Y-K women reported more ST product use, while men reported more cigarette use. Among dual- and multi-product users, the majority reported concurrent use, with no significant differences between men and women. Distinct regional differences include high smoking prevalence in Norton Sound and frequent use of smoking and ST products in Y-K. Findings support modification of cessation programmes to address regional variations in tobacco use patterns.Tobacco use prevalence among Alaska Native (AN) people living in Alaska is greater than the general population prevalence statewide and nationally. Better understanding of regional tobacco use is needed to improve cessation efforts and reduce prevalence. Using self-reported baseline data from the Western Alaska Tribal Collaborative for Health study, we describe tobacco use patterns among AN people in two western Alaska regions. Data were stratified by age group and sex. Dual- and multi-product use in the Yukon-Kuskokwim (Y-K) region was stratified by concurrent vs sequential use. Overall, 87% of the cohort reported having used tobacco. In Norton Sound, cigarette (98%) was the predominant tobacco type. In Y-K 71% smoked, 76% used smokeless tobacco (ST), with 47% reporting use of both products. ST use in Y-K consisted of commercial ST and homemade  Since 1991, data collected by the Alaska Behavioural Risk Factor Surveillance System (ABRFSS) [1] have consistently shown greater prevalence of tobacco use among Alaska Native (AN) people over the general Alaska population . In addiMultiple tobacco product use is a growing concern in the US and globally –15. DualGreater understanding of the patterns of ST use alone and in combination with other tobacco products among AN persons is an essential first step in adapting cessation programmes to address multiple forms of tobacco, especially in communities where ST use is well established. In some Alaska regions, ST use is not only accepted, but considered a healthy alternative to smoking and closely tied to cultural lifestyle ,21,22. EWe sought to describe tobacco use patterns among male and female AN people in two rural western Alaska regions, Norton Sound and Yukon-Kuskokwim (Y-K) Delta, where tobacco use prevalence exceeds that of both the Alaska and US general populations. The 13 communities along the coast of the Norton Sound region are located on the Seward Peninsula in northwestern Alaska . Census iqmik [iqmik. Among dual users for whom data were available, we also assessed first product used and distinguished between simultaneous or sequential initiation.While survey data from the ABRFSS demonstrate differences in smoking and ST use in Norton Sound and Y-K, survey data collected during the study timeframe did not differentiate between commercial ST and iqmik , a homemiqmik , nor do In 2009, investigators with the Western Alaska Tribal Collaborative for Health (WATCH) began consolidating data from multiple Alaska Native cohort studies, as described previously . BrieflyThe CANHR and GOCADAN studies collected self-reported demographic and tobacco use data by in-person interviews with trained study personnel. The EARTH study collected similar self-reported data using audio computer-assisted self-interview methods ,34. DemoParticipants in each study were asked to specify tobacco types used, specifically cigarettes and ST (chew or snuff), age at initiation and age at quitting (if relevant). In each study, participants were asked if they had ever smoked ≥ 100 cigarettes in their lifetime. Those who reported “yes” to the question were considered ever smokers. We defined current smokers as those who reported ever smoking and did not report an age for quitting or whose reported age at quitting was within 1 year of their age at the baseline examination. Alternatively, age at quitting was derived from reported age of smoking initiation and reported years smoked. Former smokers included participants whose age at baseline was at least 1 year older than the reported (or derived) age at which they quit. We defined ever use of ST as self-reported use of any commercial or homemade ST products. These data enabled us to determine baseline prevalence of non-tobacco use, former and current cigarette smoking and ever using ST in both study regions. We were also able to determine prevalence of exclusive ever smoking, exclusive ever ST use and ever use of both cigarettes and ST. Users of both products were defined as ever having used cigarettes and having ever used ST.iqmik, a homemade ST product commonly used in the Y-K region [iqmik use separately from commercial ST, due to inherent differences in product content and cultural beliefs and acceptance. While commercial ST and iqmik both contain tobacco, iqmik contains ground ash produced by burned Phellius iganiarius or “punk”, a tree fungus [iqmik is considered a “natural” product and, thus, its use is considered a healthier practice than cigarette smoking. Hence, iqmik use is culturally acceptable for women to use during pregnancy and, in some communities, for young children to assist in its production with pre-mastication prior to storage and later adult consumption [For ST use, the CANHR and EARTH studies, both conducted in the Y-K Delta, specifically asked participants to specify whether product use included commercial ST and/or K region ,22,35,36e fungus . The ashsumption ,38.iqmik; or commercial ST and iqmik) and ever multi-use was defined as use of all three products during one’s lifetime. Sequential use was defined as reporting cessation of one tobacco product in 1 year and the uptake of a new product in either the same year or in later years. Concurrent use was defined as any overlap in the years of use of two or more products, even if the participant reported cessation of all but one product subsequent to the overlap. Importantly, we were able to determine which tobacco product was used first  or if these products were initiated simultaneously. Participants reporting they had initiated any tobacco use with more than one product in the same year were considered simultaneous starters.For each tobacco type selected, the CANHR and EARTH studies additionally asked participants to provide the age they began using and either the number of years they used or the age at which they quit using the products, if applicable. Thus, in the Y-K region only, we were able to determine prevalence of ever using two tobacco products  and ever using more than two tobacco products (multi-use) as well as whether this use was concurrent or sequential. Ever dual-use was defined as use of any combination of two tobacco products  and participants who were exclusive smokers and exclusive ST users using logistic regression analysis, adjusting for age, sex and education. Significance was determined at p<0.05.Using SAS version 9.4 , we calculated means with standard deviations for continuous variables (age and years of education) and frequencies with percentages for categorical data, stratifying by region and sex. Differences in frequencies between strata were assessed using Chi-square statistic for categorical data and Student iqmik. Very few ever tobacco users reported single use of commercial ST. Dual-use was more prevalent among women (p=0.04). While proportionately more men than women ever tobacco users reported dual use of cigarettes and either commercial ST or iqmik (each p<0.001), more women than men ever tobacco users reported having used commercial ST and iqmik (p<0.001). Prevalence of multi-product use  was more common among men than women (p=0.004).We analysed additional data on single, dual- and multi-product use from 96% of the 2,330 ever tobacco users in the Y-K region. Of these, 43% (964/2238) reported single-product use, the remainder reporting ever use of two or more tobacco products , with substantial differences in tobacco type observed between men and women . Among tiqmik). However, very few Norton Sound residents report ST use, while ST, specifically iqmik, is far more common to the Y-K region. Therefore, only Y-K data were available to analyse when participants started and ended use of each product. Participants in each study were also allowed to skip questions they were not comfortable answering. Despite these limitations, a sub-set of 701 of 920 (76%) Y-K ever dual-users and 270 of 354 (76%) Y-K multi-product users provided information on which tobacco product type(s) they had used first  or commercial ST (n=150) was used, similar majorities initiated tobacco use with ST, although with higher proportions among women. Among dual-users who did not smoke (n=248), commercial ST was the product first used by 51% of the group, while 43% reported initiating both ST products simultaneously. Simultaneous starters comprised the largest proportion (39%) of multi-product users.The original study conducted in Norton Sound did not assess differences in ST product use , women were less likely than men (OR=0.26) to use cigarettes and ST concurrently  and multi-use (73%) was concurrent among ever tobacco users, which did not differ by sex . Compareurrently . When coThis study characterises tobacco use prevalence and patterns of use among AN people in the Norton Sound and Y-K regions, with significant regional and sex differences observed in ST use. Tobacco use in the Norton Sound region was limited almost exclusively to smoking, for both men and women. In the Y-K region, men were more likely to have been smokers, while women were more likely to have used ST. Importantly, half of Y-K participants who reported having used tobacco also reported dual- or multi-product use.iqmik, whereas men were more likely to have used cigarettes and commercial ST or cigarettes and iqmik. Male tobacco users were significantly more likely to be multi-product users of cigarettes, commercial ST and iqmik compared to female tobacco users. Among dual-users of cigarettes and ST , more than 60% reported tobacco initiation with ST. For dual-users who used commercial ST and iqmik, more than 40% were simultaneous starters of both ST products. Furthermore, there was a high prevalence of concurrent tobacco product use among Y-K participants.Y-K women who used tobacco were significantly more likely to be dual-users compared to men who used tobacco. Among dual-users, women were more likely to have used commercial ST and We recognise data collection for this project are dated, collected between 13 and 17 years ago, and that tobacco use and prevalence has since changed statewide and nationally . HoweverWhen stratified by region, data from the ABRFSS reports lower percentages of tobacco use for both cigarettes and ST than what our results demonstrate . Howeveriqmik compared to men [iqmik use between regions. Iqmik has been used in the Y-K region for more than 150 years and is perceived to be a natural, thus safer, alternative to cigarette smoking [iqmik. This availability may also contribute to some difference in use observed between the two regions. Patterns of ST use among AN women are unlike those reported for women nationally and our results support findings for high prevalence of iqmik use by AN women reported in other studies [Harmonised data have been consolidated and redefined to incorporate a larger dataset. Harmonisation, thus, results in data that are less precise than originally collected. While the WATCH tobacco data may be less precise than in their original form, they are more precise than any data collected by phone surveys conducted nationally or regionally in this population. Our findings affirm ABRFSS reports that cigarette use in Norton Sound and ST use in Y-K are the most prevalent types of tobacco used by AN adults in those regions –9. Otherd to men . Availab smoking . Fungus  studies ,42. The  studies ,44.iqmik. Recent US studies demonstrate that dual- or multi-product use is most prevalent among young adults [Only one other study assessed dual-product use by AN people, noting that men were more likely than women to be dual users . That stg adults ,20,45. Wg adults , this peg adults . While wiqmik users as well as multi-product users in the Y-K region reported initiating more than one tobacco product within the same year. However, dual users of cigarettes and ST were more likely to have initiated tobacco with a ST product, consistent with a previous retrospective review of medical record review from 665 AN adolescents in the Y-K region documenting that tobacco use was most commonly initiated with ST [The majority of adult dual commercial ST and  with ST .This study is also the first to explore sequential and concurrent tobacco use among AN adults reporting having used more than