In echo-planar imaging (EPI), such as commonly used for functional MRI (fMRI) and diffusion-tensor imaging (DTI), compressed distortion is a more difficult challenge than local stretching as spatial information can be lost in strongly compressed areas. In addition, the effects are more severe at ultra-high field (UHF) such as 7T due to increased field inhomogeneity. To resolve this problem, two EPIs with opposite phase-encoding (PE) polarity were acquired and combined after distortion correction. For distortion correction, a point spread function (PSF) mapping method was chosen due to its high correction accuracy and extended to perform distortion correction of both EPIs with opposite PE polarity thus reducing the PSF reference scan time. Because the amount of spatial information differs between the opposite PE datasets, the method was further extended to incorporate a weighted combination of the two distortion-corrected images to maximize the spatial information content of a final corrected image. The correction accuracy of the proposed method was evaluated in distortion-corrected data using both forward and reverse phase-encoded PSF reference data and compared with the reversed gradient approaches suggested previously. Further we demonstrate that the extended PSF method with an improved weighted combination can recover local distortions and spatial information loss and be applied successfully not only to spin-echo EPI, but also to gradient-echo EPIs acquired with both PE directions to perform geometrically accurate image reconstruction. Single-shot echo planar imaging (EPI)  is the mGeometric distortions, appearing locally either as stretched or compressed pixels, alter the local spatial resolution in the acquired image. Locally increased spatial resolution is acquired in stretched regions, while locally decreased spatial resolution is obtained in compressed regions. Particularly in strongly compressed regions, where several pixels of the nominal acquisition grid are compressed into a single pixel, spatial information is lost. If one assumed a smoothly varying field inhomogeneity, it is possible to recover some of the information, however this assumption is violated in strongly warped regions and in these cases no unique solution exists . Therefok-space trajectories. These approaches are based on the assumption that EPI acquisition with opposite PE polarity yields identical intensity, but opposite geometric distortion along the PE direction in the acquired image. Since the lost spatial information due to compression is retained in the corresponding EPI image with opposite distortions, a final image without loss of spatial information can be generated by combining the EPI pair after distortion correction. However, strong image compression leads to strong signal dropouts in gradient-echo EPI (GE-EPI) rather than signal summation of compressed voxels as in spin-echo EPI (SE-EPI) and these approaches [As an alternative to resolve the above problem, reversed phase gradient approaches ,5,6,7,8 proaches ,5,6,7,8 Point spread function (PSF) mapping allows very reliable distortion mapping due to its robustness to noise and field inhomogeneity . In thisHere we propose an extension of the highly accurate PSF mapping method suggested by In and Speck  to resolρ(s) with the point spread function H, a single delta approximation of the magnitude PSF leads to [δ is the Dirac delta function, and s and y correspond to the spin-warp (non-distorted) and EPI (distorted) PE coordinates, respectively. Because the field inhomogeneity term Δ(s) is a function of s-coordinates, the PSF deviates from the diagonal line along the y-direction in the s-axis. Thus integration of the PSF data along the y- and s-directions yields the non-distorted and distorted reference (Ref.) images, respectively [I is considered as the forward phase-encoded PSF image, If, (hereafter referred to as the forward PSF), the PSF will be mirrored with -Δ(s) along the y-direction in the s-coordinates from the diagonal line in the reverse phase-encoded PSF image Ir (hereafter referred to as the reverse PSF) having opposite geometric distortions:For simplicity, we consider the case of a single delta approximation of the PSF. Since the reconstructed PSF is obtained by multiplying proton density leads to ,10,11:Iectively ,10,11:Is) from the diagonal line due to the field inhomogeneity is shown in Ir  are inverted with respect to the diagonal line  , the y-pnal line  , which represents the profile along the EPI PE direction (y) in the spin-warp PE coordinates (s) in the 3D PSF space is the system function for generating image distortions, as shown in Eqs. Ic(s) can be written as:The PSF I(y) and the EPI-PSF kernel Hc. After distortion correction by the EPI-PSF kernel, the signal will be increased in previously stretched regions due to the amount of image compression and vice versa in the regions with compressed distortions. Since the scale is changed by geometric distortion correction using the EPI-PSF kernel, it includes a modulation function to correct the signal intensity. An integration of the EPI-PSF kernel along the y-coordinates yields a modulation function as a weighting map W(s) in this study:This is a convolution product of a distorted EPI W(s) departs from one when the EPI is compressed (higher than 1) or stretched (lower than 1) during the correction. Since we assume that the spatial information in the regions that were originally stretched is more reliable than the information in the compressed regions, the spatial accuracy of the distortion-corrected EPIs correlates with the values in the weighting map. Therefore, instead of simple averaging of the distortion-corrected forward Ic,f(s) and reverse Ic,r(s) EPIs, a weighted combination (WC) is proposed in this study in order to generate a combined distortion-free image IWC(s). This accounts for the amount of information present in each image, which preserves spatial accuracy:Wf(s) and Wr(s) correspond to the forward and reverse weighting maps according to n. Note that it becomes a simple average when n is equal to zero.The value in the weighting map in-vivo scans were performed on a 7T whole body scanner  using a 32 channel phase-array head coil . Single-shot EPI and corresponding PSF sequences developed by Zaitsev et al. [All phantom and v et al.  were modin-vivo experiments, the imaging parameters for SE-EPI and -PSF scans were: 12 axial slices, slice thickness = 1.2 mm, TR/TE = 2000/54 ms, bandwidth BW = 1543 Hz/pixel, field of view (FOV) = 224 mm2, matrix size = 1802, partial Fourier 6/8, standard in-plane 2D GRAPPA factor = 3, in-plane 2D GRAPPA reference lines = 45. GRAPPA acceleration in the PSF dimension [in-vivo experiment.(I) First, we tested the hypothesis that distortion correction with the extended PSF is comparable to correction with the measured reverse PE PSF dataset. For this purpose pairs of SE-EPI and corresponding PSF data with opposite PE polarity were acquired. In phantom and imension  was not imension . Total Ts-axis. The maximum value  is reached only when identical EPI-PSF profiles at the same position are measured in both PSF spaces. This was performed with the forward and extended reverse PSF data due to the opposite distortions. A pair of EPI-PSF kernels, which is applied to the corresponding pair of EPIs for distortion correction, was obtained by the proposed method from each of the forward and reverse PE PSF reference data and two pairs of distortion-corrected images were obtained using the two PSF data. To fully cover the complete EPI-PSF profile for distortion correction, a kernel size of 13 was used in this study. Finally, in order to validate the correction quality, the distortion-corrected images were subtracted from each other.The EPI-PSF kernel for distortion correction, distorted and non-distorted reference images were calculated as described in In and Speck . The cro(II) To demonstrate that accurate distortion correction with the proposed method is available even in GE-EPI, a pair of GE-EPIs with opposite PE polarity and forward phase-encoded GE-PSF data were acquired with identical protocols to the first experiment with the exception of TR/TE = 2000/22 ms. For the PSF reference acquisition, an acceleration factor of 4  = 1 min. 30 sec.) was used to obtain a distortion-free GE-reference (GE-ref.) image. Total TA for this experiment was about 2 minutes.The forward and extended EPI-PSF kernels were obtained from the forward PSF reference data to correct distortions in the forward and reverse GE-EPIs. To verify further accelerations of the PSF scan, a non-equidistant PSF acquisition scheme   was applIn-vivo DTI experiments were performed to evaluate the robustness of the proposed method in human data. A SE-PSF dataset with forward PE gradient and pairs of diffusion weighted EPI (DW-EPI) with opposite PE polarity were acquired, corresponding to two averages in regular acquisitions. The imaging protocols were identical to the first experiment with the exception of TR/TE = 8200/58 ms and the use of 80 axial slices to cover the entire brain. The SE-PSF reference scan was performed with an acceleration factor of 3  [b-value = 1000 s/mm2) respectively with one and four averages. For this experiment, total TAs were 17 and 21 minutes, respectively.(III)  8 min.)  to yieldb-value = 0 s/mm2. The FA map calculation, eddy-current correction, and registration were carried out in FSL (http://fsl.fmrib.ox.ac.uk/fsl/). Additionally, a suitable value of weighting exponent n for combination was investigated to efficiently preserve the spatial information in the final FA map. For this purpose, mean differences DiffWC,n between final FA maps with increasing weighting exponent of FAWC,n(s) and FAWC,n+1(s) were calculated:To calculate the EPI-PSF kernels, only 25 PSF-encoding steps were used  . Based oe(Wf(s)/Wr(s)) is greater than abs(log(3)). For example, the ratio between two weighting maps becomes 3 or 1/3 in regions where two adjacent pixels have a shift-difference of half a pixel resulting in 50% overlap in compressed regions. In other words, loss of spatial information has already occurred in such regions and this signal without sufficient spatial information may corrupt further DWI processing and should be discarded. This is achieved with the proposed weighted combination and the SNR in the combined image varies accordingly. Under the assumption that two distortion-corrected images with opposite PE polarity have identical SNR, the change in the SNR map due to the weighted combination can be obtained by using a simple average of two images:When both distortion-corrected images are combined into a final image, the difference of final FA maps is caused by the different contribution using two weighting maps as a ratio. Thus, the calculation was performed only in the regions where the difference is large, or the ratio is high. Pixels with a difference in contribution greater than 3 were selected for the calculation, which can be obtained when abs(logs)WC,n increases. Therefore, the corresponding SNR map change ranging from 1  to sqrt(2)  is calculated by The contribution of one of the two images is decreasing when the weighting ratio Ratio(http://fsl.fmrib.ox.ac.uk/fsl/) via a tool called TOPUP (http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/topup), were applied to in-vivo DTI data acquired in the third experiment. After distortion correction was performed with shift maps calculated using algorithms of Jacobian modulation and least-squares restoration, two corresponding final FA maps were calculated.