arrangement of RNAs and RBPs underlies the delicate regulation of these processes. A strategy called CLIP-seq (cross-linking and immunoprecipitation) has been developed to capture endogenous protein-RNA interactions with UV cross-linking followed by immunoprecipitation. Despite the wide use of conventional CLIP-seq method in RBP study, the CLIP method is limited by the availability of high-quality antibodies, potential contaminants from the copurified RBPs, requirement of isotope manipulation, and potential loss of information during a tedious experimental procedure. Here we describe a modified CLIP-seq method called FbioCLIP-seq using the FLAG-biotin tag tandem purification. Through tandem purification and stringent wash conditions, almost all the interacting RNA-binding proteins are removed. Thus, the RNAs interacting indirectly mediated by these copurified RBPs are also reduced. Our FbioCLIP-seq method allows efficient detection of direct protein-bound RNAs without SDS-PAGE and membrane transfer procedures in an isotope-free and protein-specific antibody-free manner.


Carbon Dioxide Elimination After Sodium Bicarbonate Administration as a Novel Method to Assess Cardiac Output: A Pilot Study.
Introduction Cardiac output/pulmonary blood flow measurement is an important way to assess patients during the perioperative period, as well as patients who are critically ill. Current methods of assessing cardiac output have limitations. One indicator of cardiac output may be the expired carbon dioxide (CO2) partial pressure response to intravenous sodium bicarbonate (IVSB), which is rapidly converted to CO2. Methods We conducted an initial evaluation of the relationship between expired CO2 partial pressure and blood flow after a bolus of IVSB. To assess this relationship, we used a cardiopulmonary bypass circuit with predetermined blood flows in a laboratory trial and then assessed 18 patients undergoing surgery requiring cardiopulmonary bypass. Results For the laboratory portion of this pilot study, higher peak expired CO2, faster time to reach peak, higher area under the curve, and greater kurtosis of peak were observed at higher cardiac output flow rates, and higher mean expired CO2 was significantly associated with higher flow rates (p < 0.001). In the human study, higher mean (p = 0.023) and peak expired CO2 (p = 0.028) were both significantly associated with higher cardiac output flow rates. Conclusions This technique may be a way to intermittently assess cardiac output or improve accuracy when used in conjunction with other continuous output monitors.


Inequitable access to nonpharmacologic pain treatment providers among cancer-free U.S. adults.
Using evidence-based nonpharmacologic pain treatments may prevent opioid overuse and associated adverse outcomes. There is limited data on the impact of access-promoting social determinants of health (SDoH: education, income, transportation) on use of nonpharmacologic pain treatments. Our objective was to examine the relationship between SDoH and use of nonpharmacologic pain treatment providers. Our goal was to understand policy-actionable factors contributing to inequity in pain treatment. Based on Andersen's Health Utilization Model, this cross-sectional analysis of 2016-2019 Medical Expenditure Panel Survey data evaluated whether use of outpatient nonpharmacologic pain treatment providers is driven by enabling (i.e., advantageous socioeconomic resources) or need (i.e., perceived disability and diagnosed disease) factors. The study sample (unweighted n = 28,188) represented a weighted N = 81,912,730 noninstitutionalized, cancer-free, U.S. adults with pain interference. The primary outcome measured use of nonpharmacologic providers relative to exclusive prescription opioid use or no treatment (i.e., neither opioids nor nonpharmacologic). To quantify equitable access, we compared the variance-between access-promoting enabling factors versus medical need factors-that explained utilization. Compared to enabling factors, need factors explained twice the variance predicting pain treatment utilization. Still, the adjusted odds of using nonpharmacologic providers instead of opioids alone were 39% lower among respondents identifying as Black (95% Confidence Interval [CI], 0.49-0.76) and respondents residing in the U.S. South (95% CI, 0.51-0.74). Higher education (95% CI, 1.72-2.79) and income (95% CI, 1.68-2.42) both facilitated using nonpharmacologic providers instead of opioids. These findings highlight the substantial influence access-promoting SDoH have on pain treatment utilization.


[Studies on anti-inflammation chemical constitutes of Patrinia villosa].
Patrinia villosa (Thunb. ) Juss. is a Chinese folk medicine, in order to find the material basis that were related to anti-inflammation pharmacodynamic action, we investigated for chemical constituents by chemical and spectroscopic analysis. By phytochemical research, 9 compounds were isolated from the acetic acid ethyl ester & N-Butanol of P. villosa and identified 7 compounds (beta-sitosterol, Villosol, Quercetin, Ferulic acid, Ursolic acid, beta-daucosterol, Rutin), and three compounds (Ferulic acid, Ursolic acid and Rutin) are firstly obtained from P. villosa.