one tobacco product. Use of cigarettes after initiating ST is also seen among snus users in Norway . Nationaiqmik) and use patterns  and longstanding relationships with the respective communities. Nicotine and carcinogen bioavailability appear to vary dramatically across these tobacco products [iqmik, mainly due to the minimal use of pipe or cigar smoking in these regions and by the collection of these baseline data well before the widespread use of e-cigarettes. Further, data on ST use patterns were limited to the Y-K Delta region, since cigarette use predominated in the Norton Sound region.The strengths of our study are the large sample size of AN persons, data on multiple tobacco products (cigarettes, along with separate assessment of commercial ST and products . This stiqmik content, potential harmful health effects of iqmik use and the perceptions of its use, particularly in the Y-K region. Among Y-K women, tobacco use is driven primarily by iqmik use. This is explained by the lower likelihood of women being dual cigarette and ST users than exclusive ST users and the higher likelihood of women being dual cigarette and ST users when compared to exclusive smokers. Research has demonstrated that dual- and multi-product tobacco users experience lower cessation rates [Additional research is needed to explore on rates ,18, posson rates . On averon rates  as US smon rates , but demon rates ,52. Thesiqmik use and be prepared to address both mono and dual-product use. Prevention interventions should emphasise the harms of dual- and multi-product tobacco use.Clearly, tobacco prevention efforts, cessation programmes and public health messaging must resonate with each target population. Our study demonstrates wide variations in tobacco product use between two Alaska regions and between men and women within the Y-K region. These findings emphasise the need for tailoring prevention and cessation interventions to meet regional and community needs based on tobacco product use. Given our results, we recommend that, in Norton Sound, tobacco interventions focus on cigarette cessation and prevention for both males and females. In the Y-K region, cessation efforts should be directed towards reducing ST use and dual-product tobacco use for both men and women. Programmes should have information on the benefits of stopping smoking, commercial ST and


A range of methods in clinical research aim to assess treatment-induced progress in aphasia therapy. Here, we used a crossover randomized controlled design to compare the suitability of utterance-centered and dialogue-sensitive outcome measures in speech-language testing. Fourteen individuals with post-stroke chronic non-fluent aphasia each received two types of intensive training in counterbalanced order: conventional confrontation naming, and communicative-pragmatic speech-language therapy . Motivated by linguistic-pragmatic theory and neuroscience data, our dependent variables included a newly created diagnostic instrument, the Action Communication Test (ACT). This diagnostic instrument requires patients to produce target words in two conditions: (i) utterance-centered object naming, and (ii) communicative-pragmatic social interaction based on verbal requests. In addition, we administered a standardized aphasia test battery, the Aachen Aphasia Test (AAT). Composite scores on the ACT and the AAT revealed similar patterns of changes in language performance over time, irrespective of the treatment applied. Changes in language performance were relatively consistent with the AAT results also when considering both ACT subscales separately from each other. However, only the ACT subscale evaluating verbal requests proved to be successful in distinguishing between different types of training in our patient sample. Critically, testing duration was substantially shorter for the entire ACT (10–20 min) than for the AAT (60–90 min). Taken together, the current findings suggest that communicative-pragmatic methods in speech-language testing provide a sensitive and time-effective measure to determine the outcome of aphasia therapy. More than a decade ago, clinical research has demonstrated the efficacy of intensive speech-language therapy (SLT) in neurological patients . Instead, the validity and reliability of any such analysis may improve in dialogue-sensitive speech-language testing where patients engage in communication and social interaction .Consistent with the notion that the primary function of language emerges from social interaction , and communicative-pragmatic SLT (ILAT). Patients underwent speech-language testing before and immediately after each type of training. Along with a standardized aphasia test battery, our outcome measures included a newly created diagnostic instrument focusing on (i) utterance-centered object naming, and (ii) communicative-pragmatic social interaction based on verbal requests. As summarized above, linguistic-pragmatic theory and neuroscience data suggest that verbal requests might be especially suited to evaluate the outcome of SLT, given their distinct action-sequence structure and relevance to everyday life.www.germanctr.de; identifier: DRKS00005482) and approved by the ethics review board at the Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Germany (reference number: EA4/122/12), with written informed consent obtained from all patients.Fourteen persons with post-stroke chronic non-fluent aphasia were recruited, screened and agreed to participate in the current study. All patients were native speakers of German who had not received intensive SLT in the year prior to inclusion in the study. Patients were aged 32–73 years  and right-handed before stroke according to the Edinburgh Handedness Inventory . All patients had suffered a single cerebrovascular accident with subsequent lesions in parts of the left frontal, parietal, and temporal lobes, as well as in adjacent subcortical areas. Two clinical neuroscientists manually delineated and superimposed the precise locations of lesioned voxels in all patients using the software MRIcron , or vice versa . The group allocation was consistent with a previously determined computer-generated series of random numbers. Mann-Whitney U tests suggested that this randomization procedure did not lead to significant differences between Group I and Group II with regard to: age, education level, months after onset of disease, aphasia test scores at baseline, non-verbal short-term memory, individual lesion size, and weekly hours of SLT before inclusion in the study. Since patients with aphasia usually suffer from concomitant deficits in motor planning, it is important to note that Group I and Group II were similarly affected by apraxia of speech, as diagnosed by two clinical linguists.In a crossover design, patients were randomly assigned to one of two treatment orders: ILAT administered prior to Naming Therapy  and carrier phrases  tailored to the patients' individual language skills. Both types of training were delivered with the same high intensity (3.5 h per therapy session) and duration (six consecutive working days), resulting in overall 42 h of treatment within less than 4 weeks. The schedules included a 6-day recreation interval between the two treatments. None of the patients attended any other form of SLT throughout the entire trial. A clinical neuropsychologist tested each patient 1 day before (T1) and 1 day after the first training period (T2), as well as 1 day after the second training period (T3). The neuropsychologist was blinded to the group assignment and did not have patient contact apart from the testing sessions . In step two of the procedure , the patient verbally requested sets of five objects presented on the table, again one by one. Whenever utterances were correct, the experimenter handed over the requested object to the patient who, eventually, placed it in a bag. After two failed attempts to make a request, the experimenter ensured via pointing that the patient received the intended object. As during step one, each target utterance was preceded by a standardized question (experimenter: “What do you want?”). Moreover, the subscale ACT Requests encouraged the use of formulaic expressions when handing over objects to the patient . This linguistic category of utterances is often preserved in aphasic speech and may be viewed as a motivational resource in diagnostic sessions . This battery was designed to directly compare the practicability of utterance-centered and dialogue-sensitive outcome measures in SLT. In step one of the procedure , sets of five real generic objects were presented on a table . The patient was asked to name each of these objects, one by one. If the patient named an object correctly, the experimenter subsequently removed it from the table. If the patient failed to name an object twice, the experimenter removed this item, after ensuring via pointing that it was the intended one, and placed it in a bag. Target utterances were always preceded by a standardized question (experimenter: “What do you t-scores (with reference to language performance at T1). The combined t-scores on the subscales ACT Naming and ACT Requests served as primary outcome measure (Composite ACT).Testing materials of the ACT consisted of 40 standardized objects that were allocated to two parallel lists (List A and List B). Each list included four sets of five items. The composition of these different sets did not change throughout the testing sessions. In both steps of the ACT, patients could freely choose the sequence of objects per set to be named or requested. Notably, even severely affected patients did not have problems to understand these procedures. Items of List A and List B were matched for a variety of psycholinguistic features, such as mean normalized lemma frequency, as well as the average number of syllables, phonetic sounds and consonant clusters at word onset. To prevent any item-specific influences, we used List A and List B in counterbalanced order across ACT subscales and treatment groups  and varied with symptom severity, as patients with global aphasia and severe Broca's aphasia are typically trained with a limited selection of high-frequency items, whereas patients with mild-to-moderate Broca's aphasia benefit from a larger repertoire of card sets. This fact rules out the possibility to contrast trained and untrained items in the current RCT.For correlation analyses between the Composite ACT and an external criterion, language assessment also included an established aphasia test battery, known for its good construct validity, re-test reliability and suitability to interpret individual numerical changes over time . Further Mann-Whitney U tests confirmed that Group I and Group II did not differ significantly with regard to their performances on the ACT  or on the AAT  at baseline (T1). For each outcome measure, a repeated-measures analysis of variance (ANOVA) was conducted, including within-subject factor Time  and between-subject factor Group . Wilcoxon signed-rank tests were used for planned comparisons, and Kendall's τ for correlation analyses between the Composite ACT and AAT results. Preference was given to non-parametric methods, whenever possible, to account for the small sample size. A post-hoc repeated-measures ANOVA investigated the interaction of Time , ACT Subscale  and Group . For all statistical analyses, two-tailed p-values and alpha levels of 0.05 were applied.Mann-Whitney F = 3.90, p = 0.03, η2 = 0.10]. In the first training period, Wilcoxon signed-rank tests suggested significantly increased scores on the Composite ACT with ILAT  and with Naming Therapy . In the second training period, ILAT alone was found to be effective , in contrast to Naming Therapy  = 3.69, p = 0.04, η2 = 0.11], but not on the subscale ACT Naming . Exploring this potential difference in utterance-centered and dialogue-sensitive speech-language testing, a post-hoc repeated-measures ANOVA showed a positive trend for the interaction of Time, ACT Subscale and Group .A repeated-measures ANOVA revealed a significant interaction of Time and Group based on the Composite ACT scores . Consistent with the Composite ACT scores, Wilcoxon signed-rank tests indicated similar patterns of changes in language performance on the AAT. In the first training period, we observed significant progress with ILAT  and a positive trend with Naming Therapy . Once more, only patients receiving ILAT continued to make progress in the second training period , while patients receiving Naming Therapy did not . The achieved statistical power exceeded the critical threshold of 95% on both