Electronic-sports (e-sports) is a form of organized, online, multiplayer video game competition, which requires both action skills and the ability and process of forming and adapting a strategy (referred to as strategization hereafter) to achieve goals. Over the past few decades, research has shown that video gaming experience has an important impact on the plasticity of the sensorimotor, attentional, and executive brain areas. However, little research has examined the relationship between e-sports experience and the plasticity of brain networks that are related to strategization. Using resting-state fMRI data and the local functional connectivity density (lFCD) analysis, this study investigated the relationship between e-sports experience (League of Legends [LOL] in this study) and brain plasticity by comparing between top-ranking LOL players and lower-ranking (yet experienced) LOL players. Results showed that the top-ranking LOL players had superior local functional integration in the executive areas compared to lower-ranking players. Furthermore, the top-ranking players had higher lFCD in the default mode areas, which have been found related to various subprocesses  essential for strategization. Finally, the top-ranking players' lFCD was related to their LOL expertise rank level, as indicated by a comprehensive score assigned by the gaming software based on players' gaming experience and expertise. Thus, the result showed that the local functional connectivity in central executive and default mode brain areas was enhanced in the top-ranking e-sports players, suggesting that e-sports experience is related to the plasticity of the central executive and default mode areas. E-sports is also gaining increasing research attention given its adaptive effect on human development, since e-sports can be physically and cognitively demanding just like traditional sports. Thus, e-sports can be an important platform for studying brain plasticity [One of the most prominent changes to our modern lives is the use of computers and Internet, which has changed our entertainment experience with the introduction of electronic-sports (e-sports). E-sports can take the form of organized, multiplayer video game competition, which may require less infrastructure preparation and team development than traditional team sports . Thus, e-sports is becoming increasingly popular worldwide across a wide age range . This isasticity  and an eE-sports may owe its origin to single-player action video games , which A significant and growing body of research has examined the influence of e-sports experience on human development, most of which focuses on the effect of action video gaming (AVG) experience on human sensorimotor and attentional development. For example, behavioral research showed that AVG experience promoted primary cognitive processes  who is still learning the basic rules of the game, (ii) a lower-ranking but experienced player (between the 51 and 82.1 percentiles), or (iii) a top-ranking, expert player (above the 98.33 percentile) who often focuses on planning and implementing the strategy and tactics in LOL gaming. A player's ranking data are assigned by the LOL software based on the player's experience and expertise compared against the average level across all players worldwide. The ranking data used in this study are available on http://www.laoyuegou.com. This study focused on the top- and lower-ranking LOL players with the lowest-ranking players excluded, because they are still learning the basic rules of LOL. Therefore, any neural plasticity observed in them may be driven by their learning of the basic rules of LOL rather than the acquisition of strategization skills. We predict that compared with the lower-ranking players, the top-ranking players should have improved development in (i) the brain areas related to sensorimotor and cognitive control, which supports their superior action skills in e-sports, and (ii) the default mode network (DMN), which supports long-term memory and planning and thereby is essential for strategization [This study examined this issue by comparing between top- and lower-ranking LOL players. Based on one's skill level, an LOL player can be either (i) a lowest-ranking player  based on resting-state fMRI data and their four-dimensional consistency of local neural activities (FOCA), as research shows that the resting-state brain function is adaptable according to age  and leartop = 90.1 ± 10.13, meanlower = 89.85 ± 9.57 ), and weekly physical exercise time . All participants were right-handed according to the Edinburgh Inventory [The participants were 26 top-ranking players , who were among the top 1.77% players among all LOL players worldwide according to the aforementioned ranking, and 34 lower-ranking but experienced players  who were ranked between the 51 and 82.1 percentiles. The two groups were matched in age, IQ assessed through Ravens Progressive Matrices , with an eight channel-phased array head coil. All participants underwent a 510 sec resting-state scan that yielded 255 volumes (32 slices per volume).Images were acquired on a 3T MRI scanner (GE Discovery MR750). Resting-state functional MRI data were acquired using gradient-echo EPI sequences . These procedures included discarding the first five volumes of each run, slice scan time correction, head motion correction, and image normalization using an EPI template from the Montreal Neurological Institute (MNI) atlas space. Temporal filtering (band-pass) was between 0.01 and 0.08 Hz, and the mean signal was removed.Functional MRI data preprocessing followed typical preprocessing procedures using SPM8  and NIT1.2  between x0 and the closest neighboring voxels. The correlation threshold of R = 0.6 was used following the standard data processing procedure [r0j was greater than R, xj was then added to the list of functionally connected voxels. This procedure of data calculation was repeated for the next neighbors in the list. When no new neighbors were available, the number of elements in the list of neighbors (k) was defined as the lFCD of x0. Then, the calculation was initiated for another x0. This procedure of data calculation was performed for all x0 voxels. Finally, the individual lFCD maps were normalized to the mean value of each individual map and then spatially smoothed using an FWHM of 8 mm.The calculation of lFCD followed the standard data analysis procedure used in previous research , 35. Forrocedure . If r0jp < 0.05 and a cluster threshold k > 20.To investigate whether the brain enhancement observed in the top-ranking players was correlated with their e-sports experience, we examined Pearson correlations between the lFCD and the rank level—a comprehensive score assigned by the gaming software based on players' gaming experience. Multiple comparisons were corrected according to the FDR with Comparative analyses showed that the top-ranking players had a significantly higher level of lFCD in the integrative brain regions  than the lower-ranking players. However, an opposite pattern of results emerged in the primary input-output regions . See Among the top-ranking players, there was a significant, positive correlation between their rank level and lFCD in the brain regions  that are responsible for higher-level cognitive functions such as analyzing and integrating information from different sources. However, there were no significant associations in the primary brain regions. See This study found that the top-ranking players had increased lFCD in bilateral DLPFC compared to the lower-ranking players. Furthermore, among the top-ranking players, their degree of increase in lFCD was associated with their LOL ranking data assigned by the gaming software. This finding suggested that the top-ranking players' LOL experience was related to the plasticity of lFCD. The increase in lFCD may indicate an enhanced local functional integration, supporting the top-ranking players' advanced skills in LOL gaming. Furthermore, the current findings suggest that bilateral DLPFC may be important for the top-ranking players' acquisition of e-sports expertise. Since bilateral DLPFC is essential for central executive network (CEN), the enhanced lFCD observed in bilateral DLPFC may support the top-ranking players' superior integration of CEN, which can improve various subprocesses including updating information, shifting attention, and inhibiting responses, facilitating cognitive control, and executive function , 37. Thedefault mode areas, including the bilateral PCC, parahippocampal gyrus, and right angular gyrus. Furthermore, the enhancements observed in the top-ranking players' DMN areas were also related to their rank level assigned by the LOL gaming software—an objective reflection of the players' gaming experience and expertise . Thus, the findings revealed a relationship between e-sports experience and the plasticity of default mode areas. Nevertheless, research has demonstrated that DMN is an intrinsic network that tends to be activated in the resting-state but deactivated during the cognitive task [This study also found that the top-ranking LOL players had enhanced local functional integration in ive task . Unlike ive task , 39, 40,ive task . For exaive task ). Thus, ive task . Howeverive task –45.local connectivity. Our analyses of the global connectivity measures  did not reveal significant results depending on the participants' LOL experience, which may suggest that LOL experience facilitates the specific brain networks, which are closely related to LOL gaming, more than the global brain connectivity.Nevertheless, this study focuses on the relationship between LOL experience and the plasticity of This study investigated the relationship between e-sports experience and neural plasticity. Results showed that compared with the lower-ranking players, the top-ranking players had a higher level of lFCD in the executive areas, which may be related to their superior action skills in e-sports. More importantly, the top-ranking players also had a higher level of lFCD in the DMN compared with the lower-ranking players. The enhancement of DMN may be related to their advanced strategization skills in e-sports. To our knowledge, the present study is the first to show that e-sports experience is related to enhanced local functional integration in default mode areas.