(IV) For comparison, the reversed gradient approaches, which are available in FSL (s) in the EPI PE coordinates (y) from the forward and extended reverse PSF data, as seen from the correlation map in in-vivo experiments although the correlation values were slightly reduced to 0.84 in the strongly distorted anterior regions  and distortion-corrected forward and reverse GE-, SE-, and DW-EPIs and FA maps are shown in e8n = n×2.16, n = 2) to the combined image in the anterior regions (see arrows in n≠0) rather than a simple average (n = 0). Under the assumption that the spatial resolution in the stretched areas is more reliable, meaningful FA values from forward images were retained in the final FA map when n was 2 or larger. For such values of n, the combined map contains signal mainly from one of the two acquisitions in strongly distorted regions with loss of spatial information, as shown in SNR map of the combined image  was selected, as shown in In this study, we have proposed and demonstrated an extension of the PSF method for the reversed gradient approach to allow distortion correction in both EPI images with opposite PE directions without an additional PSF reference scan. Combined with further accelerations, the reference scan time for high correction fidelity becomes acceptable. We have further proposed and shown the effectiveness of a novel weighting scheme that accounts for the signal intensity variations using information from the single PSF reference scan. For effective combination of both EPI images, a very precise distortion correction is essential to allow geometrically well-matched forward and reverse EPI images with an anatomical image. In addition, an appropriately weighted combination of corrected images is also necessary to obtain the correct signal levels and exploit information from scans with both PE directions. With the proposed method, it is possible to obtain a distortion-free image using a single PSF scan without loss of spatial resolution. We have shown how the reversed gradient approach can be used to avoid loss of spatial resolution caused by local EPI compression.in-vivo experiments. This supports our hypothesis that the EPI-PSF profiles in the forward and reverse 3D PSF spaces are identical except for opposite distortions . Only in in-vivo experiments, slightly reduced correlation values were measured since the EPI-PSF profiles were shifted differently. It seems that the field inhomogeneity was slightly changed due to subject motion between the two PSF reference scans. However, the two EPI-PSF profiles were still very similar, as shown in 3) was acquired in this study. Therefore, the proposed method can correct geometric distortions in both forward and reverse EPIs with sub-voxel accuracy without loss of correction fidelity and even in very high resolution EPI with strong distortions.An appropriate pair of EPI-PSF kernels for distortion correction can be calculated from a single PSF reference data set by the proposed method. As shown in Our results emphasize that not only geometric distortions but also intensity distortions of the PSF are caused by the field inhomogeneity. Some residual differences in the subtraction maps between the forward and reverse images still remain in the regions with strong field inhomogeneity or artery and ventricle regions even after distortion correction  coordinate in the distorted (y) axis and yields a voxel intensity by s) coordinate , which are usually performed with GE-EPI. As shown in the GE-reference image  calculatCompared to the previous study , a largeThe additional PSF reference scan time becomes a main disadvantage of this method compared to the reversed gradient approaches ,5,6,7,8 The work in this study assumes the B0 field homogeneity does not change during subsequent EPI acquisitions. Inaccurate correction may occur when subject motion alters the magnetic field distribution relative to the object and thus alter the geometric distortions. Image based coregistration can reduce such errors for magnetic field changes that move with the object. In order to fully account for motion-induced field changes, the proposed approach should be applied together with a real-time motion detection and motion-induced varying distortion correction ,23.Loss of spatial information in the FA map cannot be avoided if either the forward or reverse PE DW-EPIs are used for the calculation since the compressed distortions usually appear within a slice  as well in-vivo at 7 Tesla.We introduce an extension of the PSF method for reversed gradient approaches to calculate a distortion-free image for EPI-based application studies without bias due to the PE direction. Since the proposed method extends the PSF reconstruction and yields an additional PSF dataset containing opposite distortions equivalent to a reversed gradient PSF data set, both geometric distortions in the forward and reverse EPI images can be corrected from a single PSF reference scan. Furthermore, the weighting maps for an appropriate combination of the two images were derived from the corresponding EPI-PSF kernels. The results show that very accurate geometric distortion correction in both images can be carried out by the proposed method and that the proposed summation of the two distortion-corrected images can resolve the local loss of spatial information due to compression. The benefits of the proposed method for reversed gradient approaches are demonstrated in phantom and


Total knee arthroplasty (TKA) has been reported to be the most successful treatment for patients with advanced osteoarthritis, however, early postoperative pain has become an unresolved issue. The aim of this Meta-analysis is to evaluate the efficacy and safety of steroid addition to multimodal cocktail periarticular injection (MCPI) in patients undergoing TKA.Clinical randomized controlled trials concerning the efficacy and safety of MCPI containing steroids in TKA published up to December 2014 were retrieved from PubMed, Cochrane library, EMbase databases. The methodological quality of the included studies was assessed by the 12-item scale. Data analysis was performed using StataSE12.0.P < 0.05). Neither the early postoperative nor the long-term range of motion of knee showed any statistical difference between the non-steroid and steroid group (P >0.05). For safety, steroids did not increase the incidence of postoperative infection and wound oozing (P >0.05); no tendon rupture was reported up to now. In addition, steroids did not decrease the postoperative drainage through the reduction of prostaglandins (P >0.05).Six randomized controlled trials involving a total of 567 patients were assessed; the steroid group included 305 patients, and the control group included 262 patients. The meta-analysis showed that MCPI with steroids in TKA significantly reduced postoperative pain; duration of time required to perform straight-leg raising and length of hospital stay was  or the long-term ROM of knee, nor did it reduce the postoperative drainage. However, the best results are acquired in patients without any altered immunological status. Total knee arthroplasty (TKA) has been reported to be the most successful treatment for patients with advanced osteoarthritis; however, the early postoperative pain has become an unresolved issue . Statist. ) OR “Randomized Controlled Trial” [Publication Type])) AND  OR ((((knee arthroplasty[Title/Abstract]) OR knee replacement[Title/Abstract]) OR knee replacements[Title/Abstract]) OR knee prosthesis[Title/Abstract])))))))))) AND (((((((“Steroids”[Mesh]) OR ((steroid[Title/Abstract]) OR corticosteroid[Title/Abstract])))))) OR ((“Glucocorticoids”[Mesh]) OR glucocorticoid [Title/Abstract])). The reference list of the relevant literatures were also reviewed manually for any further relevant studies. Languages were not restricted in this search.Inclusion criteria were as follows: (1) The target population consisted of patients undergoing unilateral primary TKA; (2) The interventional group should merely have a steroid in addition to the control group; (3) The outcomes were analyzed with respect to visual analogue scale (VAS), ROM of knee, postoperative drainage, duration of time required to perform a straight-leg raise (SLR), length of hospital stay, incidence of complications such as postoperative infection, and wound oozing; (4) The methodological criterion was prospective RCT.Exclusion criteria were as follows: (1) Patients undergoing bilateral TKA, unicondylar knee arthroplasty or revision; (2) Other difference between the steroid group and control group besides the administration of steroids; (3) Animal studies.After the consecutive procedures of screening of titles and abstracts, obtaining the full text of each article and reviewing them, articles that met the eligibility criteria and did not meet the exclusion criterias were selected to be included. Data were extracted and collated independently by two authors (ZXY and QJ), including author, published year, sample size, patient age, sex, body mass index, drug composition and quantity of the cocktail, injection method, other intervention protocol, and the aforementioned outcome indexes. The data of a published updated study involving the same cohort of patients was extracted synthetically. The original investigators were contacted when requisite data were lacking in the publications. The methodological quality of each included RCT was assessed by two observers independently by the 12-item scale ; trials I2. If heterogeneity was low , a fixed-effects model was used. If heterogeneity was significant , sensitivity analysis and subgroup analyses were conducted to find the source of the heterogeneity. If the heterogeneity could not be eliminated, a random-effects model would be used when the result of meta-analysis had clinical homogeneity, or a descriptive analysis would be used.The meta-analysis was conducted with StataSE12.0 software. The weighted mean difference (WMD) and 95 % confidence interval (CI) were calculated for continuous data, and the relative risk (RR) and 95 %CI were calculated for dichotomous data. The statistical heterogeneity was tested with the chi-square test and No external funding was received in support of this study.A total of 71 potential articles were identified and screened for the meta-analysis. After screening of titles and abstracts, obtaining the full text of each article and reviewing them, six RCTs were selected for this meta-analysis , 14–16 ; the resP < 0.1, I2 > 50 %); sensitivity analysis did not detect the source of heterogeneity, and subgroup analyses divided by possible diversity failed to eliminate the heterogeneity. Then we found that, regardless of the exclusion or inclusion of every study, the results were all the same and had clinical agreement, so we conducted the meta-analysis by the random-effects model for the reason that all studies were of high quality. The fixed-effects model was used in the rest postoperative period as heterogeneity was not detected . The pooling results indicated that the VAS at postoperative days 2, 3, and 7 of the steroid group were significantly lower than those of the control group . The pooling result showed no statistical difference of postoperative drainage between the two groups . The result of meta-analysis indicated that patients in the steroid group could perform a straight-leg raise significantly earlier than those in the control group . The results of meta-analysis indicated that the length of hospital stay of the steroid group was significantly shorter than that of the control group . The pooling results manifested that the incidence of postoperative infection had no statistical difference between the steroid group and control group  The meta-analysis of ROM and some postoperative VAS appeared heterogeneous, and sensitivity analysis and subgroup analyses failed to eliminate the heterogeneity. As those results of meta-analysis had clinical agreement, we included all those studies and conducted the meta-analysis by the random-effects model for the reason that those studies were of high quality, which may slightly influence the reliability of the meta-analysis. (2) The included studies were lacking in, inflammation evaluating indexes like interleukin-6, serum C-reactive protein, and erythrocyte sedimentation rate, so we could not evaluate the efficacy of MCPI with steriod comprehensively.For patients undergoing TKA, the addition of steroids, which is proved to be highly safe, further improves the analgesic efficacy of MCPI. MCPI with steroids might neither increase the early or long-term postoperative ROM of knee nor may it reduce the postoperative drainage. However, the duration of time required to perform straight-leg raising and length of hospital stay are reduced. However, the best results are acquired in patients without any altered immunological status. New RCTs which evaluate the changes in hematocrit levels and those which incorporate knee-score system should be performed for the purpose of evaluating the efficacy of MCPI with steriod comprehensively.