outcome measures , a repeated-measures ANOVA confirmed the interaction of Time and Group [The present study aimed to compare the suitability of utterance-centered and dialogue-sensitive outcome measures in speech-language testing. Fourteen individuals with post-stroke chronic non-fluent aphasia each received two types of intensive training in counterbalanced order: conventional confrontation naming (Naming Therapy), and communicative-pragmatic SLT (ILAT). Both types of training were delivered with the same high intensity and duration, with therapy materials and number of utterances carefully matched between treatment groups. Results on the Composite ACT and the AAT revealed similar patterns of changes in language performance over time: ILAT proved to be effective, regardless of when this method was administered, whereas Naming Therapy led to significant increases (Composite ACT) or a positive trend (AAT) in aphasia test scores only when given at the onset of the treatment. Changes in language performance were relatively consistent with the AAT results also when considering both ACT subscales separately from each other. Taken together, these promising findings emphasize the need for further studies to confirm the psychometric properties of the ACT in an extended patient sample.p ≤ 0.001). These correlations may reflect the strong congruence between our two outcome measures over and above the utterance-centered or communicative-pragmatic character of the training, indicating a possible general adequacy of the ACT in evaluating treatment-induced progress. Overall, the Composite ACT and AAT scores shared 60% of the variance explained by changes in language performance in our data. However, testing duration was substantially shorter for the ACT (10–20 min) than for the AAT (60–90 min). While traditional aphasia test batteries are likely to be more accurate in documenting isolated skills in verbal expression and comprehension, our findings suggest that the Composite ACT may be equally sensitive and more time-effective in assessing the efficacy of SLT.Although we acknowledge the slightly elevated risk of false-positive results arising from multiple comparisons, we wish to highlight that correlations between the Composite ACT and the AAT were large at each point in time, ranging from 0.66 to 0.83 .A main motivation for using dialogue-sensitive diagnostic instruments in aphasia therapy comes from linguistic-pragmatic theory and from neuroscience data. A number of studies indeed show an increase of neural activity associated with verbal requests compared to object naming , treatment protocols and materials , trial coordination and therapy sessions (BS), testing sessions (BM), structural magnetic resonance imaging and lesion overlay maps (FD and GL), statistical analyses (BS), data interpretation , manuscript drafting and artwork (BS), and revisions .This research was supported by Deutsche Forschungsgemeinschaft (Pu 97/15-1 to FP) and Deutscher Akademischer Austauschdienst (fellowship to GL).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.


The fifth-generation (5G) communications systems are expecting to support users with diverse quality-of-service (QoS) requirements. Beside these requirements, the task with utmost importance is to support the emergency communication services during natural or man-made disasters. Most of the conventional base stations are not properly functional during a disaster situation, so deployment of emergency base stations such as mobile personal cell (mPC) is crucial. An mPC having moving capability can move in the disaster area to provide emergency communication services. However, mPC deployment causes severe co-channel interference to the users in its vicinity. The problem in the existing resource allocation schemes is its support for static environment, that does not fit well for mPC. So, a resource allocation scheme for mPC users is desired that can dynamically allocate resources based on users’ location and its connection establishment priority. In this paper, we propose a public safety users priority-based context-aware resource allocation (PS-CARA) scheme for users sum-rate maximization in disaster environment. Simulations results demonstrate that the proposed PS-CARA scheme can increase the user average and edge rate around 10.3% and 32.8% , respectively because of context information availability and by prioritizing the public safety users. The simulation results ensure that call blocking probability is also reduced considerably under the PS-CARA scheme. The demand for ubiquitous availability of broadband data, low latency applications, and massive connectivity is compelling to instigate fifth-generation (5G) systems .The industry and academia forecasted a 1000× increase in data traffic within the next decade. To meet these huge data traffic requirements, device-to-device D2D) communications D communi,4, and mInspired by this, we presented 3GPP LTE-A based mobile personal cell (mPC) that follows users to meet their emergency data rate and latency demands. The mPC deployment can meet the public safety low latency and high priority requirements as it can expeditiously establish the communication link among the base station and public safety emergency users. However, mPC resource allocation poses some serious challenges because users frequent movements rapidly changes their location in disaster situations; this results in rapidly fluctuating channel conditions. Moreover, in disaster hit areas users also needs priority in connection establishment over the conventional users. So, the conventional static resource allocation schemes designed for low mobility or static environments are not suitable for varying channel conditions . TherefoIn this paper, we consider software-defined network (SDN) based architecture  which haHowever, mPC deployment has the issue of resource allocation because the rapid change in mPC position can result in severe co-channel interference. Moreover, it also requires mPC’s context information to efficiently allocate the resources, which restricts the utilization of the conventional resource allocation schemes discussed in , becauseMost of the existing works on QoS-aware resource allocation such as QoS priority-based dynamic fractional frequency reuse (QoS-DFFR)  and QoS-To meet the growing data rate demand for mobile data in urban areas, network densification is the best possible solution. The network densification can be achieved by deploying low-power small cells as they maximize the capacity by reusing the same frequency band. The small cells with moving capability can also fulfill the emergency communication requirement by deploying them in disaster hit areas.Numerous interference management schemes related to moving networks are summarized in ,23,24,25In , authorsSimilarly, authors in  presenteContributions: Motivated by this, we propose a public safety users connection priority-based context-aware resource allocation (PS-CARA) scheme. The proposed PS-CARA scheme has the following differentiating characteristics: (1) It uses the context information  to allocate the resources among users. (2) Moreover, PS-CARA scheme dynamically adjusts the mPC spectrum access ratio s factor , and henN and L are number of users attached per MBS and mPC, respectively. To clearly understand the system model, we plotted a single cell scenario with one BS and We consider a two-tier HetNet UL scenario with underlayed mPC cellular network. A two-tier HetNet consists of a macrocell base stations (MBS) set m transmits with a maximum power k transmits with maximum power of u transmits with maximum power of u can associate with maximum one BS at a time. The total bandwidth (BW), B, is divided into R resource blocks (RBs) in the frequency domain. Since, there can be different types of small cells in the 5G systems, so the possible interference situations after deploying mPC in HetNet is shown in m-th BS and from MUE → k-th mPCs for backhaul, sidehaul, and access links. The major difference among the conventional small cells and mPC interference is the rapidly changing environment which in turn needs context-aware resource allocation schemes to counter this interference.In this scenario, macro BS u from BS j, and that BS can be either macro BS (MBS) or mPC and In the literature, numerous user association schemes are discussed. For instance, in  authors fractional power control (fpc) [u-th transmitting (tx) user (mPUE/MUE) to k/m-th receiving (rx) BS (mPC/MBS) is written asSince all users ol (fpc)  is implek-th rx user during the j-th subframe and on the r-th RB. Furthermore, u-th user to k-th BS, whereas In , xu→k ismilarly,  can be aL, F, and S are the pathloss, fading, and shadowing models, respectively. In this paper, L for user u connected to MBS and mPC can be evaluated by using Urban area path loss model and WINNER + B1 model [d is the distance from user u to BS. The fading F is calculated by using Ped-B model defined by International Telecommunication Union (ITU) [S follows the log-normal distribution, that is if any positive random variable The channel gain hu in  can be eB1 model , respectB1 model . To modeB1 model  for moviB1 model . The patu is associated with m/k-th BS and (2) the public safety priority indicator variable u is non-public safety user and To efficiently allocate the access link (AL) resources among users, mPC spectrum access ratio nditions . That isu. Moreover, in (7) there is an additional Since our target is to associate users based on the loading conditions of BSs. The total load on k-th MBS and m-th mPC is calculated asuated asCkNPS=ρkPIn this section, our objective is to maximize the system sum-rate of PS and non-PS users connected with either MBS or mPC by considering the SINR, transmit power, and priority constraints. Thus, we propose the sum-rate maximization problem (P1) asu trying to associate with BS can be given asU is the total number of user sending the admission request. In this paper, we also minimize the CBP of the users associated with the BS, by considering the user association and priority constraints. Thus, CBP minimization problem (P2) can be evaluated asSince we are also dealing with connection level priority instead of a service level priority model, call blocking probability (CBP) is a good performance metric to judge the quality of the system. The CBP measures the call admission rejection probability because of the limited available resources. The CBP RB , where RHence, the solutions to these problems are not feasible and only a sub-optimal solution can be achieved. To solve these problems, we propose a PS-CARA scheme that heuristically solves the constructed optimization problem (P1) in (12) and (P2) in (14) by system-level simulations. By these simulations we found the sub-optimal solution to these problems. The proposed PS-CARA scheme’s major steps are summarized in the next section.Deployment: We propose PS-CARA scheme under the SDN-based cloud network architecture because of its capability to centrally manage all the base stations. The number of mPC required per macro BS varies according to the deployment situation or scenario. That is, in the PS scenario a higher number of mPCs are desired to meet the user requirements. Therefore, more mPCs are deployed in PS scenario and the resources are allocated by considering the context information of the users.BH, SH, and AL resource allocation: In the proposed scheme, mPUE and MUE are connected to mPC and MBS, respectively via AL, whereas mPCs are connected to MBS via BH links. Similarly, mPC is connected with neighbor mPC by using SH links. All these links are using the orthogonal frequency band in order to avoid interference. mPC can switch to use different BH and SH modes to allocate different ratio of resources for BH and SH depending on the nature of deployment situation. That is, more BH resources can be reserved for non-PS deployment and less for PS scenario. For example, the system with 10 MHz BW and 50 RBs in non-PS scenario, has RB distribution ratio of mPC call admission control (CAC): In LTE system, CAC determines whether to accept or reject a new call based on the availability of sufficient network resources to guarantee the QoS parameters without affecting the existing calls. Since CAC is the connection provisioning module in mPC for the user initially accessing the system. Therefore, CAC is capable of identifying the call type at any moment. Hence, the number of PS users are decided based on the connection request information. However, if there is a large number of PS users sending the connection request to mPC, then