This meta-analysis evaluated the efficacy of behavioral classroom programs on symptoms of Attention-deficit Hyperactivity Disorder or Oppositional Defiant and/or Conduct Disorder in primary school children.N = 18,094), comparing behavioral classroom programs  to no treatment/treatment as usual. Random-effects meta-analyses were conducted for teacher-rated and classroom-observed disruptive classroom behavior and for classroom-observed on-task behavior. Post-hoc analyses investigated whether effects depended on type and severity of problem behavior. Meta-regressions studied the moderating effects of age, gender, and intervention duration.Online database searches  yielded nineteen randomized controlled trials (d = -0.20) and classroom-observed on-task behavior (d = 0.39). Program effects on teacher-rated disruptive behavior were unrelated to age, gender, type and severity, but negatively associated with intervention duration (R2 = 0.43).Small positive effects were found on teacher-rated disruptive behavior (Behavioral classroom programs have small beneficial effects on disruptive behavior and on-task behavior. Results advocate universal programs for entire classrooms to prevent and reduce disruptive classroom behavior. Attention-Deficit Hyperactivity Disorder (ADHD) and Disruptive behavior disorders are two of the most common psychiatric disorders in children , 2 and cMedication is commonly used to effectively reduce the core symptoms of ADHD and to reduce severe and persistent aggression. However, 20–30% of children with ADHD using psychostimulants fail to show symptom improvements or suffer from adverse side effects such as insomnia, headache or loss of appetite , 11 and Behavioral programs are often used at school to address disruptive classroom behavior. The majority of these programs use antecedent techniques to prevent behavioral problems (e.g. by clear rules and effective instructions) and consequent techniques to reinforce appropriate behavior and reduce inappropriate behavior (e.g. by reward systems and time-out systems). The Summer Treatment Program, for example, contains a behavioral classroom program for children with ADHD, in which positive reinforcement is used within classroom-settings and during activities outside the classroom such as during sports . The GooSeveral reviews and meta-analyses have addressed the efficacy of behavioral classroom programs on disruptive behavior, and on ADHD symptoms in particular , 15–28. Our study contributes to the literature with a comprehensive quantitative meta-analysis of all available RCTs into the effects of behavioral classroom programs in primary school, including multimodal programs that involve a behavioral classroom program. Our focus was on disruptive behavior in the classroom, as assessed by teachers and classroom observations, and on classroom-observed on-task behavior. Based on earlier work, significant intervention effects were expected for disruptive behavior rated by teachers as well as independent classroom observations . HoweverThis meta-analysis was performed in conformity with the guidelines provided by the PRISMA group  [This meta-analysis included efficacy studies on behavioral classroom programs that met the following inclusion criteria: the study (1) was a randomized controlled trial assessing the effects of behavioral classroom programs compared to ‘no care’ or ‘care as usual’. Behavioral programs were defined as programs using behavioral techniques on a daily basis (e.g. token economy). To incorporate all available RCTs on the efficacy of behavioral classroom programs in this meta-analysis, more comprehensive treatment programs  that used a behavioral classroom program as one of the main elements were also included; (2) included one of the following outcome measures: (a) disruptive classroom behavior  as assessed by validated teacher ratings or classroom observations by an independent rater, or (b) classroom-observed on-task behavior. Studies that only assessed disruptive behavior at the classroom level  rather than disruptive behavior of individual children were not included; (3) included predominantly elementary school children as participants (6–12 years old on average) in regular education or school-related settings, regardless of severity of problem behavior  and (4) were published between 1980 and 1DSM-III) . StudiesDSM-III) , 47) or DSM-III) , 49. If To identify relevant articles for this meta-analysis, the electronic databases PubMed, Embase, Psycinfo and Eric were searched. Search terms and equivalent mesh terms describing participants’ problem behavior  were combined with the term ‘classroom interventions’ and related terms (e.g. ‘teaching method’), which were applied to both titles and abstract  or on type of sample . In clinical samples, all participants or a large majority thereof (≥85%) met diagnostic criteria for one or more externalizing behavior disorders. At-risk samples consisted of participants with elevated levels of disruptive behavior problems at school as assessed in each study. In community samples, non-selective samples were studied including entire classrooms or entire schools.Gender was defined as percentage of male participants in the study sample. Age was defined as the average age (in years) of the study sample at baseline. If age was not reported (in 8 of the 19 studies), an estimation of age was made based on participants’ grade levels , takingThe quality of the studies was assessed by two independent researchers (BV and ML) using the Jadad criteria  that incd) were calculated for the effects of the behavioral program within each study for each dependent variable by using the mean, SD and sample size of both groups (intervention and control) at baseline and the follow-up assessment. The pooled SD was weighted by its inverse variance to control for sample size and measurement error [SDs without any covariates when available. If mean, SD, or sample size information were not available, the t-value of the effect of the intervention on the dependent variable was calculated by dividing the regression beta coefficient of the group x time interaction by its standard error [z score was calculated using the correlation-value of each dependent variable together with the sample size, which were then converted into Cohen's d [Statistical analyses were performed using Comprehensive Meta-Analysis . Effect nt error . In orderd error , or the ohen's d . For stuohen's d .First, we investigated meta-analytic effects of behavioral classroom programs on (1) disruptive behavior, distinguishing between teacher-ratings and classroom observations, and on (2) on-task behavior as measured by classroom observations. To test whether the meta-analytic results on these outcome measures were confounded by baseline behavior differences between groups, sensitivity analyses were conducted excluding those studies reporting behavior differences at baseline  or program components other than behavioral techniques . One meta-analysis was performed on intervention studies that only involved behavioral components, thus excluding studies into programs that also comprised other treatment components see . AnotherIn case of significant intervention effects, several post-hoc analyses were performed to investigate for whom and under which conditions behavioral classroom programs would be most effective. These analyses were only performed on teacher-rated disruptive behavior, as the number of available studies were too limited to carry out these analyses for the other outcome measures. Firstly, program effects were assessed separately for symptoms of ADHD and for ODD/CD to investigate whether effects depended on type of problem behavior. Secondly, the potential moderating effect of severity of problem behavior was investigated by comparing the type of samples  through a Q-between test, using the nature of the sample as a nominal variable . This anQ and I2 tests were used to test the assumption that the data were heterogeneously distributed. The threshold for performing a meta-analysis was set at the frequently-used limit of three studies [d = 0.20, 0.50, and 0.80 into thresholds for small, medium, and large effects, respectively [Given the heterogeneity between trials , the random-effects model for heterogeneously distributed data was used to calculate meta-analytic effect sizes . Q and I studies , 74. Effectively . NegativN to determine the number of studies necessary to nullify the overall effect and linear regression methods to examine the degree of funnel plot asymmetry [α was set at 0.05.For all meta-analyses, the possibility of publication bias was assessed through Rosenthal’s fail-safe symmetry , 77. To symmetry . SignifiSD = 0.58; range 49–53), whereas in studies using clinical or at-risk samples, percentages of male subjects were on average 75% . While all studies predominantly involved primary school children, seven studies also included children from kindergarten and one study included children from middle school. All studies used behavioral programs as main element of their program, but some studies additionally included cognitive behavioral elements (n = 9), social skills training (n = 5), peer tutoring (n = 5), academic assistance (n = 2), problem solving training (n = 2), or sport skills training (n = 1). Eleven programs were multimodal, of which seven involved a parent training, one involved a child training, and three involved both a parent and child training.A total of 18,074 children from 19 different studies were included in this meta-analysis. Study characteristics are displayed in d = −0.20, p < 0.001), indicating that behavioral classroom programs resulted in larger reductions of disruptive behavior compared to no treatment or treatment as usual. The sensitivity analysis on studies without significant group differences in baseline level of problem behavior revealed a similar significant effect that was somewhat smaller . For classroom observations, no significant beneficial effect was found on disruptive behavior .A total of 17 studies investigated the efficacy of behavioral programs in reducing disruptive behavior through teacher-ratings and three studies used classroom observations by an independent rater as the dependent measure. Results are shown in d = -0.24, p = .01). The separate meta-analysis on the studies that were confined to classroom programs without interventions in other settings (e.g. parent programs), also revealed a significant effect . These meta-analytic findings confirm the robustness of the positive effects of behavioral classroom programs on teacher-rated disruptive behavior.The additional meta-analysis on intervention studies that only involved behavioral management  yielded a significant small effect , but this bias seemed unlikely based on Rosenthal’s fail-safe N statistic which showed that 176 studies were necessary to bring the p-value above the alpha-level of .05. There was no evidence of publication bias for classroom-observed disruptive behavior, . Between-study heterogeneity was significant in the meta-analyses on teacher-rated and classroom-observed disruptive behavior, supporting the use of random effects meta-analyses. Study quality was not significantly associated with the studies’ effect sizes for teacher-rated disruptive behavior .For teacher-rated disruptive behavior, indications of a publication bias were found based on Egger’s regression . A sensitivity analysis on four of these studies that showed no baseline group differences revealed identical findings . There was no evidence of publication bias . Between-study heterogeneity was significant.Meta-analytic results of six studies using classroom observations to assess on-task behavior, reported a significant beneficial effect that was small in size  and teacher-rated ODD/CD symptoms . No indications for publication bias were found for the meta-analytic effect sizes for teacher-rated symptoms of ADHD and ODD/CD based on Rosenthal’s fail-safe N , but Egger’s regression did suggest an asymmetric funnel plot for both outcome measures . Between-study heterogeneity was significant for teacher-rated ADHD, and close to significant for teacher-rated ODD/CD (p = .05).There were nine studies investigating the effects of behavioral programs on teacher-rated ADHD and nine studies assessing the effects on teacher-rated ODD/CD symptoms. Behavioral programs had significant but small beneficial effects on teacher-rated ADHD symptoms , than for clinical and community samples . The between-group comparison was not significant though (Q(2) = 0.95, p = 0.62). There was no evidence of publication bias for at-risk  and clinical samples . For community samples, some evidence of a publication bias was found based on