Urethral duplication is a rare congenital anomaly. We report a 6-year-old male with type IIA2 (Y-type) using Effmann's classification. The accessory urethra, in which a urinary stone existed, arose from the posterior urethra to the scrotum. Because of recurrent urinary tract infection and urinary discharge from the accessory urethra, surgical removal of the accessory urethra through a scrotal incision was performed. At 7-month postoperative follow-up the patient was completely free from urinary incontinence and urinary tract infection. Patients with urethral duplication, an extremely rare congenital anomaly, can present with incontinence, urinary tract infection (UTI), and double stream or can be asymptomatic with the duplication being found on routine physical examination . We repoA 6-year-old boy with a history of pale yellow discharge from the opening of the sinus and a stony excrescence of the sinus in the midline scrotum was evaluated . Other pCystourethroscopy, retrograde urethrography (RUG), sinus graphy, and surgical removal of the sinus through a scrotal incision were performed simultaneously. The patient was placed in lithotomy position. An elliptic incision was accomplished in the skin around the opening and the surrounding tissues were delicately dissected up to near the bifurcation of the urethra. The ectopic channel received double ligation with 3-0 polyglactin, and it was excised. The subcutaneous tissue was closed with 4-0 polyglactin 910 and the skin was sutured with 4-0 polydioxanone. The 4.5 cm long sinus extended to the left side of the verumontanum . No postUrethral duplication is a rare anomaly with about 300 cases reported to date, usually seen in males and often associated with genitourinary and gastrointestinal anomalies . One-thiOur case was classified as type IIA2 (Y-type) because of the accessory urethra arising from the posterior urethra to the scrotum. In almost all cases of Y-type, the accessory urethras were opened on the perineum or rectum arising from orthotropic urethra. The primary aim of surgical repair of Y-type urethral duplication is to preserve normal functioning orthotopic urethra with intact verumontanum, good caliber, and intact sphincter . SurgicaIn conclusion, urethral duplication is a rare congenital anomaly, either isolated or associated with other anomalies, with varied presentations and requires radiologic and also endoscopic examination to define the anatomy and planning of the surgical approach.


Allergoids are chemically modified allergen extracts administered to reduce allergenicity and to maintain immunogenicity. Oralair® (the 5-grass tablet) is a sublingual native grass allergen tablet for pre- and co-seasonal treatment. Based on a literature review, meta-analysis, and cost-effectiveness analysis the relative effects and costs of the 5-grass tablet versus a mix of subcutaneous allergoid compounds for grass pollen allergic rhinoconjunctivitis were assessed.A Markov model with a time horizon of nine years was used to assess the costs and effects of three-year immunotherapy treatment. Relative efficacy expressed as standardized mean differences was estimated using an indirect comparison on symptom scores extracted from available clinical trials. The Rhinitis Symptom Utility Index (RSUI) was applied as a proxy to estimate utility values for symptom scores. Drug acquisition and other medical costs were derived from published sources as well as estimates for resource use, immunotherapy persistence, and occurrence of asthma. The analysis was executed from the German payer’s perspective, which includes payments of the Statutory Health Insurance (SHI) and additional payments by insurants. Comprehensive deterministic and probabilistic sensitivity analyses and different scenarios were performed to test the uncertainty concerning the incremental model outcomes.The applied model predicted a cost-utility ratio of the 5-grass tablet versus a market mix of injectable allergoid products of € 12,593 per QALY in the base case analysis. Predicted incremental costs and QALYs were € 458  and 0.036 , respectively. Compared to the allergoid mix the probability of the 5-grass tablet being the most cost-effective treatment option was predicted to be 76% at a willingness-to-pay threshold of € 20,000. The results were most sensitive to changes in efficacy estimates, duration of the pollen season, and immunotherapy persistence rates.This analysis suggests the sublingual native 5-grass tablet to be cost-effective relative to a mix of subcutaneous allergoid compounds. The robustness of these statements has been confirmed in extensive sensitivity and scenario analyses.The online version of this article (doi:10.1186/s13601-015-0045-z) contains supplementary material, which is available to authorized users. According to the World Health Organization (WHO), allergic respiratory diseases have been recognized as the fourth most important chronic disease in the world and represent a major public health problem with significant quality of life (QoL) impairment . With apAR is an inflammation of the nasal passage that is characterized by a combination of the following symptoms: sneezing, nasal itching and/or congestion, rhinorrhoea and watery and itchy eyes ,8. It isTreatment of AR mainly consists of symptom control achieved by allergen avoidance or use of pharmacotherapy such as antihistamines. Since symptomatic medications have no long-lasting effect following discontinuation and some patients remain uncontrolled, causal treatments like AIT may be required in persistent disease and should begin as early as possible ,10-12. AOralair® (the 5-grass tablet) is a SLIT tablet for treatment of seasonal, grass pollen induced AR. The active substance of the 5-grass tablet comprises freeze-dried extracts from five grasses: perennial rye (Lolium perenne), meadow (Poa pratensis), timothy (Phleum pratense), cocksfoot (Dactylis glomerata), and sweet vernal grass (Anthoxanthum odoratum) . These sTo provide healthcare resources within the restrictions of the healthcare system, physicians and decision-makers carefully assess the clinical benefits and economic consequences of different AIT treatments. Accordingly, a study was conducted in 2010 to assess the cost-effectiveness of the 5-grass tablet compared to Grazax® (SLIT mono-grass tablet), Alutard® (SCIT with native extracts) and symptomatic treatment for grass pollen induced AR in Germany . The outA Markov-model with a nine-year time horizon was applied to predict the distribution of patients over a number of health states over a sequence of discrete one-year time periods after receiving therapy, and subsequently to assess the associated costs and effects Figure . A similPatients who entered the analysis either received AIT with the 5-grass tablet or an averaged hypothetical allergoid mix, both with optional symptomatic medication in addition, or underwent symptomatic treatment alone. The length of the pollen season was estimated at three months per year . After dPatients included in the model (mean age 29 years) suffered from grass pollen AR and/or conjunctivitis with a positive grass allergen-specific skin prick test and/or elevated serum grass allergen-specific IgE. Baseline characteristics of the modelled cohort reflect the average patient characteristics in the treatment arms of the included clinical trials. At entry time, none of the patients suffered from co-existing chronic asthma. Only intermittent use of ß-agonists was allowed.Within the available range of allergoid products, the most widely used products in Germany with citable references from double-blind placebo-controlled (DBPC) trials were identified. The allergoid SCITs, namely Allergovit®, Depiquick®, Pollinex® Quattro and Purethal® , met the search criteria. The data was then grouped and averaged as one single comparator  were performed.Clinical trial data on allergoid compounds published before March 2012 was retrieved from a meta-analysis performed by Di Bona et al.   has been developed. RSUI represents a preference-based utility index for rhinitis symptoms using standard gamble and visual analogue scale (VAS) . Using tThe analysis was conducted from the German payer perspective, including payments of the SHI and additional payments by insurants. All AIT agents were used for a maximum time period of three years. Costs for the 5-grass tablet administered once daily were based on usage of seven months per year  in the base case analysis . For theAll pharmaceutical costs reflect SHI and consumer (co-)payments. Additionally, costs for symptomatic medication were calculated by multiplying the costs of loratadine and budesonide by the number of actuations. The number of tablets and puffs used during the season for the AIT and symptomatic treatment arm presented in Bachert et al.  were adjApart from pharmaceutical costs, the model included costs for specialist visits, treatment administration, diagnostics and asthma. In Germany, costs for health care are paid in four different settings: Public sector (90%), which is separated in lump sums (80%) , ambulatThe number of specialist visits associated with the use of the allergoid mix was estimated based on a weighted average of the number of injections each year taken from the Summary of Product Characteristics (SmPC). 5-grass tablet patients were assumed to see their doctor every three months during treatment for optimal adherence . All patModel outcomes were calculated and presented as total and incremental (un)discounted QALYs and costs. Then, a cost per Quality Adjusted Life year (QALY) was derived for the 5-grasss tablet and the allergoid mix. In accordance with the guideline for pharmacoeconomic research in Germany, discounting was applied at 3% per year for both costs and effects .Deterministic and probabilistic sensitivity analyses (PSA) were performed as well as a number of scenarios to assess the influence of uncertainty of input parameters. To identify the main drivers of the model outcomes, all uncertain parameters were placed separately at their outer limits of their 95% confidence intervals within the deterministic univariate sensitivity analyses.To constitute the uncertainty around the predicted incremental costs and effects, 1.000 simulations were performed in the PSA by simultaneously changing the parameters by random draws from their estimated distributions. For transition probabilities and utility values, beta distribution was applied. Normal distributions were used in case of risk estimates, and treatment efficacy of the 5-grass tablet, and allergoid mix . Gamma distributions were applied for healthcare costs and the duration of the pollen season. If the publication did not provide information on variance, the standard error was supposed to vary 20% around the mean value.A scatterplot and an acceptability curve were designed estimating the 95% confidence intervals around incremental model outcomes and the probability of the 5-grass tablet being cost-effective versus its comparators at a given willingness-to-pay (WTP) threshold per obtained QALY. Since the effects of assumptions and choices may not be completely captured by the sensitivity analyses, a number of scenario analyses were carried out.For the base case analysis, an assumption was made on the distribution of patients on the various remuneration pathways. Due to variations in this respect, costs for specialist visits, treatment administration, and diagnostics were calculated based on lump sum payments (scenario 1) and the ambulatory setting (scenario 2).In another scenario, costs were obtained from the societal perspective, incorporating indirect costs. Labour hours missed  over oneSince the length of the pollen season varies in different geographical areas, in scenario 5 a shorter duration of two months was evaluated.The results after nine years indicate higher total and incremental effects (QALYs) for the 5-grass tablet, for both discounted and undiscounted values Table . This isAIT treatment with the allergoid mix show a substantial use of health care services, as injections need to be administered by the specialist. Analyzing the absolute and relative distribution of the total costs over separate cost components, AIT treatment costs were found to be the main cost drivers , followed by cost for dermatologist visits Table . DiscounTable For the comparisons of the 5-grass tablet versus allergoid mix, extensive deterministic univariate sensitivity analyses and one probabilistic multivariate sensitivity analysis have been conducted, as well as a number of scenarios.Incremental QALYs resulting from the calculations are mainly sensitive to changes in efficacy estimates, because these are directly linked to utilities from the RSUI Figure a. The leThe joint uncertainty around the incremental costs and QALYs are displayed in Figure In the first two scenario analyses, healthcare costs are calculated by lump sums or 1 fold GOÄ  prices. In contrast to the first scenario, the second one did remunerate for extra services performed by the physician. As a result, incremental costs of the 5-grass tablet increased (lump sums) and decreased (1-fold GOÄ) versus SCIT allergoids, since injections correspond to extra visits  are, in most cases, mild and reversible, appearing mostly only during the early phase of treatment . AlthougComparable health economic comparisons are rare in the literature. An economic evaluation assessed the outcomes and costs as well as cost-effectiveness of the 5-grass tablet vs. Grazax® and Alk Depot SQ  alongside symptomatic medication and symptomatic treatment alone for grass pollen allergic rhinoconjunctivitis . In thisThe present analysis suggests the 5-grass tablet to be cost-effective in comparison to a selected allergoid mix, mirroring a representative average of a therapeutic class in AIT. The robustness of this statement has been addressed and confirmed in extensive deterministic and probabilistic sensitivity and scenario analyses.