Information and communication technology use in asthmatic patients: a cross-sectional study in Latin America.
Rapid diffusion, low cost and broad availability of information and communication technologies (ICTs) make them an attractive platform for managing care, communication and interventions in asthma. There is little information in Latin America about usage frequency of ICTs in asthmatic patients. The analysis undertaken consisted of an observational, cross-sectional study that aimed to identify the frequency and type of ICTs most often used by asthmatics. The Spanish version of the Michigan questionnaire was employed in five Latin American countries. Age and educational level was categorised. Logistic regression was performed among these groups concerning the frequency of ICT usage and the level of interest shown in seeking and receiving information about asthma. In total, 673 asthma patients were surveyed. The mean age was 43.44 years. Over two-thirds of the participants were female (68.4%). The most used ICT was the short message service (SMS) (69.9%). SMS and E-mail are useful tools for communicating (i.e. receiving and seeking information) with all asthma patients, irrespective of their age. WhatsApp (61.5%) and Facebook (32.0%) were rated as being the most interesting channels of communication for receiving information. Regression analysis showed that younger asthmatics and asthmatics with higher educational levels were most likely to use almost all forms of ICTs. ICTs are generally an attractive platform for managing care, communication and interventions to improve asthma care. SMS and E-mail were found to be the preferred ICT forms among users. However, social media forms such as WhatsApp and Facebook may also be appropriate for certain types of patient.


ω-Hydroxyemodin limits staphylococcus aureus quorum sensing-mediated pathogenesis and inflammation.
Antibiotic-resistant pathogens are a global health threat. Small molecules that inhibit bacterial virulence have been suggested as alternatives or adjuncts to conventional antibiotics, as they may limit pathogenesis and increase bacterial susceptibility to host killing. Staphylococcus aureus is a major cause of invasive skin and soft tissue infections (SSTIs) in both the hospital and community settings, and it is also becoming increasingly antibiotic resistant. Quorum sensing (QS) mediated by the accessory gene regulator (agr) controls virulence factor production essential for causing SSTIs. We recently identified ω-hydroxyemodin (OHM), a polyhydroxyanthraquinone isolated from solid-phase cultures of Penicillium restrictum, as a suppressor of QS and a compound sought for the further characterization of the mechanism of action. At concentrations that are nontoxic to eukaryotic cells and subinhibitory to bacterial growth, OHM prevented agr signaling by all four S. aureus agr alleles. OHM inhibited QS by direct binding to AgrA, the response regulator encoded by the agr operon, preventing the interaction of AgrA with the agr P2 promoter. Importantly, OHM was efficacious in a mouse model of S. aureus SSTI. Decreased dermonecrosis with OHM treatment was associated with enhanced bacterial clearance and reductions in inflammatory cytokine transcription and expression at the site of infection. Furthermore, OHM treatment enhanced the immune cell killing of S. aureus in vitro in an agr-dependent manner. These data suggest that bacterial disarmament through the suppression of S. aureus QS may bolster the host innate immune response and limit inflammation.


Independent influence of negative blood cultures and bloodstream infections on in-hospital mortality.
The independent influence of blood culture testing and bloodstream infection (BSI) on hospital mortality is unclear. We included all adults treated in non-psychiatric services at our hospital between 2004 and 2011. We identified all blood cultures and their results to determine the independent association of blood culture testing and BSI on death in hospital using proportional hazards modeling that adjusted for important covariates. Of 297 070 hospitalizations, 48 423 had negative blood cultures and 5274 had BSI. 12 529 (4.2%) died in hospital. Compared to those without blood cultures, culture-negative patients and those with BSI were sicker. Culture-negative patients had a significantly increased risk of death in hospital (adjusted hazard ratio [HR] ranging between 3.1 and 4.4 depending on admission urgency, extent of comorbidities, and whether the blood culture was taken in the intensive care unit). Patients with BSI had a significantly increased risk of death (adj-HR ranging between 3.8 and 24.3] that was significantly higher when BSI was: diagnosed within the first hospital day; polymicrobial; in patients who were exposed to immunosuppressants or were neutropenic; or due to Clostridial and Candidal organisms. Death risk in culture negative and bloodstream infection patients decreased significantly with time. Risk of death in hospital is independently increased both in patients with negative blood cultures and further in those with bloodstream infection. Death risk associated with bloodstream infections varied by the patient's immune status and the causative microorganism.


Role of liver ICAM-1 in metastasis.
Intercellular adhesion molecule (ICAM)-1, is a transmembrane glycoprotein of the immunoglobulin (Ig)-like superfamily, consisting of five extracellular Ig-like domains, a transmembrane domain and a short cytoplasmic tail. ICAM-1 is expressed in various cell types, including endothelial cells and leukocytes, and is involved in several physiological processes. Furthermore, it has additionally been reported to be expressed in various cancer cells, including melanoma, colorectal cancer and lymphoma. The majority of studies to date have focused on the expression of the ICAM-1 on the surface of tumor cells, without research into ICAM-1 expression at sites of metastasis. Cancer cells frequently metastasize to the liver, due to its unique physiology and specialized liver sinusoid capillary network. Liver sinusoidal endothelial cells constitutively express ICAM-1, which is upregulated under inflammatory conditions. Furthermore, liver ICAM-1 may be important during the development of liver metastasis. Therefore, it is necessary to improve the understanding of the mechanisms mediated by this adhesion molecule in order to develop host-directed anticancer therapies.