Egger’s regression (p = .01), but not based on the Rosenthal’s fail-safe N statistic (22 studies). Between-study heterogeneity was significant for the community and at-risk sample, but not for the clinical sample.Meta-analytic results on teacher-rated disruptive behavior were calculated for clinical, at-risk and community samples to investigate whether treatment response was stronger for children with higher levels of disruptive behavior compared to children with less problem behavior. Meta-analytic results revealed significant small effects on disruptive behavior in all three samples, although effects were somewhat larger for at risk samples  = 0.006(0.003), p = 0.06, R2 = .22), suggesting larger effects for behavioral programs with a shorter duration. To assess the possibility that this trend was driven by one study [b(SE) = -0.03(0.01), p = 0.02, R2 = .43) in the same direction (see b(SE) = -0.005(0.05), p = 0.91). Furthermore, gender  did not moderate the teacher-rated effect on disruptive behavior (b(SE) = 0.19(0.40), p = 0.64), and similar non-significant effects were found when power was increased by inserting the data for boys and girls separately for two studies reporting gender-specific effect sizes [Meta-regression analyses revealed a negative trend between intervention duration and effect sizes for teacher-rated disruptive behavior . Results confirm our hypothesis that behavioral programs effectively reduce teacher-rated disruptive behavior and improve classroom-observed on-task behavior, albeit with small effects. The effect on classroom-observed disruptive behavior was not significant, but more studies are necessary to confirm these findings given the limited number of studies contributing to this analysis (n = 4). Post-hoc results indicated that behavioral classroom programs had similar positive effects on both teacher-rated ADHD symptoms and teacher-rated ODD/CD symptoms. Furthermore, results suggested that program effects were similar for a wide group of children, irrespective of severity of problem behavior, gender, and age. However, programs of a shorter duration were more effective than lengthier programs.This is the first meta-analysis of RCTs into the efficacy of behavioral classroom programs on elementary school disruptive behavior problems  observed positive effects of behavioral classroom programs. Although these raters did not report positive effects for disruptive behavior, they did report an improvement of on-task behavior. This result implies that children are able to pay more attention to their school work after participating in behavioral classroom programs. Our findings are in line with a recent meta-analysis  demonstrOur results also reveal that behavioral classroom programs were equally effective for clinical, at-risk and community samples, indicating that program effects did not depend on severity of problem behavior. This contrasts with our expectations, because superior program effects were hypothesized for children with clinical levels of disruptive behavior as there would be more room for improvement in these children . Althougacross trials, and thus are unable to take into account the variability of participant characteristics within each study [The absence of a moderating effect of gender was unexpected , becausech study . Individch study , 57 and ch study , 65. FurAgainst our hypothesis, our meta-regression results indicate that behavioral programs with a shorter duration are more effective than more lengthy programs. The unexpected negative association between program duration and effect size might be related to implementation fidelity. Possibly, it was more difficult for teachers to effectively implement more lengthy programs since program implementation often degrades over time and implementation fidelity affects responsiveness to an intervention , 85. UnfSeveral clinical implications of our results need to be mentioned. First, our results suggest that behavioral classroom programs effectively reduce symptoms of ADHD and ODD/CD for a wide range of children differing in age, gender, and sample. These findings suggest that behavioral classroom programs may be used as universal programs for the entire classroom, so that many children will be able to benefit from these programs at the same time. This approach has an advantage over selective programs targeting individual students, which will, in general, be relatively more time-consuming and thus more expensive. Second, the beneficial program effects found in the current meta-analysis were all small, indicating that other types of treatments (e.g. medication) might be needed to normalize problem behavior of these children in the classroom.Some limitations have to be taken into account. First, there was heterogeneity between studies as a result of differences between behavioral programs, sample characteristics, as well as type of instruments. However, our results were bolstered by several additional analyses  and meta-regression analyses showed that the effects on teacher-rated disruptive behavior were unrelated to age, gender, type of problem behavior or clinical status, highlighting the robustness of our findings. Second, the aggregation of measures of ODD and CD into one outcome measure could be disputed due to, for example, gender- and age-specific differences between these two disorders . SeparatOur meta-analysis of 19 RCT studies, including 18,047 elementary school children, showed that behavioral classroom programs result in small but significant improvements of teacher-rated disruptive behavior and classroom-observed on-task behavior at school. Results further suggest that the effects on disruptive behavior are unrelated to age, gender, type of problem behavior (ADHD versus ODD/CD) or clinical status, but that shorter programs are more effective than more lengthy programs. Since the effects of these programs are small, other types of treatments  or enhancement of treatment fidelity might be needed for normalization of disruptive classroom behavior. Nonetheless, our findings confirm that behavioral classroom programs can contribute to a reduction of disruptive classroom behavior for a large group of children, thus helping to prevent escalation of problem behavior in the classroom.S1 Supplement(PDF)Click here for additional data file.S2 Supplement(DOCX)Click here for additional data file.