Background: Speech understanding may rely not only on auditory, but also on visual information. Non-invasive functional neuroimaging techniques can expose the neural processes underlying the integration of multisensory processes required for speech understanding in humans. Nevertheless, noise  limits the usefulness in auditory experiments, and electromagnetic artifacts caused by electronic implants worn by subjects can severely distort the scans . Therefore, we assessed audio-visual activation of temporal cortex with a silent, optical neuroimaging technique: functional near-infrared spectroscopy (fNIRS).Methods: We studied temporal cortical activation as represented by concentration changes of oxy- and deoxy-hemoglobin in four, easy-to-apply fNIRS optical channels of 33 normal-hearing adult subjects and five post-lingually deaf cochlear implant (CI) users in response to supra-threshold unisensory auditory and visual, as well as to congruent auditory-visual speech stimuli.Results: Activation effects were not visible from single fNIRS channels. However, by discounting physiological noise through reference channel subtraction (RCS), auditory, visual and audiovisual (AV) speech stimuli evoked concentration changes for all sensory modalities in both cohorts (p < 0.001). Auditory stimulation evoked larger concentration changes than visual stimuli (p < 0.001). A saturation effect was observed for the AV condition.Conclusions: Physiological, systemic noise can be removed from fNIRS signals by RCS. The observed multisensory enhancement of an auditory cortical channel can be plausibly described by a simple addition of the auditory and visual signals with saturation. Viewing a talking person’s face and mouth may enhance speech understanding in noisy environments  and deoxygenated (HbR) hemoglobin . fNIRS assesses cortical hemodynamic changes in blood oxygenation based on changes in the transmission of near-infrared light through biological tissue and its absorption by oxygenated  speech-evoked activity from temporal cortex of normal-hearing adults and post-lingually deaf unilateral CI users. We use a limited number of fNIRS channels in order to reduce the time and complexity of applying the optodes. Figure We also tested a limited number of post-lingually deaf unilateral CI users mainly to examine the feasibility of recording multisensory speech processing at the level of temporal cortex with easily-applied, 4-channel fNIRS in the presence of electrical innervation of the auditory nerve by a CI.Thirty-three adult native Dutch-speaking normal-hearing subjects  and five adult Dutch-speaking post-lingually deaf unilateral CI users  source-detector pairs above the preauricular point at the T7 and T8 location of the International 10/20 system on the left and right hemisphere, respectively . Even the shortest intermittent period of 25 s allowed the hemodynamic response to return to baseline, while the randomization limited time locking of any periodic physiological signal to stimulus onsets. The segments were presented in three blocks of 12 stimuli each. A single session consisted of these three blocks with intermittent breaks of about 4–5 min wherein the light was turned on. Every block started with a baseline measurement (in silence and darkness) of 2 min. A session of three blocks (36 segments) took about 45 min to complete.For every block, the 12 segments were pseudo-randomly assigned to an experimental condition . Subjects were instructed to pay attention to the segments , and were asked afterwards whether they understood the gist of the storyline. Other than that, subjects were not given further task instructions.oxysoft2matlab. The 250-Hz sample-rate data were downsampled to 10 Hz , for computational efficiency.The optical densities for each channel and wavelength were stored on disk (in the native oxy-format from the Artinis system) for offline analysis in Matlab . Data was read into Matlab via Artinis’ proprietary function removeheartbeat function from the NIRS Analysis Package  using the modified Lambert-Beer law  for the shallow (black line), deep channel (red line) and the residual signal, during presentation of auditory snippets, is plotted in Figure Despite these filtering procedures, a considerable amount of noise originating from non-cortical physiological processes still remained  to determine the mean response for both cohorts.Functional signals were averaged across the 12 repeats of each stimulus modality to calculate the average hemodynamic response for each participant and hemisphere. These traces were averaged across participants and hemispheres . The HRF consists of a canonical impulse response function h , which peaks at ~5 s, convolved with the boxcar function . After convolution the HRF signal is expected to peak at ~12 s. All pre-processing steps performed on the data were also applied to the HRF signal.(with aβ) and visual (vβ) inputs independently elicit a hemoglobin concentration change. An extra, third component (avβ) is added in this model, which represents the type and amount of multisensory integration during the presentation of audiovisual stimuli:We employed a general linear model (GLM) to quantify the strength between the measured responses to each stimulus condition and the HRF. This model assumes that auditory (C and Gaussian noise ε(t).with fNIRS data y(t), the explanatory variables X(t), constant regression coefficients β, offset R2-value, and the corresponding F and p-values). We took the significance of every regression coefficient as a measure of activation compared to baseline, by determining the corresponding t- and one-sided p-value .For each GLM fit, we determined the goodness of fit  generally increase and decrease, respectively, during the stimulus epochs  stimuli increases from baseline at sound onset reaching its maximum after about 15 s . Typically, and as exemplified for this subject, the hemodynamic response corresponds well to the actual signals  followed by a recovery back to baseline after stimulus offset. The data of the CI users . Most channels did not exhibit an additional AV component (AV: 7/54 and 9/54).To quantify the evoked responses, we fitted a GLM  that assumes that auditory and visual inputs independently elicit a hemoglobin amplitude change, also during audiovisual stimulation. An extra, third component is added in this model, which represents the type and amount of multisensory integration during the presentation of audiovisual stimuli. The analysis yields a set of three beta coefficients Figure  represen Figures , signifi2  on a group-level, although there is a large intra-coefficient variability, with beta values ranging between −0.3 and 1.9. In contrast, comparisons between coefficients show a systematic trend of visual coefficients being smaller than auditory coefficients . A similar, opposite pattern arises for HbR . The auditory data signify that we can reliably obtain auditory responses from temporal cortex with fNIRS, and the slightly weaker visual response data arguably imply that cross-modal, visual activation can arise from the same recording site .In line with the significance of unisensory individual channel activation, the coefficients for both the auditory and visual components reveal a general positive amplitude change for HbO2: 49 of 54; HbR: 43 of 54), we chose to compare only the auditory response with the bimodal response for all subjects .To test for multisensory integration, researchers typically compare the bimodal response to the largest unimodal response . This might be indicative of a saturation effect as the extra audiovisual interaction effect almost exactly counterbalances any effect a visual component might have .The audiovisual interaction components are almost exactly inversely related to the visual amplitudes , the Radboud University Nijmegen (AJvO), and the RadboudUMC . The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Using instrumental temperature data from the early 1800s from Fort Snelling (Minnesota), we assessed the signal distortion and bias introduced by using the conventional method of inferring temperature from pollen assemblages in comparison to a calibration set from pre-settlement pollen assemblages and the earliest instrumental climate data. The early post-settlement calibration set provides more accurate reconstructions of the 19th century instrumental record, with less bias, than the modern set does. When both modern and pre-industrial calibration sets are used to reconstruct past temperatures since AD 1116 from pollen counts from a varve-dated record from Lake Mina, Minnesota, the conventional inference method produces significant low-frequency  signal attenuation and positive bias of 0.8-1.7°C, resulting in an overestimation of Little Ice Age temperature and likely an underestimation of the extent and rate of anthropogenic warming in this region. However, high-frequency  signal attenuation exists with both methods. Hence, we conclude that any past pollen spectra from before Euro-American settlement in this region should be interpreted using a pre-Euro-American settlement pollen set, paired to the earliest instrumental climate records. It remains to be explored how widespread this problem is when conventional pollen-based inference methods are used, and consequently how seriously regional manifestations of global warming have been underestimated with traditional pollen-based techniques.The inference of past temperatures from a sedimentary pollen record depends upon the stationarity of the pollen-climate relationship. However, humans have altered vegetation independent of changes to climate, and consequently modern pollen deposition is a product of landscape disturbance and climate, which is different from the dominance of climate-derived processes in the past. This problem could cause serious signal distortion in pollen-based reconstructions. In the north-central United States, direct human impacts have strongly altered the modern vegetation and hence the pollen rain since Euro-American settlement in the mid-19 Both climate and landscape disturbance have important impacts on vegetation. Analysis of pollen in well-dated sediment cores has been used to estimate past changes in climate, but these relationships have been based on modern pollen-climate transfer functions. Due to large-scale landscape disturbance, the relationship between modern climate and pollen deposition is quite possibly different from the relationship between climate and pollen rain in the pre-industrial past. This largely overlooked problem is of concern because the inference of past climates from the sedimentary pollen record relies upon the pollen-climate relationship being constant in time from the calibration period to the reconstruction period ., 11.9, 1 the MCA –17. Ther the MCA , 18–20.th century instrumental record.In the American Midwest, logging, fire suppression, deforestation and agriculture have greatly changed