Are type C viruses transforming agents?
Type C RNA viruses have been considered oncogenic because they are found associated with animal tumors and can induce cancers in several animal species. Those viruses that rapidly cause cancer appear to contain an oncogenic gene which resembles genetic sequences present in normal cells. This gene codes for a transforming protein which may be a normal cellular enzyme or a slightly altered cellular product. Its mechanism for transforming a cell is not yet known. Other oncogenic viruses, such as the chronic leukemia viruses, may not produce an oncogenic protein but may affect, by other means, specific target cells so they become malignant. Recent evidence now suggests that the majority of endogenous type C viruses are not transforming agents but inherited in the host to function in other biologic processes. These viruses do not contain transduced cellular genes which are responsible for cancer. Their role probably depends on their expression of other gene products which aid in normal development. These observations suggest that the ultimate control of human cancer may result from the identification of the oncogenic cellular-like genes transduced by some type C viruses even if a true human oncogenic virus is not isolated.


Chimeric Antigen Receptor T Cells for Glioblastoma: Current Concepts, Challenges, and Future Perspectives.
Glioblastoma is the most common malignant primary brain tumor and is associated with a poor prognosis even after multimodal therapy. Chimeric antigen receptor (CAR) T cells have emerged as a promising therapeutic avenue in glioblastoma. CARs incorporate antigen-recognition moieties that endow autologous T cells with specificity against antigens expressed on glioblastoma (e.g., interleukin [IL]-13Rα2, epidermal growth factor receptor variant III [EGFRvIII], and human epidermal growth factor receptor 2 [HER2]). Compelling antitumor effects of such therapy have been shown in murine glioblastoma models. In humans, 5 phase I/II studies on IL-13Rα2-, EGFRvIII-, and HER2-directed CAR T cells for the treatment of glioblastoma have been published suggesting an acceptable safety profile. However, antitumor effects fell short of expectations in these initial clinical studies. Tumor heterogeneity, antigen loss, and the immunosuppressive tumor microenvironment are among the most important factors to limit the efficacy of CAR T-cell therapy in glioblastoma. Novel target antigens, modification of CAR T-cell design, the combination of CAR T-cell therapy with other therapeutic approaches, but also the use of CAR natural killer cells or CAR macrophages may optimize antitumor effects. Numerous clinical trials studying such approaches are ongoing, as well as several preclinical studies. With an increasing understanding of immune-escape mechanisms of glioblastoma and novel manufacturing techniques for CARs, CAR T cells may provide clinically relevant activity in glioblastoma. This review focuses on the use of CAR T cells in glioblastoma, but also introduces the basic structure, mechanisms of action, and relevant side effects of CAR T cells.


Multifaceted roles of alkyltransferase and related proteins in DNA repair, DNA damage, resistance to chemotherapy, and research tools.
O(6)-Alkylguanine-DNA alkyltransferase (AGT) is a widely distributed, unique DNA repair protein that acts as a single agent to directly remove alkyl groups located on the O(6)-position of guanine from DNA restoring the DNA in one step. The protein acts only once, and its alkylated form is degraded rapidly. It is a major factor in counteracting the mutagenic, carcinogenic, and cytotoxic effects of agents that form such adducts including N-nitroso-compounds and a number of cancer chemotherapeutics. This review describes the structure, function, and mechanism of action of AGTs and of a family of related alkyltransferase-like proteins, which do not act alone to repair O(6)-alkylguanines in DNA but link repair to other pathways. The paradoxical ability of AGTs to stimulate the DNA-damaging ability of dihaloalkanes and other bis-electrophiles via the formation of AGT-DNA cross-links is also described. Other important properties of AGTs include the ability to provide resistance to cancer therapeutic alkylating agents, and the availability of AGT inhibitors such as O(6)-benzylguanine that might overcome this resistance is discussed. Finally, the properties of fusion proteins in which AGT sequences are linked to other proteins are outlined. Such proteins occur naturally, and synthetic variants engineered to react specifically with derivatives of O(6)-benzylguanine are the basis of a valuable research technique for tagging proteins with specific reagents.


Achieving abstraction: Generating far analogies promotes relational reasoning in children.
Analogical reasoning is essential for transfer by supporting recognition of relational similarity. However, not all analogies are created equal. The source and target can be similar (near), or quite different (far). Previous research suggests that close comparisons facilitate children's relational abstraction. On the other hand, evidence from adults indicates that the process of solving far analogies may be a more effective scaffold for transfer of a relational strategy. We explore whether engaging with far analogies similarly induces such a strategy in preschoolers. Children were provided with the opportunity to solve either a near or far spatial analogy using a pair of puzzle boxes that varied in perceptual similarity (Experiment 1), or to participate in a control task (Experiment 2). All groups were then presented with an ambiguous spatial reasoning task featuring both object and relational matches. We were interested in the relationship between near and far conditions and two effects: (a) children's tendency to spontaneously draw an analogy when solving the initial puzzle, and (b) their tendency to privilege relational matches over object matches in a subsequent, ambiguous task. Although children were more likely to spontaneously draw an analogy in the near condition, those who attempted the far analogy were more likely to privilege a relational match on the subsequent task. We argue that the process of solving a far analogy-regardless of a learner's spontaneous success in identifying the relation-contextualizes an otherwise ambiguous learning problem, making it easier for children to access and apply relational hypotheses. (PsycINFO Database Record