Oral route maintains its predominance among the ones used for drug delivery, especially when medicines are self-administered. If the dosage form is solid, therapy gains in dose precision and drug stability. Yet, some active pharmaceutical substances do not present the required solubility, permeability, or release profile for incorporation into traditional matrices. The combination of nanostructured drugs (nanoparticle [NP]) with these matrices is a new and little-explored alternative, which could bring several benefits. Therefore, this review focused on combined delivery systems based on nanostructures to administer drugs by the oral cavity, intended for buccal, sublingual, gastric, or intestinal absorption. We analyzed published NP-in-matrix systems and compared main formulation characteristics, pharmacokinetics, release profiles, and physicochemical stability improvements. The reported formulations are mainly semisolid or solid polymers, with polymeric or lipid NPs and one active pharmaceutical ingredient. Regarding drug specifics, most of them are poorly permeable or greatly metabolized. The few studies with pharmacokinetics showed increased drug bioavailability and, sometimes, a controlled release rate. From our knowledge, the gathered data make up the first focused review of these trendy systems, which we believe will help to gain scientific deepness and future advancements in the field. Medicines administered by the oral cavity have different fates, according to their varied processes: (i) immediate delivery and absorption, (ii) slow delivery from an adherent drug delivery system (DDS), followed by absorption or local action; and (iii) transport to the gastrointestinal region for absorption or local action. The latter is the gold standard for medicines and the most common process used for self-administered drug intake. Recently, buccal permeation (items i and ii) strategies increased in number of developments; this route bypasses hepatic and gastrointestinal effects, which is advantageous to sensitive drugs .Regardless of the process, drug solubility can impair efficient release from DDS and subsequent mucosal crossing. Therefore, several solubilization strategies are available, such as salt forms of active molecules, pH modifiers, cosolvents, amorphization, solid dispersions, inclusion complexes, microemulsions, and nanotechnology . The latIn addition to the solubility enhancement, nanoparticles (NPs) aid drug efficacy in at least four different ways Figure 1ex vivo test . Combined systems resulting in nanosized carriers (NP-in-NP) were not included in this work. Based on the theoretical analysis, we intend to verify and clarify matrix role on permeation and bioavailability of nanocarriers.Considering all points above, this review intends to analyze pharmacokinetic improvements with the use of NPs incorporated in matrices for drug delivery (NP-in-matrix). Therefore, we focused here on pharmacokinetic data from animal and humans (when available). Several NP-in-matrix systems were tested only with in vivo tests must be a final step toward product development. It should succeed an extensive physicochemical characterization, together with promising in vitro data assessing biorelevant properties. in vivo parameters related to pharmacokinetics, together with drug and NP predictors. Because matrix-based formulations aid mainly in absorption, this process will be discussed in more detail below.Pharmacokinetics describes absorption, distribution, metabolism, and excretion processes after drug intake. This knowledge remains essential for safety and efficacy assessments of the therapy in the search for the optimal DDS. However, In vivo absorption is generally better predicted by ex vivo mucosal permeation than in vitro tests with synthetic membranes; the extracted tissue offers a biochemical, anatomical, and structural resemblance to its in vivo counterpart that is difficult to replicate  and subsequent cellular uptake for transcytosis  or paracellular transport. eplicate .in vivo intestinal permeability stressed the test fragility. Based on several studies, the authors concluded that the model is applicable to hydrophobic drugs but fails to predict hydrophilic molecule absorption. Even with hydrophobic drugs, variability is high yet minimized with internal standards. The paracellular route and active transport seem to correlate with higher variability and in vivo–in vitro lack of correlation  promoted different ex vivo permeation profiles with predigestion, showing its relevance for in vivo prediction , the highest drug level detected (Cmax), and the time the latter happened (tmax). On the other hand, NPs are seldom classified based on plasma levels. Nanoparticle tracking relies mainly on marked particles with fluorescent dyes to observe biodistribution in tissues. An important reminder is that plasma levels do not discriminate buccal from gastric or intestinal absorption.Drug/NP in vivo pharmacokinetic data of NP-in-matrix DDSs. The NP type directed subdivisions based on their main constituent. Exact values and formulation details are presented in The following items present a discussion of all articles we could find with via desorption without significant burst effects  indicated that the gelling agent delayed carvedilol release, which diminished burst. FG1 gel contained hydroxypropyl methylcellulose (HPMC), whereas le FG2 presented the same HPMC concentration and sodium carboxymethylcellulose. Rabbits treated with FG2 formulation showed a two-fold increase in relative bioavailability compared to the market product. The increase in bioavailability occurred probably due to NP enhancement in drug solubility and the buccal bypass of the first-pass effect , often combined with glycolide to form the hydrophobic copolymer poly(lactic-co-glycolic acid) (PLGA) ; PLGA exIn vitro studies showed that film formulations prolonged drug liberation in a composition-dependent mode. The results of ex vivo studies with rabbit buccal mucosa showed that these nanospheres can permeate the tissue. In vivo results confirmed the predictions, whereas male rabbits demonstrated an increased drug bioavailability with the NP-in-film strategy. After incorporating NPs in polymeric films, the bioadhesive properties increased the residence time in oral cavity. It was also observed that Cmax, AUC, and tmax improved with the use of combined systems when compared to controls  indicated superiority of NP-in-tablet system. The improved drug bioavailability may enhance the therapeutic effects  to load lipidic self-nanoemulsions (SNEs) of finasteride. Different from the mucoadhesive sponges, the freeze-dried tablets melt on the mouth upon contact with saliva. These macrocarriers aim as fast release as possible for buccal and gastrointestinal absorption. Both formulated tablets (with or without SNE) presented in human higher  effects .1 was also incorporated into regular tablets, but with different vitamin loadings. Because SNEs form nanoparticles upon contact with gastrointestinal fluid, NP deformation was not a concern. Beagle dogs administered with SNE-in-tablet showed a 2.3-fold increase in vitamin K1Cmax and 1.98-fold in AUC , when compared to the free suspension drug. Also, the matrix did not interfere with Cu B-micelles original structure  of the free base drug after administration of a single oral dose in mongrel dogs; however, NP-in-microparticle alginate/chitosan particles performed much better than pure nanocrystals . This represented an increase of the oral bioavailability and the apparent t½ of 47 and 95 times, compared to the free drug. The increment in release time may improve HIV treatment, which demands long-term therapy and frequent dosing  and t dosing . Likewist dosing .® tablets)  compared to the free prodrug  . Nekkant prodrug .Cmax of the buccal patch was 7.3 times higher than that of the oral tablet, and tmax exhibited by the patch was 4 h in comparison to 2 h for oral tablet. The NP-in-microparticle structured buccal patch has been designed as a novel platform for potential buccal delivery of drugs having high first-pass metabolism  compared to Tricor (654.6 ± 251 µg·h/mL) and pristine FNB (514.8 ± 374 µg·h/mL); and the tmax (h) of OSFs was found to be 2 h earlier than the tmax of Tricor and pristine FNB  and the third received the oral striped-films containing fenofibrate nanocrystals (OSF). Pharmacokinetics data showed a higher tine FNB .tmax, and bypassed first-pass metabolism . Thus, the systemic bioavailability of the tested drugs was successfully enhanced.Because most of the articles we gathered date from this decade, NP-in-matrix approach still has a long way for exploitation. In our findings, most matrices belong to the polymeric group, based on classical excipients in the market, like HPMC. However, they vary from buccal to oral delivery, with rapid or slow degradation to offer an immediate or modified release. The use of an external matrix to incorporate nanoparticles brought several advantages to formulations. This type of system reduced burst effect, avoided NP degradation in gastrointestinal tract, increased residence time in the mouth, modulated Buccal release belongs to the trending strategies for drugs, so we expect an increase in pharmacokinetic studies concerning NP-in-matrix buccal delivery. Nanoparticle types will probably expand too, as the actual group is mainly PLGA, nanocrystals, and some lipid particles. In summary, we believe this article compiled several evidences and possible pitfalls of this strategy, which will help future developments on the field.RC: synthetic polymeric NP-in-matrix research and writing. DG— inorganic NP-in-matrix research and writing. VB-d-A: lipidic NP-in-matrix research and writing. JC: tables, figures and conclusion. LO-N: review design, introduction and pharmacokinetics writing, scientific revision.FAPESP 14/14457-5 - article charges funding CAPES 001 - scholarships for graduate students . This study was financed by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001 and FAPESP project 2019/08281-5 and 2019/19696-1.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.