vegetation composition and the composition of its pollen rain since Euro-American settlement in the mid-1800s. Minnesota is uniquely rich in early climate stations from military forts which predate large-scale Euro-American settlement , allowinQuercus-dominated deciduous forest which closely follows the southern edge of USDA Climate Zone 3 . The locations of these ecotones can be traced in pre-settlement vegetation patterns reconstructed from General Land Office surveys in Minnesota (AD 1847–1907) . Hence, this sensitive location can be used to track paleoclimate signals from climate-driven shifts in these ecotones over at least the past several millennia.Minnesota is a sensitive locale for paleoclimate reconstructions because it is quartered by two orthogonal continental-scale ecotones controlled by climate. The prairie-forest ecotone, with its wide transitional expanse of parkland, runs north-south, following the gradient in effective moisture  (modern Minnesota climate maps are shown in 7–1907) , giving a total of 133 sites. We added AD 1895–1924 climate normals  from nearby early instrumental records  to produce a “pre-settlement” or “1870” calibration set ) per se, which makes comparisons to the pollen record less direct, but presumably these large weather pattern shifts were antecedent to or accompanied the cooler temperatures of the LIA. The pollen PC1 (a metric of temperature) shows the initiation of the LIA at AD 1505–1508. Hence, there is a 0–35 year lag in the pollen response at Lake Mina, depending on the type of climate change. This lag is short enough to make our analysis valid. Furthermore, our analysis does not need the full reconstruction of the annual high-frequency band in the climate record. A reasonable capturing of the variability in the 20–1000 year band with some of the annual variability is sufficient, and we argue that the Lake Mina 1870-based temperature reconstructions contain this.The swift response of the Lake Mina pollen record to changing weather/climatic conditions can be explicitly examined because there are three other independent proxy climate records from the lake: varve thickness, and diatom and chrysophyte microfossils from split samples , 26. Theth century pollen-based temperature reconstructions and 18th century reconstructions are not possible because the 20th century reconstructions are unreliable due to landscape alterations. However, the differences between the instrumental Alexandria monthly climate normals of AD 1961–1990 and the average monthly temperature reconstruction for the 18th century can be calculated for both February and May. The mean difference from both months can be used as an estimate of the annual temperature change during the past 300 years. For the pre-settlement reconstruction, the difference was 1.3°C; whereas the difference was -0.1°C for the modern reconstruction. The pre-settlement reconstruction matches the borehole temperature changes well; the modern reconstruction does not match the borehole reconstructions.Independent evidence from borehole annual temperature reconstructions supports the reconstructions based upon the pre-settlement calibration set, but not those based upon the conventional set. Borehole studies from the adjacent prairie provinces of Canada have shown a regional warming of about 1.5–2.5°C over the past 300 years –51. DireAlthough not perfect, the 1870 calibration set captures the pre-settlement relationship between the pollen rain and climate better than the modern set. The pollen data reflect the pre-Euro-American vegetation controlled by climate and other natural processes relatively undisturbed by humans, unlike the most recent (core-top) pollen spectra, which is an integration of both climate and land use. Contemporaneous lake ice-out and ice-in records  show thaOn the other hand, a modern pollen-climate calibration set has some problems. The most important is that the pollen data comes from vegetation typically heavily modified by human impacts. Furthermore, not all locales have received the same amount of direct human impact. Due to the rapidity of anthropogenic global warming, vegetation is likely lagging behind climate and not all pollen taxa are responding to the rapid global warming at the same rate. A modern pollen calibration set is typically drawn from a compiled mixture of present-day surface samples and core-top samples, the latter of which can date from anytime in the past hundred years or so , and not from the exact three decades that the climate normals are computed from. Our study shows that, if we want to use high-resolution pollen in millennial climate reconstructions, it is important to construct our transfer functions more carefully and address these known, but overlooked issues.Ambrosia and Amaranthaceae pollen, at the expense of northern taxa such as Pinus and Betula .S1 FigMap of Minnesota and environs showing locations of Lake Mina (Mi), Fort Snelling (FS) and the main vegetation patterns.(TIF)Click here for additional data file.


Acute inflammation, an integral part of host defence and immunity, is a highly conserved cellular response to pathogens and other harmful stimuli. An inflammatory stimulation triggers transcriptional activation of selective pro-inflammatory genes that carry out specific functions such as anti-microbial activity or tissue healing. Based on the nature of inflammatory stimuli, an extensive exploitation of selective transcriptional activations of pro-inflammatory genes is performed by the host to ensure a defined inflammatory response. Inflammatory signal transductions are initiated by the recognition of inflammatory stimuli by transmembrane receptors, followed by the transmission of the signals to the nucleus for differential gene activations. The differential transcriptional activation of pro-inflammatory genes is precisely controlled by the selective binding of transcription factors to the promoters of these genes. Among a number of transcription factors identified to date, NF-κB still remains the most prominent and studied factor for its diverse range of selective transcriptional activities. Differential transcriptional activities of NF-κB are dictated by post-translational modifications, specificities in dimer formation, and variability in activation kinetics. Apart from the differential functions of transcription factors, the transcriptional activation of selective pro-inflammatory genes is also governed by chromatin structures, epigenetic markers, and other regulators as the field is continuously expanding. The survival of all living organisms relies on their ability to respond to a wide range of harmful stimuli such as microbial infection, environmental stresses, and tissue injures. The responses are initiated by immune mechanisms designed to detect and eliminate foreign pathogens, as well as heal damaged tissues. The effective responses by the immune system are mediated by the activation of signal transduction pathways leading to the altered expression of a subset of genes that are required to combat harmful consequences. Therefore, the expression patterns of selective genes at the transcriptional level are of central importance for the host defence mechanism.Inflammation is one of the highly conserved and beneficial responses evolved in higher organisms in response to pathogens and other harmful stimuli. When a host with a functional innate immune system encounters foreign pathogens or tissue injuries, the inflammatory response initiates within minutes. Acute inflammation is therefore considered as the first line of host defence and an integral part of innate immunity. The inflammatory response triggers transcriptional activation of numerous genes, which carry out diverse physiological functions ranging from initiation of antimicrobial activities to the development of acquired immunity. Some of these gene products, such as antimicrobial peptides, directly target pathogenic microorganisms, while others, such as inflammatory cytokines and chemokines, activate the host defence by recruiting immune cells to the site of infection, as well as initiating healing of the injured tissues. Due to the enormous variety of pathogenic microorganisms and harmful stimuli routinely experienced by an organism, the inflammatory response involves an extensive exploitation of the transcriptional activation of selective genes intended for specific antimicrobial defence and tissue repairs. For example, bacterial pathogens induce the expression of inflammatory cytokines including tumour necrosis factor alpha (TNF-α), interleukin-1 (IL-1) and interleukin-6 (IL-6), as well as chemokines such as chemokine (C-C motif) ligand 2 , and chemokine (C-X-C motif) ligand 8 . On the other hand, viral infections induce type-1 interferons , and parasitic worm infections or exposure to allergens are associated with the expression of histamine, IL-4, IL-5 and IL-13 [This review focuses on the diversity of molecular mechanisms underlying the selective transcription of inflammatory genes. Apart from differential transcriptional activation, stimulus-dependent inflammatory signals also active the inflammasome, a molecular complex of several proteins that cleaves pro-IL-1β and pro-IL-18 into active IL-1β and IL-18. Since the latter has been reviewed in detail elsewhere , it willThe main purpose of inflammation is to protect the host from any damaging consequences to cellular homeostasis. Once the inflammatory stimuli and sequelae have subsided, the acute inflammatory response is terminated. The resolution of inflammation, which includes the termination of inflammatory responses and the restoration of the homeostatic state, is in fact an integral part of the inflammatory process and needs to be carefully controlled. As an adaptive response to harmful stimuli, the inflammatory response is not only associated with host side effects, but is also maintained at the expense of normal physiological activities. Therefore, the duration of an inflammatory response is precisely regulated in order to avoid any unfavorable consequences to the host. Down-regulation of the response occurs via elaboration of anti-inflammatory molecules, such as IL-10, transforming growth factor-β (TGF-β), and glucocorticoids, which act to minimize the risk of excessive inflammation ,4. HowevInflammatory signals are initiated by the recognition of inflammatory stimuli by specific transmembrane and intracellular receptors, called pattern-recognition receptors (PRRs). PRRs are germ-line encoded receptors that can specifically sense either pathogenic microorganisms or any cellular damage, and are expressed by cells of both the innate and adaptive immune systems . PathogeUpon interaction with their cognate ligands, PRRs transduce signals to the cell nucleus to effect differential activation of gene transcription. Selectivity in the transcriptional regulation of these genes is largely dictated by the differences in the signal transduction