Processing of the luteinizing hormone-releasing hormone precursor in the preoptic area and hypothalamus of the rat.
The LHRH precursor is known to contain the decapeptide and a 56 amino acid peptide termed gonadotropin-releasing hormone-associated peptide (GAP). The purpose of our study was to characterize the proLHRH and its processed products from the cell body and fiber region and from the nerve terminal region of LHRH neurons. The median eminence (ME) and a tissue block containing the preoptic area and hypothalamus (POH) were dissected separately. Tissues were homogenized and peptides were separated according to mol wt. Three different LHRH antisera bound to one immunoreactive (IR) substance which eluted at approximately 1200 mol wt. Subsequently, this material coeluted with synthetic LHRH on a reversed-phase column as a single peak. There was approximately 1.6-fold more LHRH-like IR in the ME than in the POH. The four different GAP antisera recognized multiple mol wt forms of GAP-like IR at approximately 16,000 to 14,000, 8,200, 6,500, 3,500, and 2,800 mol wt. There were more of the high mol wt materials and less of the 6500 and lower mol wt materials in the POH than in the ME. The most abundant species in both regions was the 6500 mol wt form. This IR substance coeluted with synthetic rat GAP1-56 on a reversed-phase column as a single peak. These experiments demonstrate 1) that multiple IR forms of the LHRH prohormone exist in the POH of the rat and 2) that nerve terminals of the LHRH neurons contain LHRH, GAP1-56, and some lower mol wt GAP-like substances. These results provide the first information concerning the processing scheme for the LHRH prohormone in the rat brain.


A pre-solution mixing precursor method for improving the crystallization quality of perovskite films and electroluminescence performance of perovskite light-emitting diodes.
Quasi-two-dimensional (Q-2D) perovskites are one kind of efficient luminescent material with fast energy transfer and radiative decay of excitons due to the energy cascade formed by the mixed perovskite phase. However, the existence of monolayer or bilayer nanosheets in the Q-2D perovskite film results in poor charge transport, high trap density and rough film surface because of the high ratio of ligands, which leads to poor performance of Q-2D perovskite light-emitting diodes (PeLEDs). Herein, we proposed a new strategy of a pre-solution mixing (PSM) precursor to inhibit the formation of ultrathin perovskite nanosheets, which significantly enhanced the charge carrier mobility, reduced the concentration of defects and improved the film morphology. The PeLEDs based on the PSM precursor achieved the maximum luminescence of 7832.1 cd m-2 (∼218% enhancement) and the peak current efficiency of 6.0 cd A-1 (∼131% enhancement). By introducing mixed cations in the PeLED, the maximum brightness of 14 211.0 cd m-2 and current efficiency of 14.6 cd A-1 were realized, demonstrating the generality of our PSM method for the preparation of high performance PeLEDs.


Resin-supported iridium complex for low-temperature vanillin hydrogenation using formic acid in water.
Biorefinery seeks to utilize biomass waste streams as a source of chemical precursors with which to feed the chemical industry. This goal seeks to replace petroleum as the main feedstock, however this task requires the development of efficient catalysts capable of transforming substances derived from biomass into useful chemical products. In this study, we demonstrate that a highly-active iridium complex can be solid-supported and used as a low-temperature catalyst for both the decomposition of formic acid (FA) to produce hydrogen, and as a hydrogenation catalyst to produce vanillyl alcohol (VA) and 2-methoxy-4-methylphenol (MMP) from vanillin (V); a lignin-derived feedstock. These hydrogenation products are promising precursors for epoxy resins and thus demonstrate an approach for their production without the need for petroleum. In contrast to other catalysts that require temperatures exceeding 100 °C, here we accomplish this at a temperature of <50 °C in water under autogenous pressure. This approach provides an avenue towards biorefinery with lower energy demands, which is central to the decentralization and broad implementation. We found that the high activity of the iridium complex transfers to the solid-support and is capable of accelerating the rate determining step; the decomposition of FA into hydrogen and carbon dioxide. The yield of both VA and MMP can be independently tuned depending on the temperature. The simplicity of this approach expands the utility of molecular metal complexes and provides new catalyst opportunities in biorefinery.


International variation in treatment procedures for ADHD: social context and recent trends.
Scientific and clinical interest in attention-deficit hyperactivity disorder (ADHD) is increasing worldwide. This article presents data from a cross-national workshop and survey related to questions of variability in diagnostic and, particularly, treatment procedures. Representatives of nine nations (Australia, Brazil, Canada, China, Germany, Israel, the Netherlands, Norway, and the United Kingdom), plus the United States, who attended a 2010 workshop on ADHD, responded to a survey that addressed diagnostic procedures for ADHD; treated prevalence of medication approaches, as well as psychosocial interventions; types of medications and psychosocial treatments in use; payment systems; beliefs and values of the education system; trends related to adult ADHD; and cultural and historical attitudes and influences related to treatment. Use of both medication and psychosocial treatment for ADHD varies widely within and across nations. More expensive long-acting formulations of medications are becoming more widespread. Nations with socialized medical care provide a wide array of evidence-based interventions. Economic, historical, and political forces and cultural values are related to predominant attitudes and practices. Strong antipsychiatry and antimedication voices remain influential in many nations. There is considerable variation in implementation of care for ADHD. Recognition of the social context of ADHD is an important step in ensuring access to evidence-based interventions for this prevalent, chronic, and impairing condition.