Recently, LIBRA, a tool for active/ligand binding site prediction, was described.LIBRA’s effectiveness was comparable to similar state-of-the-art tools; however, itsscoring scheme, output presentation, dependence on local resources and overallconvenience were amenable to improvements. To solve these issues, LIBRA-WA, a webapplication based on an improved LIBRA engine, has been developed, featuring a novelscoring scheme consistently improving LIBRA’s performance, and a refined algorithm thatcan identify binding sites hosted at the interface between different subunits. LIBRA-WAalso sports additional functionalities like ligand clustering and a completelyredesigned interface for an easier analysis of the output. Extensive tests on 373apoprotein structures indicate that LIBRA-WA is able to identify the biologicallyrelevant ligand/ligand binding site in 357 cases (∼96%), with the correct predictionranking first in 349 cases . The earlierstand-alone tool has also been updated and dubbed LIBRA+, by integrating LIBRA-WA’simproved engine for cross-compatibility purposes.http://www.computationalbiology.it/software.html.LIBRA-WA and LIBRA+ are available at: Bioinformatics online. In recent years, structure-based protein function recognition has gained renewed interestdue to the availability of a large number of experimental protein structures, determinedwithin the context of structural genomics initiatives, whose function is unknown , RMSD value, and the relative size of the clustercontaining the ligand. A detailed description of the calculation of this combined score isprovided in the E.coli adenylate kinase (apoprotein PDBcode 4AKE) which, upon ADP binding undergoes a large conformational change (holoprotein PDBcode 2ECK). Therefore, the program does not identify the ADP binding site contained in thedatabase entry 2ECK as a correct match. Nonetheless, it correctly identifies the ADP bindingsite in the input protein by virtue of the structural similarity with the ADP binding siteof the human kinesin-8 motor domain (PDB code 3LRE). As detailed in the E.coli adenylate kinase and the human kinesin-8 motor domain do notdisplay a similar fold and share a non-significant 11% sequence identity. A combinedexecution of LIBRA-WA using both the ligand binding sites and the catalytic sites databasesallows a user to obtain information on both the location of the binding site, the identityof the ligand(s) and, in case the input protein is an enzyme, its catalytic activity, andthus assign a function to the input protein with high confidence. For example, on theE.coli adenylate kinase and using the ligand binding sites database,LIBRA-WA detects as first hit an ADP binding site similar to that of the kinesin-8 motordomain. However, an execution using the catalytic sites database detects as first hit acatalytic site similar to that of Bacillus stearothermophilus adenylatekinase (PDB code 1ZIO). Combining the two information together leads to a highly reliablefunction prediction for the input protein.The effectiveness of LIBRA-WA has been tested on the LigaSite set. A detailed analysis ofthe results is reported in In this paper, the development of LIBRA-WA, a web application based on an improved LIBRAengine has been described. By employing an enhanced, composite scoring system, in LIBRA-WAboth precision and recall are significantly improved with respect to LIBRA, as it can beclearly seen from the results of the extensive tests detailed in Conflict of Interest: none declared.Supplementary DataClick here for additional data file.


In silico meta-analysis was performed on 15 male malignant and five benign tumor cohorts (2928 karyotypes) extracted from the Mitelman Database, comparing their ploidy and combinations of sex chromosomes. A distinct near-triploid fraction was observed in all malignant tumor types, and was especially high in seminoma. For all tumor types, X-chromosome doubling, predominantly observed as XXY, correlated strongly with the near-triploid state , negatively correlated with near-diploidy, and did not correlate with near-tetraploidy. A smaller near-triploid component with a doubled X-chromosome was also present in three of the five benign tumor types, especially notable in colon adenoma. Principal component analysis revealed a non-random correlation structure shaping the X-chromosome disomy distribution across all tumor types. We suggest that doubling of the maternal genome followed by pedogamic fusion with a paternal genome  associated with meiotic reprogramming may be responsible for the observed rearrangements of genome complements leading to cancer triploidy. The relatively frequent loss of the Y-chromosome results as a secondary factor from chromosome instability.Triploidy in cancer is associated with poor prognosis, but its origins remain unclear. Here, we attempted to differentiate between random chromosomal and whole-genome origins of cancer triploidy.  Aneuploidy  is a well-known hallmark of malignant tumors and is generally associated with their aggressive development ,2. With It therefore appears that an exit from the “blind corner” of Muller’s ratchet may be provided by the option for the aneupolyploid genome to convert chaos into order using the ploidy cycle as it operates with the genome complements, in contrast to the mitotic cycles, whose task is to orderly segregate chromosomes. The reproductive ploidy (life) cycles are doubling and halving the whole genome complements in order with the help of meiosis, performing recombination and reduction ,24. The Among aneuploidies of solid tumors, a near-triploid karyotype is often a hallmark of chemotherapy resistance and thus of increased survival potential ,30. We pHere, we decided to use the advantage of the presence of two different sex chromosomes, X and Y, in a normal diploid male karyotype, in an attempt to differentiate between two potential constituents of tumor near-triploidy: The chromosomal aberrations and the rearrangements of the whole-genome complements. For this purpose, we performed an in silico meta-analysis of the male tumor karyotypes deposited in the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer .The karyotypes from 15 male malignant solid tumor types (untreated and presented in the >50 number of cases), epithelial and mesenchymal, somatic and germinative, and karyotypes from five benign tumor types were obtained from the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer  in the pThe tumor nomenclature used was based on the International Classification of Diseases for Oncology (ICD-O), the Systematized Nomenclature of Medicine (SNOMED), and the WHO Classification of Tumours of Soft Tissue and Bone—the same sources as the Mitelman database’s nomenclature. Seminoma was the germ cell tumor. Among somatic tumors, the lung carcinoma cohort included a total of five lung tumor types , united from the evidence that both bronchoepithelial and neuroendocrine lung stem cells likely have one common precursor . The gasThe 2013 edition of the International System for Human Cytogenetic Nomenclature (ISCN) defines