pathways, which are exclusively governed by the nature of the stimuli initiating the PRR activation. In response to an inflammatory stimulus, activated genes have been divided into two categories based on the pattern of their transcriptional activation: primary and secondary response genes. Primary response genes, also referred to as immediate early genes, are activated rapidly after stimulation, whereas activation of secondary response genes is much slower ,9,10. ItThe discovery of the TLRs provided significant insight into how the host initiates inflammatory responses against microbial pathogens . TLRs arThe differential regulation of gene activation at the transcriptional level is indicative of a precisely controlled binding of selective transcription factors to DNA motifs at the promoter of these genes. In fact, the efforts to identify transcription factors and their corresponding DNA binding motifs on target genes began decades ago. The nuclear factor κ(kappa)-light-chain-enhancer of activated B cells (NF-κB) was the first transcription factor identified whose binding to DNA is induced by a post-translational mechanism . NF-κB iIn conjunction with the activation of NF-κB, the stimulation of TLRs also activates major mitogen-activated protein kinase (MAPK) subfamilies: the extracellular signal-regulated kinase (ERK), p38 and Jun N-terminal kinase (JNK) . FollowiFollowing the discovery of NF-κB, a number of other transcription factors were identified that can also be activated by inflammatory stimuli via post-translational mechanisms, such as phosphorylation or dephosphorylation of these factors or their inhibitors. For example, activator protein-1 (AP-1), cyclic-AMP (cAMP) response element binding protein (CREB), serum responses factor (SRF), and the associated ternary complex factors (TCFs) ,19. MostEven though a transcription factor binds to the promoter of a defined set of genes through a specific DNA motif, the selective activation of most genes is dependent on the synergistic effect of multiple transcription factors. Many inflammatory genes contain more than one DNA binding motif recognized by multiple transcriptions factors, and the binding of each and every transcription factor to its corresponding DNA motif is indispensable for the activation of these genes . For exaDespite the discovery of many transcription factors involved in the selective regulation of pro-inflammatory gene activations, NF-κB still remains at the forefront of eukaryotic transcriptional mechanisms because of its predominant role in inducing gene expression in response to a wide variety of stimuli in all cell types. Due to the extensive range of contributions of NF-κB, selective regulatory mechanisms are in place to ensure the activation of only a subset of genes in response to a defined stimulus. Although the NF-κB activation is initiated by its inducible nuclear translocation and binding to the corresponding DNA motifs, a number of different regulatory layers are involved for differential activation of target genes.H. pylori infection; for the latter this event is dependent on the PI3K/Akt pathway -dependent signaling complex in which E3 ubiquitin ligases along with E1 ubiquitin-activating and E2 ubiquitin-conjugating enzymes attach ubiquitin molecule(s) to a lysine of the substrate protein. Depending on the nature of the ubiquitin chains linked to the substrate protein, ubiquitination serves critical signaling roles. For example, Lys63 (K63)-linked chains allow assembly of protein complexes that lead to the activation of kinases and Lys48 (K48)-linked chains target substrates for proteasomal degradation . FollowiThe outcomes of the inflammatory signaling pathways are profoundly dictated by differential ubiquitination-mediated regulation. In response to LPS stimulation, the selective transcriptional activation of either inflammatory genes or type-1 IFNs is mediated by the alternative ubiquitination modes of the adaptor protein TRAF3 . Being iNF-κB signal transduction is strongly modulated by cIAP1 and cIAP2 through their activity as E3 ligases. Best studied in TNF family-induced NF-κB signaling, cIAPs are critical regulators of stimulus-dependent activation of the canonical as well as constitutive suppression of the non-canonical NF-κB pathways . The actIn non-canonical NF-κB signaling, cIAPs are responsible for the ubiquitination and subsequent degradation of NF-κB-inducing kinase (NIK), the key regulator of non-canonical NF-κB signaling. Under unstimulated conditions, non-canonical NF-κB signaling is normally suppressed because of constitutive proteasomal degradation of NIK, mediated by a complex consisting of TRAF2, TRAF3 and cIAPs. Through a heterodimeric bond with TRAF3 that directly binds to NIK, TRAF2 brings cIAP proteins in the proximity of NIK, thus promoting K48-linked ubiquitination of NIK for its degradation. Following stimulation of any one of several TRAF3-binding TNF superfamily receptors , the cytoplasmic TRAF3-TRAF2-cIAP complex is disrupted by the membrane recruitment and degradation of its components. The depletion of the TRAF3-TRAF2-cIAP E3 complex results in stabilization of NIK, which subsequently phosphorylates IKKα and the NF-κB precursor p100. Activated IKKα homodimers phosphorylate additional residues in p100, which triggers its partial degradation to generate the p52 form. The p52 fragment dimerizes with RelB and translocates to the nucleus where it binds the promoter regions of NF-κB-dependent genes to activate their transcription ,56 Figu.The selective transcription of pro-inflammatory genes involving differential binding of transcription factors to specific DNA sequences is largely influenced by chromatic structures that make up chromosomes. The fundamental subunits of chromatin are nucleosomes, which consist of a segment of DNA wrapped around a histone octamer containing two copies each of four histone proteins, H1A, H2B, H3, and H4 . The strS. cerevisiae that the acetylation of histone H3 is mediated by a transcriptional coactivator, Gcn5 [The first evidence for a direct role for chromatins in transcriptional regulation came from an observation in or, Gcn5 . The SWIor, Gcn5 ,63,64. Tor, Gcn5 . Based oor, Gcn5 . The proor, Gcn5 ,67. SWI/The activation of SWI/SNF-dependent genes through nuclear remodeling suggests a model in which the recruitment of the SWI/SNF complex to its target genes is dependent on stimulus-specific primary response gene products such as transcription factors. In accord with this model, a substantial number of SWI/SNF-dependent genes possess consensus IRF3 binding sites on their promoters and the activation of these genes in response to LPS stimulation was shown to be dependent on IRF3 binding to their promoters . FurtherThe transcriptional regulator PLZF is a critical co-factor that limits NF-κB-mediated inflammatory responses by maintaining a transcriptionally repressed chromatin state. PLZF stabilizes a repressor complex consisting of HDAC3 and the NF-κB p50 subunit to the promoters of select genes , therebyPausing of the early elongation complex has also been described for several genes in which the synthesis of a short RNA-by-RNA polymerase II is paused until an appropriate signal for productive elongation appears . This phThe transcription of a target gene is also positively influenced by enhancers located at a considerable distance. It has been suggested that that enhancers facilitate recruitment of the transcription machinery to the target promoter via DNA loops, bringing enhancer to the close proximity of the promoter ,75. The The concept of nucleosome remodeling for the activation of selective genes is far from being completely understood, as the primary gene products required for remodeling remain largely unknown. Moreover, the potential involvement of additional regulatory layers in chromatin structures and remodeling cannot be ignored, as the activation of the SWI/SNF complex following its recruitment to target genes upon LPS stimulation was shown to be dependent on a calcium signaling pathway .Recent observations suggest that the differential kinetics of gene activation cannot be explained solely based on the promoter accessibility ,82,83. TThe selective transcription of pro-inflammatory genes is predominantly dictated by both the specificity of the signaling cascades, ubiquitination, and transcription factors, and the nature of the chromatin states of these genes as discussed above. According to the current literature, inflammatory gene transcription is also subjected to the consequences of various molecular features and/or physiological events at the cellular level. Some of these influences are briefly discussed below.Over the last decade, an array of epigenetic markers has emerged as defining features for active or repressed chromatin states, thereby influencing transcriptional activation. For example, the recruitment of NF-κB to the promoter regions of many pro-inflammatory genes is promoted by the acetylation of histone H3 at these promoters . AcetylaThe chromatin structures at the promoters of inducible genes in resting cells, and the patterns of the subsequent transcriptional activation of these genes upon stimulation vary significantly from one cell type to another in eukaryotic organisms. These cell-type-specific variations indicate the existence of multiple transcriptional mechanisms operating in a developmental-stage-specific manner. In fact, this view was supported by several reports demonstrating that the cell-type-specific variations in chromatin structures and transcriptional mechanisms were established early in development long before these genes are activated ,96,97. CIt would be hard to imagine that the mechanistic diversity in selective inducible gene activations as discussed above operates without any physiological relevance. For example, macrophages are prominent for their ability to fight against infectious agents, as well as for tissue healing and therefore they remain abundant at the sites of infections or tissue injuries. Compared to other responsive cell types such as fibroblasts, macrophages are mobile and can easily accumulate as needed. Therefore, the production of pro-inflammatory cytokines by macrophages at these sites needs to be precisely controlled with additional regulatory layers, not only to cope with the presence of a plentiful supply of inflammatory stimuli associated with these sites, but also to avoid excessive tissue injuries. As a result, SWI/SNF-dependent and SWI/SNF-independent expression of IL-6 in macrophages and fibroblasts, respectively, upon LPS stimulation , is likeThe induction of selective transcriptional activation of pro-inflammatory genes has been considered to be driven by inflammatory stimuli through a common set of transcription factors such as NF-κB, AP-1, CREB, and others, as mentioned above. However, a number of recent observations have revealed that pro-inflammatory signal transduction pathways are far more diverse than previously realized, indicating an involvement of multiple signaling pathways in selective transcription of pro-inflammatory genes. As mentioned above, a calcium signaling pathway plays a critical role in activating the SWI/SNF complex following its recruitment to its target genes . The traH. pylori infection [A great depth of knowledge has been gained about the selective transcription of pro-inflammatory genes since the discovery of NF-κB more than 25 years ago . Using Rnfection . Since Infection ,114,115.nfection , osteoblnfection , bladdernfection , and rhenfection . The MAPnfection , which i