Dose mapping sensitivity to deformable registration uncertainties in fractionated radiotherapy - applied to prostate proton treatments.
Calculation of accumulated dose in fractionated radiotherapy based on spatial mapping of the dose points generally requires deformable image registration (DIR). The accuracy of the accumulated dose thus depends heavily on the DIR quality. This motivates investigations of how the registration uncertainty influences dose planning objectives and treatment outcome predictions.A framework was developed where the dose mapping can be associated with a variable known uncertainty to simulate the DIR uncertainties in a clinical workflow. The framework enabled us to study the dependence of dose planning metrics, and the predicted treatment outcome, on the DIR uncertainty. The additional planning margin needed to compensate for the dose mapping uncertainties can also be determined. We applied the simulation framework to a hypofractionated proton treatment of the prostate using two different scanning beam spot sizes to also study the dose mapping sensitivity to penumbra widths. The planning parameter most sensitive to the DIR uncertainty was found to be the target D95. We found that the registration mean absolute error needs to be ≤0.20 cm to obtain an uncertainty better than 3% of the calculated D95 for intermediate sized penumbras. Use of larger margins in constructing PTV from CTV relaxed the registration uncertainty requirements to the cost of increased dose burdens to the surrounding organs at risk. The DIR uncertainty requirements should be considered in an adaptive radiotherapy workflow since this uncertainty can have significant impact on the accumulated dose. The simulation framework enabled quantification of the accuracy requirement for DIR algorithms to provide satisfactory clinical accuracy in the accumulated dose.


Repertoire-wide gene structure analyses: a case study comparing automatically predicted and manually annotated gene models.
The location and modular structure of eukaryotic protein-coding genes in genomic sequences can be automatically predicted by gene annotation algorithms. These predictions are often used for comparative studies on gene structure, gene repertoires, and genome evolution. However, automatic annotation algorithms do not yet correctly identify all genes within a genome, and manual annotation is often necessary to obtain accurate gene models and gene sets. As manual annotation is time-consuming, only a fraction of the gene models in a genome is typically manually annotated, and this fraction often differs between species. To assess the impact of manual annotation efforts on genome-wide analyses of gene structural properties, we compared the structural properties of protein-coding genes in seven diverse insect species sequenced by the i5k initiative. Our results show that the subset of genes chosen for manual annotation by a research community (3.5-7% of gene models) may have structural properties (e.g., lengths and exon counts) that are not necessarily representative for a species' gene set as a whole. Nonetheless, the structural properties of automatically generated gene models are only altered marginally (if at all) through manual annotation. Major correlative trends, for example a negative correlation between genome size and exonic proportion, can be inferred from either the automatically predicted or manually annotated gene models alike. Vice versa, some previously reported trends did not appear in either the automatic or manually annotated gene sets, pointing towards insect-specific gene structural peculiarities. In our analysis of gene structural properties, automatically predicted gene models proved to be sufficiently reliable to recover the same gene-repertoire-wide correlative trends that we found when focusing on manually annotated gene models only. We acknowledge that analyses on the individual gene level clearly benefit from manual curation. However, as genome sequencing and annotation projects often differ in the extent of their manual annotation and curation efforts, our results indicate that comparative studies analyzing gene structural properties in these genomes can nonetheless be justifiable and informative.


Clutter invariant ATR.
One of the central problems in Automated Target Recognition is to accommodate the infinite variety of clutter in real military environments. The principle focus of our paper is on the construction of metric spaces where the metric measures the distance between objects of interest invariant to the infinite variety of clutter. Such metrics are formulated using second-order random field models. Our results indicate that this approach significantly improves detection/classification rates of targets in clutter.