near-triploidy as a modal chromosome number that falls in the 58–80 range . In our Principal component analysis (PCA) was applied to the X-chromosome disomy (#X-disomy) distribution across different tumor types in order to check for the departure of the #X-disomy patterns from randomness . The depIn all examined malignant solid tumor types, listed in It is seen that they include near-diploid karyotypes, near-triploid karyotypes, a degree of tetraploidy (high in rhabdomyosarcoma), and in some cases also hyper-tetraploid karyotypes. The near-triploid karyotypes were present in all malignant tumor types. Their percentage share for malignant tumor types 1–15 is presented in We also analyzed the sex chromosome sets with #X-disomy, which are presented alongside their percentage for each malignant tumor cohort in Further, we compared the relationship of the karyotypes exhibiting #X-disomy with different ploidy ranges of the modal chromosome numbers for all malignant tumors and for only somatic tumor cohorts, excluding seminoma. The results of this comparative statistical analysis are shown in r = 0.88; p < 0.001) to the median and widest range, equally  , while in the near-tetraploidy range .Strikingly, in spite of the many-fold differences in the proportions of the near-triploid karyotypes among 15 malignant tumor types, taken together, they provided a very high Pearson correlation between #X-disomic sex chromosome karyotypes and all tested ranges of near-triploidy, from the narrower range (< 0.001) A–C. In t< 0.001) D, the cody range E, no corFurther, we examined the influence of different #X-disomic karyotypes on Pearson correlation in the median range of near-triploidy (62–78 chromosomes). The results are presented in r = 0.88, p < 0.001), which remains the same, adding also near-diploid karyotypes with #X-disomy . The loss of #Y from #X-disomic near-triploid and near-diploid karyotypes presented for all malignant tumors in r = 0.54, p < 0.05).The results show a very high contribution of XXY karyotypes A in the X-disomy B. For soThe relationship between near-triploidy (62–76) and all sex chromosome sets is presented in a bar-plot form for all malignant tumors in As triploidy in association with #X-disomy was found in all malignant tumors, we were interested to find out whether these features could also be observed in premalignant somatic lesions. Thus, four available pairs of sufficiently large tumor cohorts were compared: Astrocytoma versus glioblastoma, colon adenoma versus adenocarcinoma, renal adenoma and oncocytoma versus renal carcinoma, and lipoma versus liposarcoma—and salivary gland adenoma was added as the fifth cohort. The results are presented in In colon adenoma and adenocarcinoma, the proportion of #X-disomic karyotypes with near-triploidy was rather high; however, triploidy in adenoma was lower than in colon adenocarcinoma . All triploid colon adenoma karyotypes except one were XXY, while the remaining one was XX,-Y . In astrPCA was applied for the exploration of the X-chromosome disomy (#X-disomy) pattern in order to demonstrate the non-randomness of different #X-disomy categories distribution in near-triploidy across different tumor types. The initial four-dimension space having four different categories of #X-disomy as axes, namely #X-disomy _62–76 (chromosomes), #X-disomy _58–80, XXY+XX,-Y_62–76, and #X-disomy _66–72 and 15 malignant tumor types as statistical units, was submitted to PCA .p < 0.0001) against the null hypothesis of no common factor. As evident from Commenting on the space distribution of #X-disomy for different tumor types, it should be noted that 12 of 14 somatic tumor types form a common “shape” cluster with the germ tumor seminoma underlying a common biological phenomenon. The peculiarity of mesothelioma (Nr 12) may be due to its (still unknown) highly plastic progenitors switching between different phenotypes depending on the local microenvironment . Thus, tIn this study, we hypothesized that tumor near-triploidy, which is associated with chemoresistance, may originate primarily from the rearrangement of whole-genome complements. Therefore, we attempted to differentiate it from aneuploidy resulting from chromosomal aberrations. As a method, we chose to analyze the sets of sex chromosomes in relation to modal chromosome numbers in male tumor karyotypes. Through all analyzed material representing 20 types of 2928 epithelial and mesenchymal, somatic and germ, malignant and benign male tumor karyotypes, we found that near-triploid karyotypes were characterized by X-chromosome disomy. r ~ 0.9, p < 0.001) with triploidy, while PCA resulted in an extremely ordered X- chromosome disomy distribution in the near-triploid space of all tumor types, clearly indicating a departure from randomness.The simplest explanation for #X-disomic chromosomes would be their origin from the mis-segregation of sister chromatids in aberrant mitosis. The random mis-segregation of individual chromosomes is a well-known mitotic aberration in breakage–fusion–bridge cycles. Tumor aneuploidy concerning the re-arrangements of whole chromosomes and near-triploidy, in particular, has been hitherto explained mostly from the position of the random aberrations in mitotic cycles . HoweverIn addition, #X-disomic tumors were clearly repulsing from the near-diploid chromosome range with a strong negative correlation, and thus collectively depart from the null hypothesis of the random origin of X chromosome mis-segregation.It is also worth noting, in addition, that the dominating set of #X-disomy in male cells was XXY, while the XYY sets, which at random would exhibit a 50% possibility, were practically non-existent in the dataset . This indicates that #X-disomy and near-triploidy of male tumor karyotypes are two facets of the same phenomenon, rather than stemming from random aberrant chromosome mis-segregation in a mitotic cycle. p-value, but also constituted a common “shape” cluster in PCA space. So, the identified novel phenomenon of the persuasive link between #X-disomy and near-triploidy dominated by the “feminized” XXY karyotype may not be of mitotic origin. Rather, it may possess meiotic features programmatically directed towards the oogenic pathway.We also found that somatic tumor types and seminoma are not only highly correlated together with #X-disomy related to near-triploidy by the Pearson coefficient and Although the above analysis points towards the concerted mis-segregation of the chromosome complement of the maternal genome, which would be expected in a process similar to oocyte development, the direct data confirming this process have not yet been elaborated. However, the study of Ozery-Flato et al.  on the sHow may this process proceed? XXYY sets could possibly serve as a starting point. A configuration of XXYY sex chromosomes was found to be present in each malignant tumor cohort of our tumor sets (except for gastric carcinoma) and was particularly high in seminoma (10.3%). Although designated as triploid XXY,+Y , occurring here in a parasexual, pedogamic manner, could explain the