B-type natriuretic peptide (BNP) and the inactive amino-terminal pro-B-type natriuretic peptide (NT-proBNP) have a prognostic value in heart failure and in myocardial infarction. There has been some evidence that BNP and NT-proBNP can be used in the diagnosis of myocardial ischaemia by improving the sensitivity of exercise-stress testing.99mTc-sestamibi single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) to diagnose reversible ischaemia, were enrolled. NT-proBNP was determined at rest and one hour after infusion of dipyridamole.To observe the relationship between dipyridamole-induced ischaemia and the secretion of NT-proBNP. Methods: A total of 52 consecutive patients, referred for dipyridamole stress Of the 52 patients, 25 had normal scans, 12 had scans with fixed defects  and 15 had reversible perfusion defects (inducible ischaemia). There was no correlation between ischaemia and resting NT-proBNP, post-stress NT-proBNP and the change in NT-proBNP. There was a correlation between ejection fraction, ventricular volumes and resting NT-proBNP.NT-proBNP does not add to the diagnosis of myocardial ischaemia in dipyridamole stress MPI. The cardiac natriuretic peptides (CNP) have been shown to be of value in the diagnosis, prognosis, treatment and monitoring of heart failure.Myocardial ischaemia can be induced using physical or pharmacological stress. Dipyridamole is often used in the setting of MPI. Dipyridamole has been shown to induce perfusion and regional wall motion abnormalities. The mechanism of this regional redistribution of blood flow is probably multifactorial. A proposed mechanism is due to steal, whereby the normal vessels vasodilate, with resultant enhanced blood flow, leaving relatively reduced pressure and flow across areas of haemodynamically important coronary artery stenoses, inducing ischaemia and regional wall motion abnormalities. Another proposed mechanism is that due to the afterload reduction of dipyridamole, there is a degree of hypotension and reflex tachycardia and this causes or contributes to the myocardial ischaemia.13Dipyridamole-induced myocardial ischaemia has also been shown to increase atrial natriuretic peptide (ANP),in vitro.There are many terms referring to the natriuretic peptides. Pro-BNP (108 AA) is cleaved by a serine protease corin into an inactive protein pro-BNP 1-76 , and into BNP 32, the active hormone, also referred to as BNP. BNP and NT-proBNP can reliably be measured The aim of this study was to observe whether dipyridamole-induced myocardial ischaemia caused a predictable change in NT-proBNP values, and whether these changes could be used to diagnose myocardial ischaemia.Fifty-two consecutive patients referred for dipyridamole stress SPECT MPI at the Nuclear Medicine Department of the Johannesburg Hospital to exclude reversible ischaemia, were enrolled into the study. The study had institutional ethics approval, and informed consent was obtained from the subjects prior to enrolment. The study period was between January and October 2006. The median age was 63 years (40−83); the male-to-female ratio was 26:26.The exclusion criteria were: asthma or severe chronic obstructive pulmonary disease, beta-blocker use, the intake of caffeine in the 24 hours preceding the test, and refusal of consent. There were no adverse reactions to dipyridamole during the time of the study.99mTc-methoxyisobutyl isonitrile (Sestamibi) SPECT MPI protocol was used. On the first day the stress test was performed, with the rest study being done on day two. Dipyridamole and 99mTc sestamibi (740 MBq) were given according to protocol. The patient was allowed to rest and images were acquired between 30 and 60 minutes after the injection of the radiotracer. Imaging was performed using a double-head rotating field-of-view gamma camera  equipped with low-energy, high-resolution, parallel-hole collimators. SPECT images were acquired on a 64 × 64 matrix using the step-and-shoot mode with a total of 180-degree angular range and 20 seconds per image.A two-day Myocardial ischaemia was assessed visually and by means of semi-quantitative scoring of the extent and severity of perfusion abnormality − summed difference score (SDS). This was calculated by subtracting the summed resting score (SRS) from the summed stress score (SSS), using the xeleris multisync work station for processing data, which was fitted with the QGS/QPS and uses a 20-segment model to quantify myocardial perfusion on an arbitrary scale. The sensitivity of the SPECT MPI technique in diagnosing ischaemic heart disease is 91% and the specificity is 81%,An SDS of more than four indicates the presence of myocardial ischaemia. This can be graded: an SDS of 4–8 is mild, 9–12 is moderate and greater than 13 is severe myocardial ischaemia. If there was any doubt about the significance of the myocardial ischaemia, the visual inspection of the MPI study was used to assess the significance of the perfusion defect.The reported timing of blood sampling for NT-proBNP is in subjects undergoing physical stress testing and in some cases where BNP is analysed in conjunction with NT-proBNP. BNP has a half-life of 19 minutes and this forms the rationale for early blood sampling when BNP is the analyte under investigation. NT-proBNP has a half-life of 90 minutes. These differing half-lives have an effect on optimal timing of blood sampling; it cannot be extrapolated that an optimal time for BNP would be optimal for NT-proBNP. A further factor to consider is that even though dipyridamole has a maximal cardiac effect after five minutes of infusion, this effect persists for 10 to 30 minutes after infusion.Blood samples were obtained at rest, 15, 30 and 60 minutes after the infusion of dipyridamole in 15 subjects. The maximal change was observed at 60 minutes. The experiment was repeated on 10 more subjects to confirm this observation, only sampling at 15 and 60 minutes A resting blood sample was obtained before the dipyridamole infusion and the post-stress blood sample was obtained one hour after the infusion in all subjects. The sample was allowed to clot and then centrifuged at 3 000 rpm for 10 minutes. The serum was stored at –70°C and analysed in batches.Roche Diagnostics SA supplied the assay, which is an electrochemiluminesence immunoassay that uses a sandwich technique. The analytical range is 5−35 000 pg/ml; the reference cut-off value based on the manufacturer’s data is 125 pg/ml. Patients with values below this exclude cardiac dysfunction with a high level of certainty, levels above 125 pg/ml may indicate cardiac dysfunction and this is associated with an increased risk of cardiac complications . This value is not corrected for age or gender . The analytical coefficient of variation for the assay was 1.8−2.7%.This was done using SAS Software V9.1 . Spearman correlation coefficient was used to calculate correlations, and the Kruskal−Wallis test was used to calculate differences in NT-proBNP between the groups.Of the group of 52 patients, 25 had a normal scan (no perfusion defects), 12 had a fixed perfusion defect  and 15 had a reversible perfusion defect (inducible ischaemia). Of the 15 patients with reversible defects, five had fixed defects as well The median resting NT-proBNP of all the subjects was 349 pg/ml, with a range of 6−16 334 pg/ml. The median resting NTproBNP in patients with normal scans was 236 pg/ml, for those with fixed defects, 386 pg/ml, and for patients with reversible defects, 330 pg/ml. The highest median resting NT-proBNP result was in the subjects with a fixed perfusion defect, followed by the subjects with reversible ischaemia, and the lowest was seen in the subjects with normal MPI scans. There was a large overlap of values in the different subject groups; these differences are not statistically significant r = 20.58, p < 0.0001), LV end-systolic volume  and LV end-diastolic volume   and resting, post-stress and delta NT-proBNP values This study used a sample population that was made up of the typical patient referred for dipyridamole stress SPECT MPI to assess the presence of reversible myocardial ischaemia. No selection was made on the basis of ventricular function.The subjects in this study population probably had a degree of LV dysfunction, as demonstrated by the median resting NT-proBNP of 349 pg/ml (N cutoff 5 125 pg/ml). The correlation seen between NT-proBNP and LV ejection fraction, LV enddiastolic and LV end-systolic volumes was a reflection of the relationship of NT-proBNP with ventricular function.In the exercise studies, where NT-proBNP increased significantly in individuals with myocardial ischaemia, these individuals were selected and had normal ejection fractions.The mechanism of inducing myocardial ischaemia may also be important. The effect that physical exercise has on CNP has been studied. The effect of pharmacological stress testing has not been investigated to the same extent. There has been one study demonstrating an increase in atrial natriuretic peptide with dipyridamole-induced myocardial ischaemia.24There is a debate as to which marker to use, BNP or NT-proBNP. These markers are secreted in equimolar amounts. The metabolism of NT-proBNP is not fully understood and renal failure is speculated to influence the values. In studies on the use of these markers there is little to choose between them and either can be used.In this study, using SPECT MPI with a sensitivity of 91% to diagnose myocardial ischaemia, there was no correlation between myocardial ischaemia and NT-proBNP – resting values, post-stress values or the change in values. The small number of ischaemic subjects may have limited this study and a larger study may discover statistically significant findings. The question still remains whether NT-proBNP can be used to diagnose myocardial ischaemia in the individual patient presenting with suspected myocardial ischaemia.The median NT-proBNP values were higher in the subjects with fixed defects and inducible defects compared to the subjects with normal perfusion scans. However, there was enormous overlap between the values, making the resting NT-proBNP value useless to predict ischaemia. Apart from the prognostic value of NT-proBNP, it has no value in the diagnosis of myocardial ischaemia in the typical patient referred for dipyridamole stress SPECT MPI.