A novel approach to overcome hypoxic tumor resistance: Cu-ATSM-guided intensity-modulated radiation therapy.
Locoregional tumor control for locally advanced cancers with radiation therapy has been unsatisfactory. This is in part associated with the phenomenon of tumor hypoxia. Assessing hypoxia in human tumors has been difficult due to the lack of clinically noninvasive and reproducible methods. A recently developed positron emission tomography (PET) imaging-based hypoxia measurement technique which employs a Cu(II)-diacetyl-bis(N(4)-methylthiosemicarbazone) (Cu-ATSM) tracer is of great interest. Oxygen electrode measurements in animal experiments have demonstrated a strong correlation between low tumor pO(2) and excess (60)Cu-ATSM accumulation. Intensity-modulated radiation therapy (IMRT) allows selective targeting of tumor and sparing of normal tissues. In this study, we examined the feasibility of combining these novel technologies to develop hypoxia imaging (Cu-ATSM)-guided IMRT, which may potentially deliver higher dose of radiation to the hypoxic tumor subvolume to overcome inherent hypoxia-induced radioresistance without compromising normal tissue sparing. A custom-designed anthropomorphic head phantom containing computed tomography (CT) and positron emitting tomography (PET) visible targets consisting of plastic balls and rods distributed throughout the "cranium" was fabricated to assess the spatial accuracy of target volume mapping after multimodality image coregistration. For head-and-neck cancer patients, a CT and PET imaging fiducial marker coregistration system was integrated into the thermoplastic immobilization head mask with four CT and PET compatible markers to assist image fusion on a Voxel-Q treatment-planning computer. This system was implemented on head-and-neck cancer patients, and the gross tumor volume (GTV) was delineated based on physical and radiologic findings. Within GTV, regions with a (60)Cu-ATSM uptake twice that of contralateral normal neck muscle were operationally designated as ATSM-avid or hypoxic tumor volume (hGTV) for this feasibility study. These target volumes along with other normal organs contours were defined and transferred to an inverse planning computer (Corvus, NOMOS) to create a hypoxia imaging-guided IMRT treatment plan. A study of the accuracy of target volume mapping showed that the spatial fidelity and imaging distortion after CT and PET image coregistration and fusion were within 2 mm in phantom study. Using fiducial markers to assist CT/PET imaging fusion in patients with carcinoma of the head-and-neck area, a heterogeneous distribution of (60)Cu-ATSM within the GTV illustrated the success of (60)Cu-ATSM PET to select an ATSM-avid or hypoxic tumor subvolume (hGTV). We further demonstrated the feasibility of Cu-ATSM-guided IMRT by showing an example in which radiation dose to the hGTV could be escalated without compromising normal tissue (parotid glands and spinal cord) sparing. The plan delivers 80 Gy in 35 fractions to the ATSM-avid tumor subvolume and the GTV simultaneously receives 70 Gy in 35 fractions while more than one-half of the parotid glands are spared to less than 30 Gy. We demonstrated the feasibility of a novel Cu-ATSM-guided IMRT approach through coregistering hypoxia (60)Cu-ATSM PET to the corresponding CT images for IMRT planning. Future investigation is needed to establish a clinical-pathologic correlation between (60)Cu-ATSM retention and radiation curability, to understand tumor re-oxygenation kinetics, and tumor target uncertainty during a course of radiation therapy before implementing this therapeutic approach to patients with locally advanced tumor.


Roscovitine Worsens Mycobacterium abscessus Infection by Reducing DUOX2-mediated Neutrophil Response.
Persistent neutrophilic inflammation associated with chronic pulmonary infection causes progressive lung injury and, eventually, death in individuals with cystic fibrosis (CF), a genetic disease caused by biallelic mutations in the CF transmembrane conductance regulator (CFTR) gene. Therefore, we examined whether roscovitine, a cyclin-dependent kinase inhibitor that (in other conditions) reduces inflammation while promoting host defense, might provide a beneficial effect in the context of CF. Herein, using CFTR-depleted zebrafish larvae as an innovative vertebrate model of CF immunopathophysiology, combined with murine and human approaches, we sought to determine the effects of roscovitine on innate immune responses to tissue injury and pathogens in the CF condition. We show that roscovitine exerts antiinflammatory and proresolution effects in neutrophilic inflammation induced by infection or tail amputation in zebrafish. Roscovitine reduces overactive epithelial reactive oxygen species (ROS)-mediated neutrophil trafficking by reducing DUOX2/NADPH-oxidase activity and accelerates inflammation resolution by inducing neutrophil apoptosis and reverse migration. It is important to note that, although roscovitine efficiently enhances intracellular bacterial killing of Mycobacterium abscessus in human CF macrophages ex vivo, we found that treatment with roscovitine results in worse infection in mouse and zebrafish models. By interfering with DUOX2/NADPH oxidase-dependent ROS production, roscovitine reduces the number of neutrophils at infection sites and, consequently, compromises granuloma formation and maintenance, favoring extracellular multiplication of M. abscessus and more severe infection. Our findings bring important new understanding of the immune-targeted action of roscovitine and have significant therapeutic implications for safely targeting inflammation in CF.


Optical Screening and Classification of Drug Binding to Proteins in Human Blood Serum.
Protein-drug interactions in the human bloodstream are important factors in applications ranging from drug design, where protein binding influences efficacy and dose delivery, to biomedical diagnostics, where rapid, quantitative measurements could guide optimized treatment regimes. Current measurement approaches use multistep assays, which probe the protein-bound drug fraction indirectly and do not provide fundamental structural or dynamic information about the in vivo protein-drug interaction. We demonstrate that ultrafast 2D-IR spectroscopy can overcome these issues by providing a direct, label-free optical measurement of protein-drug binding in blood serum samples. Four commonly prescribed drugs, known to bind to human serum albumin (HSA), were added to pooled human serum at physiologically relevant concentrations. In each case, spectral changes to the amide I band of the serum sample were observed, consistent with binding to HSA, but were distinct for each of the four drugs. A machine-learning-based classification of the serum samples achieved a total cross-validation prediction accuracy of 92% when differentiating serum-only samples from those with a drug present. Identification on a per-drug basis achieved correct drug identification in 75% of cases. These unique spectroscopic signatures of the drug-protein interaction thus enable the detection and differentiation of drug containing samples and give structural insight into the binding process as well as quantitative information on protein-drug binding. Using currently available instrumentation, the 2D-IR data acquisition required just 1 min and 10 μL of serum per sample, and so these results pave the way to fast, specific, and quantitative measurements of protein-drug binding in vivo with potentially invaluable applications for the development of novel therapies and personalized medicine.