mPC will switch to PS mode from the non-PS mode and start assigning resources based on PS scenario deployment configuration.Context-information collection: We use the context information by considering the PS priority of the users to dynamically schedule and allocate the resources. There are two types of context information (1) location information which is decided based on received SINR, that is if The main steps in the proposed PS-CARA scheme are shown in PS and non-PS user resource allocation: During this phase, firstly, all resources are reserved for PS users with high connection priority; then, based on round robin scheduling these resources are distributed among the high-priority users to maximize their sum rate. For low priority non-PS users, the remaining resources are allocated randomly between the non-PS users by using multi-channel slotted ALOHOA (MCALOHA) protocol. To improve the efficiency of resource allocation for non-PS users, MCALOHA is combined with energy sensing (MCALOHA-ES) if interference is very high [u considers received energy levels to allocate RBs among non-PS users.ery high . In MCALPS and non-PS users fpc implementation: Initially, all users are deployed in a system by allocating full transmission power. This may result in high interference from the neighboring users. To control this situation, fpc is implemented that allocates appropriate power to users by considering their locations, which in turn will reduce the interference.Before implementation of the PS-CARA scheme, it is important to analyze the complexity to prove its suitability. The PS-CARA scheme summarized in The complexity of the proposed PS-CARA scheme is reduced as compared to the existing schemes because we separately allocate resources for PS and non-PS users, and hence the resource selection competition is separately among PS and non-PS users. Therefore, the proposed PS-CARA is a sub-optimal scheme that requires a modest complexity, and it has a linear relationship with the number of RBs as compared to the huge number of possible combinations regarding the NP-hard problem. Since we have a distributed network and each node decision is independent of the other node, this results in less system complexity.The performance of the proposed PS-CARA scheme is evaluated by upgrading the system-level simulator designed in MATLAB . This siWe compare the performance of the proposed PS-CARA scheme with the conventional static resource allocation (C-SRA) scheme, which ignores the context information during resource allocation.The mobile mPCs are modeled in simulations by considering the random-walk mobility model. In The performance of the PS-CARA scheme is considerably improved as compared to the C-SRA scheme because of implementing fraction power control scheme. The selection of power control parameter is very important to provide the better performance, and its selection varies for each environment. The main parameters of concern in fractional power control are; SINR target control To select a proper value of The performance of the proposed PS-CARA scheme is tested under the PS scenario. The PS-CARA scheme is verified for three possible cases: (1) PS-CARA: PS and Non-PS users without power control, (2) PS-CARA: with all users using power control, and (3) PS-CARA: PS UE without power control and Non-PS UE with power control. The reason for simulating these cases is to check the suitability of the PS-CARA scheme under different power control situations, and then to find the best suitable case.The simulation results depict that the proposed PS-CARA scheme results in very low interference for case 2, where power control is applied by considering the location and deployment situation of PS and non-PS users. The results in Furthermore, we individually plotted the effect of interference on PS and non-PS users for the three cases described above. From the simulation results shown in The performance of the proposed PS-CARA scheme is compared with respect to the average (50%) and edge throughput (5%). The simulation results shown in The proposed PS-CARA scheme also reduces the call blocking probability of the users as compared with the existing C-SRA scheme. The users call blocking probability decreases because of deploying a greater number of mPC in the public safety areas. This in turn reduces the traffic congestion which occurs during the public safety scenario because a higher number of users access the limited spectrum of the MBS at the same time. We compare the simulation results in three different aspects: (1) using only C-SRA scheme where we randomly allocate the resources among users, (2) proposed PS-CARA scheme without giving priority to public safety users during resource allocation, (3) proposed PS-CARA scheme with public safety priority, where public safety users have been given high priority during resource allocation. The simulation results depicted in This paper presents the public safety priority-based context-aware resource allocation (PS-CARA) scheme for interference reduction in the PS-LTE system. This scheme takes care of the context-information and mPC mobility while allocating resources among users. From the simulation results, we found that PS-CARA with power control is the best possible solution for PS scenario as we have around 67% less interference as compared to PS-CARA without using power control. Moreover, we also found that by giving priority to the PS users, the call blocking is reduced significantly as compared with the C-SRA scheme. Similarly, we notice that by deploying a greater number of mPC in PS scenario, we can increase the mean and edge throughput of the users. In the future, we have a plan to check the performance of the PS-CARA scheme by introducing the energy consumption constraint because energy consumption is one of the important constraints in the PS scenario.


Nicotiana attenuata (coyote tobacco) is an ecological model for studying plant-environment interactions and plant gene function under real-world conditions. During the last decade, large amounts of genomic, transcriptomic and metabolomic data have been generated with this plant which has provided new insights into how native plants interact with herbivores, pollinators and microbes. However, an integrative and open access platform that allows for the efficient mining of these -omics data remained unavailable until now.Nicotiana attenuata Data Hub (NaDH) as a centralized platform for integrating and visualizing genomic, phylogenomic, transcriptomic and metabolomic data in N. attenuata. The NaDH currently hosts collections of predicted protein coding sequences of 11 plant species, including two recently sequenced Nicotiana species, and their functional annotations, 222 microarray datasets from 10 different experiments, a transcriptomic atlas based on 20 RNA-seq expression profiles and a metabolomic atlas based on 895 metabolite spectra analyzed by mass spectrometry. We implemented several visualization tools, including a modified version of the Electronic Fluorescent Pictograph (eFP) browser, co-expression networks and the Interactive Tree Of Life (iTOL) for studying gene expression divergence among duplicated homologous. In addition, the NaDH allows researchers to query phylogenetic trees of 16,305 gene families and provides tools for analyzing their evolutionary history. Furthermore, we also implemented tools to identify co-expressed genes and metabolites, which can be used for predicting the functions of genes. Using the transcription factor NaMYB8 as an example, we illustrate that the tools and data in NaDH can facilitate identification of candidate genes involved in the biosynthesis of specialized metabolites.We present the NaDH provides interactive visualization and data analysis tools that integrate the expression and evolutionary history of genes in Nicotiana, which can facilitate rapid gene discovery and comparative genomic analysis. Because N. attenuata shares many genome-wide features with other Nicotiana species including cultivated tobacco, and hence NaDH can be a resource for exploring the function and evolution of genes in Nicotiana species in general. The NaDH can be accessed at: http://nadh.ice.mpg.de/.The The online version of this article (doi:10.1186/s12864-016-3465-9) contains supplementary material, which is available to authorized users. Nicotiana attenuata, is a diploid wild tobacco native to the Great Basin desert of the United States with populations across Utah, Nevada, Arizona, Oregon, and California. This plant has adapted to an ecological niche defined by the post-fire environment, where soils tend to be nitrogen-rich and biotic stresses are highly dynamic [N. attenuata has been developed as a model organism to study plant-environment interactions in its native environment [N. attenuata have been submitted to the NCBI GEO database. However, to efficiently analyze, explore and visualize such genome-wide metabolomic and transcriptomic data remain challenging for individual researchers. In particular, most of these data were not centralized and integrated. Recently, we sequenced and annotated the genomes of N. attenuata and its close relative N. obtusifolia [ dynamic . During ironment –6, and ausifolia , which pSpecialized metabolites are of special importance in the defenses of plants, therefore, understanding their regulation and their evolutionary history are of central interests in plant biology. However, identifying genes involved in the biosynthesis of specialized metabolites remains difficult due to the large number of gene duplication events in plant genomes, and the structural diversity of the metabolites produced by plants. Recently, studies suggest that co-expression analysis is a powerful tool to rapidly identify genes involved in the biosynthesis of specialized metabolites, because many of these genes are often co-expressed . HoweverNicotiana attenuata Data Hub , a centralized publicly available platform for storing and integrating genomic, transcriptomic and metabolomic data from N. attenuata  and N. obtusifolia genomes (release r1.0), respectively. For comparative genomic analysis, additional gene sequences and structures from nine dicot plant genomes are also included in the database  are included in the NaDH. In addition, 81,859 gene duplication events detected from high confidence phylogenetic trees (approximate Bayes branch supports of greater than 0.9 for the target node and its two child nodes) using the species-overlapping algorithm implemented in Notung-2.6 [N. attenuata are found at the Solanaceae branch , the style, anthers, filaments (not including anthers), and the corolla tube and limb, collected at anthesis. Pools of 100 mg tissues were extracted using 80% methanol. Independent extractions were also conducted with 20% methanol. Samples were analyzed using UHPLC-ESI/qTOF-MS in positive ion mode. MS/MS data collection was achieved via a previously-described pipeline [www.ebi.ac.uk (accession no. MTBLS335).Metabolomic data from 14 isolated tissues of pipeline  and 895 pipeline . This MSN. attenuata, we calculated the pairwise expression correlation co-efficiency based on RNA-seq data from 20 different tissues using three different methods: Gini, Spearman and Pearson [NaDH and can be visualized in a network graph.To facilitate the identification of co-regulated genes in  Pearson . In totaNaDH.Metabolite-to-metabolite tissue associations were calculated using Ochiai similarity based on binary metabolite dataset (containing 14 tissue vectors), with a cutoff of 2 on the ZMAD transformed values . The met-to-metabolite tissue associations were calculated using Ochiai similarity with binary gene and metabolite data (presence and absence) generated from 12 shared tissues between the transcriptome dataset and the metabolome dataset . Gene expression was centered by median and median-absolute-deviation (MAD) to obtain a relative expression level [Geneon level . In totaon level . The paion level  and onlyN. attenuata secondary metabolite classes [Metabolite structure similarity was calculated from pairwise MS/MS alignments based on spectral fragment similarity and common neutral losses similarity (NL). A standard normalized dot product (NDP), also referred to as the cosine correlation method for spectral comparison, was applied for the calculations of spectral fragment similarity. The NL-based similarity between individual MS/MS was implemented using a list of 52 neutral losses (NLs) commonly encountered during tandem MS fragmentation as well as more specific ones that had been previously annotated for MS/MS spectra of  classes .NaDH database