Self-monitoring is an essential behavioral strategy for effective weight loss programs. Traditionally, self-monitoring has been achieved using paper-based records. However, technology is now more frequently used to deliver treatment programs to overweight and obese adults. Information technologies, such as the Internet and mobile phones, allow innovative intervention features to be incorporated into treatment that may facilitate greater adherence to self-monitoring processes, provide motivation for behavior change, and ultimately lead to greater weight loss success.The objective of our study was to determine whether the consistency of self-monitoring differed between participants randomly assigned to a basic or an enhanced 12-week commercial Web-based weight loss program.We randomly assigned a sample of 301 adults  to the basic or enhanced group. The basic program included tools for self-monitoring  with some feedback and reminders to weigh in (by text or email). The enhanced program included the basic components, as well as extra individualized feedback on self-monitoring entries and reminders  to engage with self-monitoring tools. We evaluated the level of self-monitoring by examining the consistency of self-monitoring of food, exercise, and weight during the 12 weeks. Consistency was defined as the number of weeks during which participants completed a criterion number of entries .P<.001; for exercise 2.5 vs 1 weeks, respectively, P=.003).The enhanced group’s consistency of use of self-monitoring tools was significantly greater than that of the basic group throughout the 12 weeks : ACTRN12610000197033; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=335159 (Archived by WebCite at http://www.webcitation.org/6gCQdj21G) Self-monitoring is a behavioral strategy considered essential for effective weight loss programs . Self-moA systematic review evaluated the effects of self-monitoring of diet, exercise, and self-weighing on weight loss as part of a behavioral intervention program . All 22 Behavioral weight loss programs are traditionally delivered in a face-to-face format and self-monitoring is completed using paper-based diaries . HoweverP=.21) or the proportion of participants who achieved a clinically significant weight loss of 5%  at 12 weeks based on intention-to-treat analysis [We previously conducted a randomized controlled trial (RCT) comparing the efficacy of 2 versions (basic vs enhanced) of a commercial Web-based weight loss program for 12 weeks . Both veTherefore, the aims of this investigation were to determine whether consistency  of self-monitoring of food intake, exercise, and weight differed between participants randomly assigned to the basic version and those assigned to the enhanced version of the commercial Web-based weight loss program, and whether the consistency of self-monitoring was related to weight loss after 12 weeks . We hypoWe collected data for this analysis as part of a commercial Web-based weight loss program RCT. The methods of the RCT have been published in detail elsewhere . We inve2) adults (18 to 60 years old) in the Hunter region of New South Wales, Australia, through media advertising  from October to December 2009. To be included in the study, participants had to agree not to take part in other weight loss programs for the study duration; pass a health screening questionnaire; have access to a computer with Internet and an email account; and be able to attend assessment sessions at the University of Newcastle campus . Participants were ineligible for the study if they were pregnant or trying to conceive; had major medical illnesses; had physical inabilities such as orthopedic or joint problems; had lost 4.5 kg or more in the preceding 6 months; or were taking medications that affected or were affected by weight loss. We obtained written informed consent from all participants before their enrollment.We recruited overweight and obese . After 12 weeks, we randomly reallocated participants in the control group to either the basic or enhanced group, using the same procedures. We analyzed the self-monitoring behaviors of all participants during their participation in the basic or enhanced group. Participants were informed of their group allocation in sealed envelopes, which contained their online program login details. Participants in the basic and enhanced groups and researchers assessing outcomes were blinded to participants’ assignment to treatment groups.We initially randomly assigned participants to 1 of 3 groups  using a stratified randomized block design. Blocks of variable length (either 3 or 6) were used to stratify participants according to their sex and baseline BMI category , and then recorded the amount. A weigh-in entry required a weight to be entered by participants either online or via text message. For the purposes of this study, we required a participant to make 1 entry per day  for the day to be counted as self-monitoring and therefore be included in the calculation of consistency of self-monitoring.Consistency of self-monitoring for this study refers to the number of weeks during which a criterion number of entries was made. For food and exercise the criterion number was ≥3 days of entries per week, as per the previous definition of Peterson et al . For weiTo determine the relationship between categories of self-monitoring consistency and weight loss, we grouped participants into 3 levels of self-monitoring consistency over the 12 weeks, based on the number of weeks when they met the criterion number of self-monitoring entries . The levels were defined as low consistency if participants met the criterion number of self-monitoring entries in ≤4 weeks; as moderate if they met the criterion between 5 and 8 weeks; or as high if they met the criterion for ≥9 weeks. Low, medium, and high were defined a priori, by dividing the number of intervention weeks  into 3 groups covering an equal number of weeks.2. Participants completed a survey at baseline that captured sociodemographic characteristics .All other measurements were taken at the Human Performance Laboratory at the University of Newcastle, Callaghan Campus, with assessments at baseline and 12 weeks of the study. Height was measured to 0.1 cm using the stretch stature method on a Harpenden portable stadiometer . Weight was measured with the participant wearing light clothing, without shoes, on a digital scale to 0.01 kg . BMI was calculated as weight (kg)/height (m)P<.004 (P=.05/12) considered statistically significant.We analyzed the data using Stata 11.0 (StataCorp LP). Descriptive statistics are described as mean and SD for normally distributed continuous variables, median and interquartile range for nonnormal continuous data, and number (n) and percentage for categorical variables. We used chi square tests to compare the self-monitoring consistency each week (weeks 1 to 12) by treatment group. Due to the multiple comparisons, we applied the Bonferroni correction, with P<.05 to be statistically significant for these single comparisons.We also used chi-square tests to compare the total number of consistent weeks and consistency of self-monitoring groups  by treatment group. Analysis of variance tested for differences in percentage weight loss at 12 weeks between consistency of self-monitoring groups . We performed post hoc comparisons using the Tukey-Kramer method. An intention-to-treat approach was used for calculating percentage weight loss, with baseline observation carried forward for those lost to follow-up at 12 weeks. We considered Of the 591 adults who expressed interest in participating in the study, 309 were randomly assigned to 1 of 3 groups . We randomly reassigned waiting list control group participants to a treatment group after 12 weeks ; therefore, this analysis included 301 participants . We previously reported participants’ characteristics at baseline . In summP=.7) in attrition rates between the basic  and enhanced groups  at 12 weeks.A total of 62 participants did not have their weight assessed at 12 weeks, resulting in 20.6% (62/301) attrition. There was no significant difference . The enhanced and basic groups differed significantly in the proportion of participants classified as having low, moderate, and high self-monitoring consistency for food , exercise  and weight  entries , exercise entries , and weigh-ins . Post hoc comparisons revealed that, for food and exercise entries to the online diary, participants whose consistency was high lost significantly more weight than those whose consistency was low or moderate, and those whose consistency was classified as moderate lost significantly more weight than those classified as low . For weigh-ins, participants whose consistency was high or moderate lost more weight  than those whose consistency was low .Consistency of self-monitoring strongly predicted weight loss. There was a significant difference in percentage weight loss by consistency of self-monitoring for food entries  being monitored and decreased over the 12 weeks for all 3 behaviors in both groups. Self-monitoring entries of weight were much more consistent in both groups throughout the 12 weeks than either food or exercise entries. Reasons for this greater consistency of weight entries are not clear but possible explanations are the relative ease of providing weight entries and positive reinforcement of effort if weight continues to decline. The consistency of food entries was also reasonably high initially, particularly in the enhanced group, but decreased substantially over time, especially in the basic group. Consistency of exercise entries was relatively poor from week 1. Although a greater proportion of enhanced group participants consistently self-monitored exercise compared with the basic group over the 12 weeks, it was only during 2 weeks (weeks 8 and 11) that a higher proportion of enhanced group participants made exercise entries ≥3 days per week. The additional features  provided in the enhanced intervention may not have prompted self-monitoring of exercise and suggests that a greater understanding of the barriers to self-monitoring of exercise is required. However, it is also possible that the poor consistency of exercise entries may be due to a lack of exercise being performed by participants.There is evidence from systematic reviews that greater self-monitoring within weight loss interventions is associated with greater weight loss ,5. The pIn a cohort study, we previously identified that a higher median number of days when participants used the self-monitoring features of the basic version of the program was associated with significantly greater weight loss . A limitA strength of this RCT was the large sample including substantial proportions of both male and female participants, and use of objective measures of self-monitoring. Potential limitations include that we evaluated self-monitoring behaviors during the 12-week weight loss intervention. Therefore, we do not know whether self-monitoring was continued or maintained beyond the 12-week period, and whether this was associated with further weight loss. This is an area where future research is warranted, as it was recently suggested that frequency and consistency of self-monitoring of dietary intake after a 6-month weight loss program improved weight loss success at 12 months . Our stuEnhanced program features, such as reminders and tailored feedback, facilitated greater consistency of self-monitoring of food, exercise, and weight during a 12-week commercial Web-based weight loss program. However, there were no significant differences in weight loss between the enhanced and basic intervention groups. Given the strong association between self-monitoring of these behaviors and successful weight change outcomes, further evaluation of individuals’ experiences with self-monitoring and intervention components designed to promote self-monitoring  is warranted. This will provide greater insight into factors contributing to group and individual variations in engagement with self-monitoring tools and facilitate the design of Web-based weight loss interventions that are adaptive and provide individually tailored features to optimize self-monitoring .


The majority of the self-adjuvanting glycopeptide cancer vaccines reported to date employ antigens from mucin 1, a protein which is highly over-expressed and aberrantly glycosylated in many forms of cancer. The adjuvants used in these vaccines predominantly include lipopeptide- or lipoamino acid-based TLR2 agonists, although studies investigating stimulation of TLR9 and TLR4 are also discussed. Many of these adjuvants are highly lipophilic, and, upon conjugation to antigenic peptides, provide amphiphilic vaccine molecules. The amphiphilic nature of these vaccine constructs can lead to the formation of higher-order structures by vaccines in solution, which are likely to be important for their efficacy in vivo.Due to changes in glycosyltransferase expression during oncogenesis, the glycoproteins of cancer cells often carry highly truncated carbohydrate chains compared to those on healthy cells. These glycans are known as tumor-associated carbohydrate antigens (TACAs), and are prime targets for use in vaccines for the prevention and treatment of cancer. Herein, we review the state-of-the-art in targeting the immune system toward tumor-associated glycopeptide antigens  It is well-established that immunological surveillance is an important method by which cancer is controlled in healthy people. As such, tumor immunology and immunotherapy have emerged as exciting new opportunities for the prevention and treatment of malignancy , which arise from over-expression of sialyltransferases  appended to the peptide backbones of these mucin-type glycoproteins  sequence GVTSAPDTRPAPGSTAPPAH. Serine and threonine residues within this repeat are h cells, respectively), vaccines usually incorporate an adjuvant which can stimulate APCs via pattern-recognition receptors. Adjuvants are thought to be a necessary feature to make cancer vaccines immunogenic enough to break through immunological self-tolerance to tumor antigens  such as dendritic cells and macrophages toward the priming of cytotoxic and helper T cells   conjugated to a polio Th epitope and Pam3Cys , CD83, and the co-stimulatory molecules CD80 and CD86. Importantly, the authors have recently demonstrated induction of CTL responses and inhibition of mouse mammary tumor growth in response to these vaccines  glycosylated with TN, T, or 2,6-ST at a single Thr residue within the VNTR (indicated by asterisk) , whereby all possible glycosylation sites were occupied with TACAs (indicated by asterisks), in order to maximize the potential recognition of glycopeptide tumor-associated epitopes  to induce IgG antibodies capable of recognizing tumor cells  and the pan HLA DR-binding Epitope or “PADRE”  agonize TLR1/2 heterodimers and TLR2/6 heterodimers, respectively, leading to signaling via the NF-κB pathway and APC activation. Monopalmitoylated peptides -2 agonists as the adjuvant. Tri- and di-palmitoylated cysteine , which contains Pam3CysSKKK  is a TLR4 agonist derived from bacterial lipopolysaccharide. Guo and coworkers reported the synthesis and evaluation of self-adjuvanting vaccines consisting of MPLA conjugated to the 2,3-ST , with deprotection of the carbohydrates after cleavage of the crude glycopeptide from resin. Various syntheses of TN, STN, T, and ST TACA-derived amino acids for incorporation into SPPS have been reported to date peptide fragments activated at the C-termini as pentafluorophenyl esters 5 to conjugate unprotected Pam3Cys to MUC1 glycopeptide 20-mers via a thioether linkage in moderate to good yields peptide antigens to lipopeptide adjuvants. The direct incorporation of lipidated adjuvants such as Pam3Cys via liposome-mediated native chemical ligation (NCL) . DM is supported by an Australian Postgraduate Award and by a John A. Lamberton Research Scholarship.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.