Evidence of small-fiber polyneuropathy in unexplained, juvenile-onset, widespread pain syndromes.
We tested the hypothesis that acquired small-fiber polyneuropathy (SFPN), previously uncharacterized in children, contributes to unexplained pediatric widespread pain syndromes. Forty-one consecutive patients evaluated for unexplained widespread pain beginning before age 21 had medical records comprehensively analyzed regarding objective diagnostic testing for SFPN (neurodiagnostic skin biopsy, nerve biopsy, and autonomic function testing), plus histories, symptoms, signs, other tests, and treatments. Healthy, demographically matched volunteers provided normal controls for SFPN tests. Age at illness onset averaged 12.3 ± 5.7 years; 73% among this poly-ethnic sample were female (P = .001). Sixty-eight percent were chronically disabled, and 68% had hospitalizations. Objective testing diagnosed definite SFPN in 59%, probable SFPN in 17%, and possible SFPN in 22%. Only 1 of 41 had entirely normal SFPN test results. Ninety-eight percent of patients had other somatic complaints consistent with SFPN dysautonomia (90% cardiovascular, 82% gastrointestinal, and 34% urologic), 83% reported chronic fatigue, and 63% had chronic headache. Neurologic examinations identified reduced sensation in 68% and vasomotor abnormalities in 55%, including 23% with erythromelalgia. Exhaustive investigations for SFPN causality identified only history of autoimmune illnesses in 33% and serologic markers of disordered immunity in 89%. Treatment with corticosteroids and/or intravenous immune globulin objectively and subjectively benefited 80% of patients (12/15). More than half among a large series of patients with childhood-onset, unexplained chronic widespread pain met rigorous, multitest, diagnostic criteria for SFPN, which extends the age range of acquired SFPN into early childhood. Some cases appeared immune-mediated and improved with immunomodulatory therapies.


Comprehensive biomarker and genomic analysis identifies p53 status as the major determinant of response to MDM2 inhibitors in chronic lymphocytic leukemia.
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world and remains incurable with conventional therapies. Patients with relapsed or resistant CLL have a significantly shortened lifespan. MDM2 inhibitors have been developed and may have significant potential in the treatment of CLL. Clinical development of these compounds would be aided through knowledge of molecular predictors of activity. To understand determinants of sensitivity or resistance to MDM2 inhibitor therapy in CLL, we comprehensively analyzed a large cohort of CLL patient-derived samples for response to MDM2 inhibition and correlated these responses with clinically important biomarkers. Furthermore, we employed high-density single nucleotide polymorphism (SNP) arrays to analyze genomewide changes of copy number and allele status, including that of p53. The results of these studies conclusively demonstrate that p53 status is the major determinant of response to MDM2 inhibitors in CLL. Additional defects in the p53 regulatory cascade do not appear operational in this leukemia. Further, we identify a novel subgroup of patients with CLL with early progressive disease that appears particularly sensitive to MDM2 inhibitor treatment. These data provide definitive evidence for target-specific and predictive activity and a rationale to proceed with this potentially important class of compounds in the treatment of CLL.


Does Becoming Fit Mean Feeling (f)it? A Comparison of Physiological and Experiential Fitness Data From the iReAct Study.
Regular exercise fosters fitness-enhancing benefits. We assume that exercise interventions become successful and sustainable if physiological benefits of exercise are also subjectively perceivable. The goal of this study was to examine how young inactive adults physiologically respond to an exercise intervention and how those responses are subjectively experienced. Furthermore, we aimed to assess whether the sequence of two distinct endurance-based exercise modes has an impact on physiological and subjectively experienced physical fitness. Thirty-one young inactive adults were assessed for this substudy of the larger iReAct study. Participants were randomly assigned to a high-intensity interval training (HIIT) or a moderate-intensity continuous training (MICT) group for 6 weeks and subsequently switched groups for a second training period. Physiological fitness data was collected at baseline, follow-up I, and follow-up II using a graded cardiopulmonary exercise test. Subjectively reconstructed (i.e., retrospective constructions) experiences relating to physical fitness were assessed at follow-up II using a biographical mapping method. A repeated-measures one-way ANOVA on each training group was performed to see whether physiological and subjectively experienced fitness differed across training periods. The rate of change between all variables was calculated for the first and the second training period in order to compare the agreement between physiological and subjective fitness improvements. Participants increased their fitness across the intervention period both physiologically and subjectively. However, the rate of change depended on the sequence of the two training modes. While VO2max increased significantly in both training periods in the MICT-HIIT sequence, a significant increase in VO2max in the HIIT-MICT sequence was only observed in the HIIT period. Participants similarly perceived those increases subjectively in their exercise-related physical fitness, although they experienced a significant decrease in the second period of the HIIT-MICT sequence. For subjectively perceived physical fitness relating to everyday activities, significant increases were only observed for the first period of the MICT-HIIT sequence. Young inactive adults can improve both their physiological and their subjectively perceived fitness through regular exercise. However, exercise modes and their sequence can make a substantial difference regarding measured and perceived physical fitness. Additionally, despite a favorable tendency toward HIIT over MICT, inter- and intra-individual variability, particularly in the subjective experiences of fitness, reiterates the necessity of individualized approaches to exercise.