architecture is shown in Fig. https://kohanaframework.org/). The unique filesystem design of the Kohana web framework allows a modular design of all NaDH features and enables easy implementations of new functions in the future. The visualization of gene and metabolites expression was implemented by a modified version of the eFP Browser [https://github.com/cytoscape/cytoscape.js).An overview of the  Browser . For intN. attenuata can be searched by name, functional annotation , orthologous genes in other species and sequence similarity based on BLAST. Metabolite spectra and fragments can be searched by name, metabolite class and measurements . In both scenarios, a table summarizes information of the corresponding genes or metabolite spectra, and guides users to downstream analysis.Search functions are implemented for finding genes and metabolites. Genes of NaMYB8 (NIATv7_g41919).This function can be used to understand the regulatory mechanisms and predict putative functions of genes. The input is the identifier of a gene, and the outputs are genes co-expressed with the input gene above the user defined threshold (correlation coefficient) and this is presented in both an interactive network graph and table formats. In the resulting co-expression network graph, each node represents a co-expressed gene, radiating position of the node represents the most recent duplication events it has experienced and clock-wise position of the node represents the region with the highest expression among four tissues  and relative tissue specificity. The resulting table shows more detailed functional annotation of each node. Figure This function can be used to find co-regulated metabolite spectra, which might indicate co-occurrence in biosynthetic pathways and signal cascades. The input of this function is the identifier of a metabolite spectrum of interest, and all co-expressed metabolite spectra above the user-defined threshold and the results are presented in co-expression network graph and table formats. In the co-expression network, each node represents a metabolite spectrum, the color of the nodes represents the annotated class of the corresponding metabolite spectrum, and the edge represents the structural similarity between two nodes: a yellow edge for NDP and red edge for NL. The network can be re-arranged based on expression similarity values or annotated metabolite classes.NaDH, we provide a function to find bi-directional searches for co-expressed genes and metabolite spectra. For searching metabolite spectra that are co-expressed with a gene of interest, the input is an identifier of the gene and the output is a metabolite spectra network with each node representing a metabolite spectrum and each edge representing the structural similarity between two metabolite spectra. In order to search for genes that co-express with a metabolite spectrum of interest, the input is an identifier of the metabolite spectrum and the output is the gene co-expression network with each node representing a gene and the position of the node representing the duplication history and expression (similar to gene-gene co-expression network graph). Figure NaAT1 (NIATv7_g11614).Co-expression between gene and metabolite can be used to both infer putative functions of the genes and to identify candidate biosynthetic pathways of the metabolites –34. In tNaDH, a phylogenetic tree can be directly uploaded and visualized with iTOL [N. attenuata genes among 20 different tissues. In addition, the intron-exon structures were also integrated with the phylogenetic tree to provide further information on the evolutionary history of the gene. Figure In the ith iTOL , 36. TheThe expression of genes and metabolites can be visualized via a modified version of the eFP Browser developed by Nicholas J. Provart et al . The inpNaDH and genes known to be involved in phenolamides biosynthetic pathway as an example, we show that the integration of gene-to-gene, gene-to-metabolite, metabolite-to-metabolite and gene duplication history can help to identify genes that are involved in specialized metabolites in the genus Nicotiana.The evolution and diversity of specialized metabolites in plants are largely shaped by gene duplication events . ConsequN-acyltransferase-dependent conjugation to polyamines or aryl monoamines  [NaMYB8 with a cutoff with a gini correlation coefficient (gcc) greater than 0.7, which resulted in 2,620 co-expressed genes. Among these genes, we searched for homologs that are putatively involved in biosynthetic steps of the main phenylpropanoid pathway. Although in each step, several copies were found in N. attenuata, only one or two copies were co-expressed with NaMYB8. Among them, functional characterization using virus-induced gene silencing (VIGS) revealed that AT1, CV86 and DH29 are indeed involved in the biosynthesis of herbivore-induced phenolamides, such as caffeoylputrescine (CP) and N’,N”-dicaffeoylspermidine (DCS), which function as anti-herbivore chemical defenses [Nicotiana. Additional co-expression analysis of gene-metabolite and metabolite-metabolite associations showed that the key metabolites  and genes  from the pathway can be retrieved by searching highly co-expressed genes and metabolites  . We firsdefenses . The duptes Fig. . AlthougNaDH, which integrates genomic, transcriptomic, and metabolomic data in N. attenuata and provides useful tools for the interactive visualization of gene expression divergence and gene duplication history. Additional tools for finding co-expressed genes and metabolites can facilitate rapid gene discovery for specialized metabolites in N. attenuata and infer their evolutionary paths. Since the most of genome-wide features are shared among the genus Nicotiana, the NaDH can also be used to explore the function and evolution of genes in other Nicotiana species.We present the aDH (http://nadh.ice.mpg.de/NaDH/).The datasets generated and/or analysed during the current study are available in N


The scale-free dynamics of human brain activity, characterized by an elaborate temporal structure with scale-free properties, can be quantified using the power-law exponent (PLE) as an index. Power laws are well documented in nature in general, particularly in the brain. Some previous fMRI studies have demonstrated a lower PLE during cognitive-task-evoked activity than during resting state activity. However, PLE modulation during cognitive-task-evoked activity and its relationship with an associated behavior remain unclear. In this functional fMRI study in the resting state and face processing + control task, we investigated PLE during both the resting state and task-evoked activities, as well as its relationship with behavior measured using mean reaction time (mRT) during the task. We found that (1) face discrimination-induced BOLD signal changes in the medial prefrontal cortex (mPFC), posterior cingulate cortex (PCC), amygdala, and fusiform face area; (2) PLE significantly decreased during task-evoked activity specifically in mPFC compared with resting state activity; (3) most importantly, in mPFC, mRT significantly negatively correlated with both resting state PLE and the resting-task PLE difference. These results may lead to a better understanding of the associations between task performance parameters  and the scale-free dynamics of spontaneous and task-evoked brain activities. During the resting-state recordings, the subjects were instructed to relax, stay awake, and keep their eyes open and fixed on the crosshairs on the screen. The details of the task state in this experiment are described in a previous paper . Grayscahttp://www.fmrib.ox.ac.uk/fsl) for extracting the ROIs in the gray matter associated with face processing. For prestatistical processing, we performed motion correction using MCFLIRT  and PCC . In contrast, a significantly increased task-evoked BOLD signal intensity was observed in bilateral AMYGs  and bilateral FFAs , as compared with the control condition . In contrast, PLE in the left FFA was significantly higher in the task state than in the resting state. Finally, the other regions such as PCC, left and right AMYGs, and right FFA did not show any significant difference in PLE between the resting state and the task state , and in left FAA, PLE in the task state was significantly higher than that in the resting state . Furthermore, the other regions such as PCC, left and right AMYGs, and right FFA did not show any significant difference in PLE between the resting state and the task state.The log transformation of the power spectrum for HM = 7 is shown in sk state . Moreover = −0.688; 95% CI: −0.239 to −0.902; p = 0.005). Moreover, mRT under the emotional face + control conditions also correlated with the resting-task difference PLE in mPFC . In contrast, no significant correlation was found between task-state PLE in mPFC and mRT . Moreover, mRT under the emotional face + control conditions was significantly negatively association with the resting-task difference in mPFC . The analyses using both HM = 3 and 5 showed no significant correlation between task-state PLE in mPFC and mRT. Unlike in mPFC, we observed no correlation of mRT with PLE in the resting state, task state, and resting-task difference in the other regions, namely, PCC and bilateral AMYGs and FFAs in all analyses using HM = 3, 5, and 7. On the other hand, mRT under each of emotional face condition or control condition showed no significant association with resting-state PLE, task-state PLE, and resting-task difference PLE for all ROIs.Pearson's correlation analysis (1000-sample bootstrapping) showed that in mPFC, mRT under emotional face + control conditions was significantly negatively associated with PLE in the resting state  a significant decrease in PLE in the face processing task compared with that in the resting state, (ii) a significant correlation between resting-state PLE and mRT under the emotional face + control conditions, and (iii) a significant correlation between resting-task difference PLE and mRT under the emotional face + control conditions. Taken together, these findings underline the central relevance of scale-free dynamics in the resting state and task-evoked activity to task performance parameters .In the analysis of the BOLD signal changes under the face discrimination condition relative to the control condition in this study, AMYG and FFA were activated whereas mPFC and PCC were deactivated. These findings are in agreement with recent brain imaging findings on facial emotion processing , 43. TheAdditionally, FFA showed an increase in PLE during task-evoked activity compared with the resting state activity, which indicates that FFA is likely required in face processing but not under the control condition . The tasIn this study, we observed that resting-state PLE in mPFC inversely correlated with mRT under the emotional face + control conditions: the higher the PLE in the resting state, the shorter the mRT during the task. An analogous relationship was observed in the PLE difference between the resting and task states in this same region. On the other hand, PLE during the task-evoked activity itself, independent of the resting state, showed no relationship with task performance parameters, for example, mRT. This suggests that in mPFC, interindividual variability in mRT is related to interindividual variability in the scale-free dynamics in the spontaneous state  and the degree of task-evoked modulation from the scale-free dynamics in the spontaneous state to those in the task state.Here, we mention the limitations of our study. We acquired MRI data for 4 min to calculate PLE both in the task and resting states, which is relatively short for determining PLE with sufficient S/N ratios. We set this duration because we had to acquire data for a moderate duration to weaken any effect of habituation during this face processing task. FFA exhibits task-evoked periodicity, as shown in In summary, we demonstrated that both resting-state PLE and resting-task difference PLE in mPFC were associated with task performance parameters, for example, mRT. This finding suggests a specific role of the scale-free dynamics of spontaneous brain activity in mediating task-evoked activity and behavioral performance in the face processing task. Our results complement previous studies showing the relevance of scale-free dynamics in perception, action, and cognition. This study further underlines the close relationship between spontaneous and task-evoked activities as shown by how scale-free dynamics mediate the transition of these processes and impact the associated behavioral performance.