RBFNN-based hole identification system in conducting plates.
A neural-based signal processing system that exploits radial basis function neural network (RBFNN) is proposed to solve the problem of detecting and locating circular holes in conducting plates by means of nondestructive eddy currents testing. The capabilities of basic multilayer perceptron and radial basis function (RBF) schemes are first investigated. Since the achieved performance revealed insufficient, a two-step procedure is then analyzed: in the first step, an RBFNN is used to estimate the distances between the hole's center and the eddy current magnetic sensors; a least square algorithm is then exploited in order to locate the hole starting from the previously estimated distances. The performance of the proposed system are tested on a database of simulated experiments based on the a priori knowledge of the corresponding boundary value direct problem solution, by taking advantage of the closed-form analytical expression of the solution in order to generate a wide range of possible sensor-hole configurations. Both noiseless and noisy measurements are taken into account for assessing the system robustness. The main result achieved is discussed.


Use of data-biased random walks on graphs for the retrieval of context-specific networks from genomic data.
Extracting network-based functional relationships within genomic datasets is an important challenge in the computational analysis of large-scale data. Although many methods, both public and commercial, have been developed, the problem of identifying networks of interactions that are most relevant to the given input data still remains an open issue. Here, we have leveraged the method of random walks on graphs as a powerful platform for scoring network components based on simultaneous assessment of the experimental data as well as local network connectivity. Using this method, NetWalk, we can calculate distribution of Edge Flux values associated with each interaction in the network, which reflects the relevance of interactions based on the experimental data. We show that network-based analyses of genomic data are simpler and more accurate using NetWalk than with some of the currently employed methods. We also present NetWalk analysis of microarray gene expression data from MCF7 cells exposed to different doses of doxorubicin, which reveals a switch-like pattern in the p53 regulated network in cell cycle arrest and apoptosis. Our analyses demonstrate the use of NetWalk as a valuable tool in generating high-confidence hypotheses from high-content genomic data.


The association of smoking and cardiovascular disease in a population with low cholesterol levels: a study of 648,346 men from the Korean national health system prospective cohort study.
The association of smoking with cardiovascular diseases in populations with low cholesterol levels is unclear and this lack of clarity may have contributed to the very high prevalence of smoking in East Asian men. The effect of smoking on stroke subtypes is particularly unclear. We used data from a prospective cohort study of 648,346 Korean men aged 30 to 64 years at their baseline assessment in 1992. Mean (SD) total cholesterol at baseline was 4.9 (1.0) mmol/L and 59% of the men were current smokers. Over the follow-up period of 10 years, 9475 men experienced any type of stroke, 4768 experienced an ischemic stroke, 2380 an intracerebral hemorrhage, 786 a subarachnoid hemorrhage, 3329 men experienced a myocardial infarction, and 269 an aortic aneurysm. Smoking at baseline was associated with marked increases in risk of ischemic stroke (hazard ratio comparing current smokers with never smokers 1.58 [95% CI: 1.49 to 1.68]), subarachnoid hemorrhage (1.91 [1.63 to 2.24]), myocardial infarction (2.01 [1.87 to 2.17]), and aortic aneurysm (1.47 [1.14 to 1.90]) with these effects remaining after adjustment for potential confounding factors and with the first 5 years of events excluded from the analyses. The effect of smoking on these outcomes was the same among men with cholesterol levels below the median value for this population as among those with higher levels. There was no association of smoking with intracerebral hemorrhage. Smoking accounted for 20% of all cardiovascular disease outcomes in this population. Smoking is a major risk factor for cardiovascular diseases in populations with low cholesterol levels and global interventions are required to halt the emerging tobacco epidemic in low- and middle-income countries.


Cell wall proteinaceous components in isolates of Candida albicans and non-albicans species from HIV-infected patients with oropharyngeal candidiasis.
Oropharyngeal candidiasis (OPC) remains a common opportunistic infection in HIV-infected patients. Candida albicans is the most frequent causative agent of OPC. However, non-albicans spp. are being increasingly isolated. Candidal cell wall proteins and mannoproteins play important roles in the biology and patogenesis of candidiasis. In the present study, we have analyzed the proteinaceous components associated with cell wall extracts from C. albicans, Candida tropicalis, Candida pseudotropicalis, Candida krusei, Candida glabrata, Candida parapsilosis, Candida guilliermondii and Candida rugosa obtained from HIV-infected patients with recurrent OPC. Cell wall proteinaceous components were extracted with beta-mercaptoethanol and analyzed using electrophoresis, immunoblotting (with antisera generated against C. albicans cell wall components, and with serum samples and oral saline rinses from patients with OPC), and lectin-blotting (concanavalin A) techniques. Numerous molecular species were solubilized from the various isolates. Major qualitative and quantitative differences in the polypeptidic and antigenic profiles associated with the cell wall extracts from the different Candida spp. were discernible. Some of the antibody preparations generated against C. albicans cell wall components were able to recognize homologous materials present in the extracts from non-albicans spp. Information on cell wall antigens of Candida species may be important in the therapy and prevention of HIV-related OPC.