Sex and race disparities in recombinant tissue plasminogen activator (rt-PA) use have been reported. We sought to explore sex and race differences in the utilization of rt-PA at primary stroke centers (PSCs) compared to non-PSCs across the US.Data from the National (Nationwide) Inpatient Sample (NIS) 2004–2010 was utilized to assess sex differences in treatment for ischemic stroke in PSCs compared to non-PSCs.p < 0.001) and non-PSCs . After adjustment for potential confounders the odds of being treated with rt-PA remained lower for women regardless of presentation to a PSC  or non-PSC . After stratifying by sex and race, the lowest absolute treatment rates were observed in black women . The odds of treatment, relative to white men, was however lowest for white women . In the multivariable model, sex did not modify the effect of PSC certification on rt-PA utilization .There were 304,152 hospitalizations with a primary diagnosis of ischemic stroke between 2004 and 2010 in the analysis: 75,160 (24.7%) patients were evaluated at a PSC. A little over half of the patients evaluated at PSCs were female (53.8%). A lower proportion of women than men received rt-PA at both PSCs (6.8 vs. 7.5%, Women are less likely to receive rt-PA than men at both PSCs and non-PSCs. Absolute treatment rates are lowest in black women, although the relative difference in men and women was greatest for white women. Intravenous recombinant tissue plasminogen activator (IV rt-PA) is a thrombolytic agent that improves outcomes in stroke patients when administered within 4.5 h of symptom onset –3. The uSex disparities in IV rt-PA use have been reported; however, whether PSCs reduce these disparities is unknown –13. GiveFurther contributing to the sex disparity in IV rt-PA utilization is evidence that sex differences may vary by race/ethnicity, with black women being treated less frequently than white women . Buildinvia personal communication from TJC on May 17th, 2011 . Methods for this work have been previously reported  codes 433.x1, 434.x1, and 436. The positive predictive value of these codes for identifying acute ischemic stroke is greater than 85% , median household income in the patient’s ZIP code, comorbid conditions  , and an t, Wilcoxon rank-sum, and χ2 tests, as appropriate. Patients were stratified by sex, and then further stratified by race/ethnicity within sex. A multivariate model was constructed to determine independent associations including year of discharge, age, sex, primary expected payer, median income by ZIP code, hospital region, teaching status, urban/rural location, and ischemic stroke admission volume, the 29 Elixhauser comorbid conditions, and the APR-DRG measure of disease severity  for continuous variables and proportions for categorical variables. Differences between the groups were evaluated using Student’s severity . Our anaseverity . An alphBetween 2004 and 2010, acute ischemic stroke was the primary diagnosis for 598,606 hospitalizations in the NIS. The inclusion/exclusion criteria for the study population and the baseline patient- and hospital-level characteristics stratified by PSC status have been previously published  and non-PSCs . Figure A lower proportion of women than men received rt-PA at both PSCs .In an unadjusted model, women were at lower odds of being treated with rt-tPA compared to men at both PSCs and non-PSCs Table . After aOur results illustrate that the relationship between PSC certification and rt-PA utilization is similar in men and women. PSCs utilize rt-PA more than non-PSCs in both men and women, regardless of race/ethnicity. However, our results also illustrate that women are less likely to receive rt-PA than men at both PSCs and non-PSCs. In absolute treatment proportions, black patients are treated in lower proportions than other racial/ethnicity groups, and black women are treated less than any other group; however, the relative odds of treatment were lowest in white women relative to white men.Sex disparities in the treatment of stroke remain a concern, particularly with the rise in incident stroke among women. IV rt-PA is effective for both men and women, but women may be even more likely to benefit from treatment than men , 28. AmoLower rt-PA treatment rates in women may be related to patient factors. First, women tend to be older than men at the time of stroke. Second, women tend to present with more severe strokes . Third, Black women have the lowest proportion of rt-PA treatment, regardless of PSC status of the treating hospital. This finding supports prior data from two academic medical centers, which also found that black women were treated less frequently with rt-PA. In prior studies, black women were more likely to have delayed presentation, and once time from onset was accounted for, the sex and race disparity in rt-PA treatment no longer remained . It is pThis study has limitations similar to prior work evaluating rt-PA use in the NIS , 20. As The sex disparities seen in rt-PA utilization remain after accounting for race/ethnicity and other known factors that contribute to rt-PA underutilization. The increased utilization of rt-PA at PSCs is consistent between men and women and stable across racial and ethnic groups. Considering women may benefit from rt-PA utilization more than men, the disparity in utilization is concerning. Further research is needed to investigate what factors are contributing to this sex disparity.This study was the analysis of de-identified data from the National Inpatient Sample and was exempt from IRB approval.AB is the primary author of this manuscript. BC and SK made critical revisions to the manuscript. KA contributed to the study idea, data interpretation, and made critical revisions. MK conducted the data analyses and made critical revisions. ME and CB made critical revisions. MM developed the study idea, obtained the data, interpreted the data, and made critical revisions.BC spends a portion of his time in the Office of the Assistant Secretary for Preparedness and Response. The findings/conclusions of this report are those of the author and do not necessarily represent the views of the Department of Health and Human Services or its components. The other authors have no conflicts to report.


The atherogenic index of plasma (AIP), which is the logarithmic ratio of triglyceride (TG) to high-density lipoprotein cholesterol (HDL-C), had a linear relationship with clinical outcomes in the general population. However, the association of each lipid profile, TG and HDL-C, with survival was not straightforward in dialysis patients. This non-linear association led us to further investigate the prognostic impact of the AIP in these patients.From a nationwide prospective cohort, 1,174 incident dialysis patients were included. Patients were categorized into quintiles according to the AIP. An independent association of the AIP with all-cause and cardiovascular mortality was determined.During a mean follow-up duration of 33.2 months, 170 patients (14.5%) died, and cardiovascular death was observed in 55 patients (4.7%). Multivariate Cox analyses revealed that the lowest  and the highest  AIP groups were significantly associated with higher all-cause mortality compared to patients in quintile 3 (reference group). In terms of cardiovascular mortality, only the highest AIP group  was significantly associated with increased risk of mortality. Sensitivity analyses showed that a U-shaped association between the AIP and all-cause mortality remained significant in non-diabetic and underweight to normal body mass index patients.Both the highest and the lowest AIP groups were independently associated with all-cause mortality, showing a U-shaped association. It suggested further studies are needed to identify targets and subgroups that can benefit from intervention of the AIP in incident dialysis patients. Dyslipidemia is an established risk factor for cardiovascular disease in the general population . In partAll ESRD patients who started HD or PD between August 1, 2008 and December 31, 2014 at 31 centers of the Clinical Research Center for ESRD (CRC for ESRD) in the Republic of Korea were initially screened for this study. This study is part of a nationwide multicenter prospective cohort study of ESRD patients that aimed to improve clinical outcomes and to develop efficient treatment guidelines in the Republic of Korea . Patients who refused to participate in the study, who did not maintain dialysis for the first 3 months, who had missing with TG or HDL-C, or who did not have intact parathyroid hormone, high-sensitivity C-reactive protein (hs-CRP), residual kidney function or residual urine output data were excluded from the initially screened 2,189 patients. In total, 1,174 incident dialysis patients were included in the final analyses . Meanwhi®, version 2.0 for Windows software . Residual kidney function and residual urine volume were determined by timed urine collection, in a 44-hour interdialytic period in HD patients and 24-hour urine collection in PD patients.Demographic, clinical, and laboratory data were extracted from the CRC for ESRD electronic database. Demographic and clinical data including age, sex, dialysis modality, primary renal disease, comorbidities, body mass index (BMI), and medications were collected at the study enrollment. Laboratory data were measured from fasting blood samples at 3 months after dialysis initiation. AIP was calculated from plasma TG and HDL-C (log [TG/HDL-C]). In HD patients, blood was taken at the predialysis period and a single pooled Kt/V urea was obtained on the day of the midweek dialysis session. In PD patients, blood was taken under usual overnight peritoneal dialysate volume and glucose concentrations, and weekly peritoneal Kt/V urea was calculated using PD AdequestStudy participants were followed until September 30, 2015. All death events and the cause of death were retrieved from the CRC for ESRD database and collated with the medical records at each participating center. Death events were also confirmed by the Korea National Statistics database. Cardiovascular death was defined as death from myocardial infarction, unstable angina, new onset, or worsening of congestive heart failure, stroke, or arterial revascularization. Loss to follow-up, kidney transplantation, or recovery of renal function was censored at the end of dialysis treatment.www.r-project.org). Continuous variables were expressed as the mean ± standard deviation or the median (interquartile range [IQR]) and categorical variables were expressed as a number (percentage). Patients were categorized into five groups according to the AIP quintiles (Q1 to Q5). Baseline characteristics were compared among the groups using ANOVA with the Bonferroni post-hoc test or the Kruskal-Wallis test for continuous variables, and the chi-square test for categorical variables. The association between the AIP and baseline characteristics was examined by uni- and multivariate linear regression analyses. The prognostic value of the AIP was ascertained by Cox proportional hazard regression analyses. Multivariate Cox models were constructed including age, sex, presence of diabetes mellitus, prior history of cardiovascular disease, dialysis modality, BMI, serum albumin levels, hs-CRP levels, and residual urine volume, which were significant risk factors for mortality in the univariate Cox analyses or independent variables associated with the AIP in the linear regression analyses. Sensitivity analyses were done only for all-cause mortality due to the limited number of cardiovascular death events. Because there was interaction between the AIP and BMI for all-cause mortality (P for interaction = 0.03), subgroup analyses were performed. Patients were divided into underweight to normal BMI (BMI <22.9 kg/m2) and overweight to obese (BMI ≥23.0 kg/m2) groups using the World Health Organization recommendations for Asian populations [Statistical analyses were performed using SPSS for Windows version 20.0  and R  died, and cardiovascular death was observed in 55 patients (4.7%) . IncidenTo determine the independent prognostic value of the AIP for all-cause and cardiovascular mortality, Cox’s regression analyses were performed . MultivaFor sensitivity analyses, the independent prognostic value of the AIP for all-cause mortality was tested in several subgroups . The proIn the present study, we investigated the prognostic value of the AIP on all-cause and cardiovascular mortality in incident dialysis patients from a nationwide prospective cohort of ESRD patients. Both the lowest (≤0.20) and the highest (≥0.71) AIP groups were independently associated with all-cause mortality risk, showing a U-shaped association. In terms of cardiovascular mortality, only the highest AIP group (≥0.71) showed a significant risk factor. A U-shaped association between the AIP and all-cause mortality was significant in non-diabetic and underweight to normal BMI patients. These findings suggested that the prognostic impact of the AIP was not straightforward.The AIP has been shown to be a good marker of atherogenicity , 19 and Although the exact mechanism by which a higher AIP affects increased risk of all-cause and cardiovascular mortality remains unclear, the association of AIP with LDL-C particle size , insulinAnother main finding of this study was a U-shaped association between the AIP and all-cause mortality in incident dialysis patients. Patients in the quintile 3 group of the AIP showed the lowest incidence rate of death events, and the lowest and the highest quintiles of the AIP were significantly associated with higher all-cause mortality risk, compared with patients in the quintile 3 group. Although the reason for higher all-cause mortality risk in the lowest AIP group was not clear, it can be speculated from the deleterious effects of low TG and high HDL-C in dialysis patients. In a large cohort of HD patients, the best survival was observed with moderately high levels 200–249 mg/dL) of TG, suggesting a higher mortality risk with lower levels of TG . This pa9 mg/dL oOur sensitivity analyses demonstrated that higher all-cause mortality risk in the lowest quintile of the AIP remained significant in non-diabetic patients and underweight to normal BMI patients. Underweight patients had higher risk of mortality compared with overweight-to-obese patients due to the adverse effects of nontraditional risk factors such as malnutrition and inflammation. Therefore, we surmised that the combined risk of low AIP and underweight-to-normal BMI via malnutrition and inflammation might lead to an amplification of the mortality risk for the lowest AIP groups of patients. By contrast, the protective effect of high BMI in overweight-to-obese patients might mitigate the harmful effect of the lowest AIP group, resulting in no significant association with increased mortality risk in these populations. In terms of diabetes, the higher proportion of underweight-to-normal BMI patients in the non-diabetic group could be a possible explanation for the increased mortality risk of the lowest AIP group. In fact, the proportion of underweight-to-normal BMI was significantly higher in non-diabetic patients than in diabetic patients . In addition, a study by Postorino et al.  demonstrThis study has several limitations. First, the AIP was not serially determined and we used only baseline values of AIP. We suggest that the prognostic effects of changes in the AIP would be worth investigating. Second, this study was not intended to evaluate the effect of lipid-lowering medications on mortality, and the data concerning lipid-lowering therapy were not available. Although the potential confounding effects of lipid-lowering medications on mortality cannot be excluded, considering the results of recent clinical trials regarding lipid-lowering therapy –29, we sThe current study demonstrated that both the highest and the lowest AIP groups were significantly associated with increased risk of all-cause mortality, showing a U-shaped association in incident dialysis patients. Furthermore, a U-shaped association between the AIP and all-cause mortality was significant in non-diabetic and underweight to normal BMI patients. These findings suggest that further studies are needed to identify targets and subgroups that can benefit from interventions of the AIP in ESRD patients.S1 Text(PDF)Click here for additional data file.S1 Table(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file.


P = 0.029), and BCSS (P = 0.013) in lymph-node-positive breast cancers. Obesity in hormone-receptor-positive breast cancer showed a poorer OS  and significantly poorer BCSS . In contrast, a high BMI in hormone-receptor-negative breast cancer revealed a better OS  and BCSS . Being underweight (BMI < 18.50 kg/m2) with hormone-receptor-negative breast cancer was associated with a significantly worse OS  and BCSS . There was no significant interaction found between the BMI and hormone-receptor status in the lymph-node-negative setting, and BMI did not interact with the menopause status in any subgroup. In conclusion, BMI interacts with the hormone-receptor status in a lymph-node-positive setting, thereby playing a role in the prognosis of breast cancer.The aim of this study was to determine the relationship between the body mass index (BMI) at a breast cancer diagnosis and various factors including the hormone-receptor, menopause, and lymph-node status, and identify if there is a specific patient subgroup for which the BMI has an effect on the breast cancer prognosis. We retrospectively analyzed the data of 8,742 patients with non-metastatic invasive breast cancer from the research database of Asan Medical Center. The overall survival (OS) and breast-cancer-specific survival (BCSS) outcomes were compared among BMI groups using the Kaplan-Meier method and Cox proportional-hazards regression models with an interaction term. There was a significant interaction between BMI and hormone-receptor status for the OS ( There has been some controversy about whether the body mass index (BMI) at the diagnosis of breast cancer is associated with the patient outcome. Several clinical trials have demonstrated that obesity at diagnosis is associated with breast-cancer-specific survival (BCSS) and overall survival (OS) –3, whichConsidering the heterogeneity of breast cancer, it is possible that the effect of BMI on its prognosis is influenced by various factors . Many stThere is also some controversy as to the impact of menopause which is another factor that has been studied in this context. Investigators from the EBCTCG  reported that obesity is a negative prognostic indicator in premenopausal patients with estrogen-receptor-positive breast cancer, while others have found that obesity was an adverse prognostic factor in postmenopausal breast cancer patients , 10. In It is likely that the complexity of the relationships between the BMI and various known factors is responsible for its varying reported effects on breast cancer survival between studies. Moreover, most of the previous studies investigating the association between BMI and other factors did not include explanatory variables such as tumor grade, lymphovascular invasion and treatment, and the definition of menopausal status has differed between trials , 12. FurThe aim of this study therefore was to determine the relationship between the BMI at diagnosis and known factors including the hormone-receptor and menopause status of the patients, and to identify if there is a specific breast cancer population according to lymph-node status for which BMI has an effect on the prognosis.Data on breast cancer patients treated at our institution between January 1997 and June 2008 were retrieved from the Asan Medical Center research database, a web-based system that includes archived anonymous information on all patients who undergo breast cancer surgery. Patients were included in the study if they were aged 80 years or younger at the time of diagnosis, were diagnosed with stage I to stage III breast cancer, and were treated surgically. The patients for whom information on the BMI at diagnosis was not available or who received neoadjuvant systemic therapy were excluded. In total, 8,742 patients were finally included in the analysis. This study was approved by the Institutional Review Board of Asan Medical Center .The following information was available on the study patients: age, weight, height, tumor size, number of metastatic lymph nodes, estrogen-receptor status, progesterone-receptor status, histology grade, lymphovascular invasion, menopause status, and the administration of chemotherapy, radiation therapy, and hormonal therapy. The weight and height of each patient were measured during the hospital stay prior to breast cancer surgery. The BMI was calculated from these measurements and categorized according to the International Classification of the World Health Organization i.e. underweight , normal weight , overweight  and obese .Descriptive statistics were summarized with absolute and relative frequencies. Continuous and categorical variables were compared among BMI groups using one-way analysis of variance and the χ2 test, respectively. The breast cancer outcome was analyzed in terms of OS and BCSS, defined as the time from the first diagnosis of primary breast cancer to death from any cause and death from breast cancer, respectively. The survival of patients who were lost to follow-up was calculated using the last date of follow-up. The survival curves for all four BMI groups were estimated using the Kaplan-Meier method, and the log-rank test was used to evaluate statistical significance. To assess the BMI category as a prognostic factor for OS and BCSS, multivariate analyses were conducted using Cox proportional-hazards regression models adjusted for previously known prognostic factors, including age, tumor size, the number of pathologically confirmed positive lymph nodes, histology grade (low or high), hormone-receptor status (positive or negative), treatment  and menopause status , with NW as a reference category. Estrogen receptor and/or progesterone receptor positivity was defined as a positive hormone-receptor status. Interaction effects between BMI and other factors (hormone-receptor or menopause status) were explored by adding interaction terms to the model in which BMI was treated as an ordinal. The patients were divided into two subgroups according to their lymph-node status (positive or negative), and subgroup analyses were performed to evaluate whether the effect of BMI on breast cancer outcome differed in different settings.P value of <0.05 was considered statistically significant.Statistical analyses were performed using R software  and SAS software . A two-sided The patients were aged 47.7± 9.9 years  with a mean BMI of 23.6 ± 3.2 kg/m2 (range = 12.6–46.8 kg/m2). P = 0.079; OW, P = 0.725; OB, P = 0.238) or BCSS . Among the lymph-node-positive breast cancer patients, neither univariate nor multivariate analysis revealed any significant difference between the BMI groups in OS  or BCSS  outcomes. Moreover, in lymph-node-negative settings, there was no significant intergroup difference found in the OS  or BCSS .During a median follow-up of 92 months, there were 1,178 deaths from any cause in our study cohort and 957 patients died of breast cancer. Ninety-eight patients died of other causes which included other cancers in 65 cases, trauma in 8 cases, cardiovascular disease in 6 cases, chronic liver disease in 5 cases, sepsis in 3 cases, acute respiratory distress syndrome in 2 cases, cerebrovascular disease in 2 cases, autoimmune disease in 2 cases, suicide in 1 case and other medical problems in 4 cases. The cause of mortality was unknown in 123 patients. Among the total study population, univariate analysis revealed significant differences in OS outcomes between BMI groups but not in terms of BCSS . HoweverAmong the hormone-receptor-positive breast cancer patients in our study cohort , univariate analysis indicated that obesity was a negative prognostic indicator for both OS and BCSS  and multP = 0.039), but not for OS (P = 0.0623). However, multivariate analysis demonstrated a significant interaction between BMI and hormone-receptor status in terms of both the OS (P = 0.029) and BCSS (P = 0.013) in lymph-node-positive breast cancers. Obesity in hormone-receptor-positive breast cancer cases was associated with a poorer OS  and significantly poorer BCSS , but a high BMI in hormone-receptor-negative breast cancer correlated with both a better OS  and BCSS . In contrast, UW in hormone-receptor-negative breast cancer demonstrated a trend toward a worse OS and significantly worse BCSS  between BMI and hormone-receptor status  or BCSS  in any subgroup , and obesity showed an association with a poorer prognosis in premenopausal women . Additionally, we explored the correlation between hormone-receptor status and menopause status using the χ2 test which revealed a significant association between these factors in our study population (P = 0.006). The rate of hormone-receptor positive breast cancers was higher for patients with a premenopausal status  compared with a postmenopausal status , which could influence the association between BMI and cancer outcome. Future studies with greater statistical power will likely be useful for determining the interaction between BMI and menopause status in the prognosis of breast cancer.There has been some controversy to date concerning the relationship between BMI and menopause status in the prognosis of breast cancer , 10, 11.In terms of using BMI as a prognostic factor in breast cancer, our current results suggest the importance of the lymph-node status. Several reports have indicated that BMI is a prognostic indicator in locally advanced breast cancer , 13. TheSeveral earlier studies have reported that not only obesity but also UW is a negative prognostic indicator in breast cancer , 14–16. There are several possible hypotheses for explaining the biological mechanisms connecting the BMI to a worse prognosis in breast cancer patients . ObesitySeveral limitations of our present study should be noted. This was a retrospective and single-institutional study that may have been influenced by selection bias. Although we performed multivariate analysis with known prognostic factors, we were not able to include other significant prognostic factors such as the expression of human epidermal growth factor receptor 2, which may influence the association between BMI and cancer outcome. In addition, although our sample size was larger than that of previous studies, the number of UW and OB patients in our cohort was relatively small, which could have affected the statistical power of our subgroup analysis. Moreover, some of our survival data were obtained from the Korean national insurance database which gives information on the date of death but not the cause. The number of deaths of unknown cause among our study population was therefore relatively high. Moreover, our study population mainly comprised Korean patients, and our findings may therefore only be generalizable to Asian populations.In conclusion, our current study has yielded clues regarding the complex relationships between BMI and various factors affecting breast cancer outcomes. The BMI interacts with hormone-receptor status in the lymph-node-positive setting, thereby playing a role in the prognosis of breast cancer. Our findings support the application of an individualized approach to the management of breast cancer survivors, given that the different role of the BMI at diagnosis differs depending on the hormone-receptor status in relation to the lymph-node status.S1 FileTable A. Cox proportional-hazards regression models with an interaction term for body mass index and menopause status in lymph-node-positive breast cancer patients. Table B. Cox proportional-hazards regression models with an interaction term for body mass index and menopause status in lymph-node-negative breast cancer patients.(DOCX)Click here for additional data file.S1 Dataset(XLSX)Click here for additional data file.


Glycosylphosphatidylinositol (GPI)-anchored proteins (GPI-APs) use a unique posttranslational modification to link proteins to lipid bilayer membranes. The anchoring structure consists of both a lipid and carbohydrate portion and is highly conserved in eukaryotic organisms regarding its basic characteristics, yet highly variable in its molecular details. The strong membrane targeting property has made the anchors an interesting tool for biotechnological modification of lipid membrane-covered entities from cells through extracellular vesicles to enveloped virus particles. In this review, we will take a closer look at the mechanisms and fields of application for GPI-APs in lipid bilayer membrane engineering and discuss their advantages and disadvantages for biomedicine. Glycosylphosphatidylinositol (GPI)-anchored proteins (GPI-APs) are generated by posttranslational modification and can be found on approximately 0.5 percent of proteins in eukaryotes , while sGE introduces recombinant DNA containing the key sorting signals of N-terminal signal peptide and C-terminal GSS into suitable producing cell lines, e.g., via transfection or infection methods –17. GSS MP exploits a specific property of the GPI-Aps, which is the ability of purified GPI-AP preparations to spontaneously reinsert into lipid bilayer membranes , 25–33. Modification of lipid membranes with GPI-APs may be employed for different goals: labeling, targeting, and manipulation of host responses (HRs), mostly for immunomodulation. Labeling may be mostly useful in research settings to follow the fate of cells, viruses, membranes, or membrane compartments such as LRs , 20. In Both GE and MP approaches have been used to modify cellular membranes. Only recently, a GE approach was suggested in the field of HIV therapy . In thisEscherichia coli and Helicobacter pylori incorporated CD59, at least in one case in an anchor-dependent manner , orthomyxo- (influenza), flavi- , phyllo- (Ebola), herpes- (Epstein-Barr), and poxviridae (Variola). In this section, we will discuss the modification not only of enveloped virus particles, but also of VLPs and VVs used for gene therapy [collectively termed virus/derived particles (V/DPs)]. What these engineered variants have in common is that they lack important parts of the full viral anatomy: in VLPs, viral structural proteins are used to generate a lipid vesicle population of good homogeneity. They are mostly used as particulate antigen-presenting platforms . As a coIn 2008, the first attempt at MP for the modification of V/DPs was published . CD59 waOne of the advantages of MP is that no metabolism is required for carrying out the functionalization. Thus, a wider range of lipid vesicles is available for modification, including liposomes, model membranes , and celExtracellular vesicles are also amenable to membrane modification by MP and may profit from the quick exchange facilitated by protein transfer. In a recent article, CD59 was attached to VVs, but protein was also retained in control samples containing concentrated supernatant from non-virus-producing cell lines . It is most likely that exosomes are the target of modification because their accumulation would be favored by the preparation method . Also, mhttps://www.jenabioscience.com/lexsy-expression), may help to overcome bottlenecks in GPI-AP production. Parasite cells  are especially rich in GPI-APs, i.e., the trypanosome variant surface glycoproteins, which cover the whole cell . This is most likely a consequence of the complex biochemistry of the GPI-anchoring metabolic pathway. In order to provide sufficient amounts for clinical testing, several options may allow increasing expression levels, including the induction of GPI metabolizing enzymes by zinc ions  and overole cell . Some isole cell . Additivole cell , 35, 36.ole cell . For thiAnother open issue is the vice versa influence of the two alternative aspects in GPI-APs: how the hydrophilic protein and the lipophilic fatty acids may influence each other and the GPI-AP performance in biomedical applications. Parameters of interest include protein size and composition, as well as the exact chemical composition of the GPI anchor. While little data is available about the latter, protein size is known to influence diffusion behavior of GPI-APs . The redIn spite of the technical challenges, there are some inherent advantages of GPI-AP applications in general, such as efficient membrane targeting , the small (and therefore less disturbing) footprint in the membrane, and a degree of mechanical/structural flexibility due to the GPI linkage, making it less likely to lose soluble protein function. Other advantages are specific to MP. These advantages include the speed of modification (hours compared with days because no expression is necessary) and the fact that time consuming or difficult GE can be completely avoided . In some cases, where GE is impossible , MP may be the only option. Additionally, the level of insertion is controllable, multiple GPI-APs can be inserted by MP  and targhttp://www.kodebiotech.com/), as well as compounds based on GPI-APs (see http://www.metaclipsetherapeutics.com/ and http://www.anovasia.com/)Finally, chemical alternatives to membrane targeting, including lipophilic carbocyanine dyes such as DiI  or DiO  , for labIn summary, a wide range of proteins have been GPI-anchored by recombinant DNA techniques and used for biomedical purposes to date  in (most likely tumor) vaccination strategies, making use of combinations of antigens and stimulatory molecules, as well as using the inherent bio-compatibility of patient-derived membranes . In conc