persuasive formation of XXY triploid karyotypes in a proportion of male tumors. It is schematically presented on The digyny-like process can use meiotic recombination for the effective repair of DNA damage and gene conversion, while the third genome can compensate for recessive lethal mutations . Thus, this variant of the whole genome aberrations in triploid tumors can favor both their perpetuation and chemoresistance. More information on the evolutionary significance of digyny for adaptation to catastrophic environments and the alternation of the digyny cycle with a mitotic cycle in triploid tumors can be found in . APC) function loss occurs in early adenoma, the acquisition of a driver mutation KRAS in late adenoma, while the exaggerated chromosome and microsatellite instability further develops with cancer progression and loss of TP53 function [KRAS2 and TP53 genes was lowest among the DNA near-triploid and highest among the near-diploid cases of sporadic colorectal adenocarcinoma. Deeper investigation into the predictive potential of our findings is needed.Our findings lead us to question if these revelations have any potentially predictive clinical significance. To this end, it is interesting to compare somatic tumors and seminoma, on one side, and colon adenoma and carcinoma, on the other side. function , the secfunction  found thThe analysis of the karyotypes of 15 male malignant tumor types, germ and somatic, from the Mitelman database revealed a very high correlation between Xchromosome disomy (predominantly represented by XXY karyotypes) with triploidy, a negative correlation with near-diploidy, and no correlation with near-tetraploid modal chromosome numbers. In addition, principal component analysis revealed the strongly non-random nature of the #X-disomy and triploidy association and clustering of the germ tumor seminoma with somatic tumors in the PCA space. Collectively, this suggests that the disomy of the X-chromosome and triploidy in the typically XXY karyotypes in male tumors represent two facets of the same biological phenomenon: The rearrangement of the whole genome complements. A hypothesis of a digyny-like process  exploiting the elements of meiosis in reprogrammed tumor cells has been proposed. The analysis of partly defective XXY triploid karyotypes still maintaining #X-disomy allows us to suggest that chromosome instability may be largely secondary to the whole genome complement rearrangements. The potential for clinical predictions based on the comparison of colon adenoma and carcinoma and of seminoma with somatic malignant tumors is preliminarily discussed.


Cryptosporidium is a leading cause of moderate-to-severe diarrhea (MSD) in young children in Africa. We examined factors associated with Cryptosporidium infection in MSD cases enrolled at the rural western Kenya Global Enteric Multicenter Study (GEMS) site from 2008-2012.Cryptosporidium detected in stool by enzyme immunoassay; in a genotyped subset, 81% were C. hominis. Among MSD cases, being an infant, having mucus in stool, and having prolonged/persistent duration diarrhea were associated with being Cryptosporidium-positive. Both boiling drinking water and using rainwater as the main drinking water source were protective factors for being Cryptosporidium-positive. At follow-up, Cryptosporidium-positive cases had increased odds of being stunted , underweight , or wasted , and had significantly larger negative changes in height- and weight-for-age z-scores from enrollment.At health facility enrollment, stool samples were tested for enteric pathogens and data on clinical, environmental, and behavioral characteristics collected. Each child’s health status was recorded at 60-day follow-up. Data were analyzed using logistic regression. Of the 1,778 children with MSD enrolled as cases in the GEMS-Kenya case-control study, 11% had Cryptosporidium contributes significantly to diarrheal illness in young children in western Kenya. Advances in point of care detection, prevention/control approaches, effective water treatment technologies, and clinical management options for children with cryptosporidiosis are needed. Cryptosporidium is an important cause of childhood diarrhea. Research on cryptosporidiosis in countries where it is endemic remains limited; few studies have comprehensively examined risk factors for children in Kenya and similar settings. We examined characteristics associated with Cryptosporidium in children with moderate-to-severe diarrhea in rural western Kenya. We found there is little to clinically distinguish cryptosporidiosis from other childhood diarrhea in the absence of point of care diagnostics. Infants had the highest odds of Cryptosporidium infection; it has been previously established that Cryptosporidium infections in infancy can have severe consequences. Prolonged/persistent duration diarrhea and growth shortfalls were significantly more pronounced among cases with Cryptosporidium. Undernutrition and stunting in children in low- and middle-income countries have predicted decreased cognitive and school performance, thus long-term consequences could be appreciable. Using rainwater as the primary drinking water source and boiling drinking water were protective against Cryptosporidium infection, thus certain water sources may contribute to transmission. Like other studies in Kenya, we predominantly identified Cryptosporidium hominis, an anthropogenic species. Advances in point of care detection, prevention and control approaches, effective water treatment technologies, and clinical management options are needed to mitigate the potentially severe and long-term consequences of Cryptosporidium infection in children. Cryptosporidium was the second-highest enteric pathogen attributable to infant MSD; in GEMS Kenya, Cryptosporidium was a major pathogen across all age groups  [Cryptosporidium was also identified as one of five pathogens with the highest attributable burden of infant diarrhea in a study of malnutrition and enteric disease (MAL-ED), a cohort study that compared diarrheal and non-diarrheal stools in children under two years old collected at community surveillance visits at 8 sites in South America, Africa, and Asia [Cryptosporidium in young children in sub-Saharan Africa [Cryptosporidium infections are estimated to cause 48,000 annual deaths in children under five years old [The Global Enteric Multicenter Study (GEMS) was undertaken to assess the burden and etiology of moderate-to-severe diarrhea (MSD) in seven countries, three in South Asia and four in sub-Saharan Africa. In all African sites, Cryptosporidium infections in young children in low- and middle-income countries have been associated with excess mortality [Cryptosporidium has been associated with decreases in height-for-age z-scores in children, even in the absence of diarrhea symptoms [Cryptosporidium infections have been associated with persistent diarrhea in Kenya [Cryptosporidium is highly tolerant to disinfection with chlorine [ortality , an exceortality , and groortality . Cryptossymptoms . Cryptosin Kenya ,9. Cryptchlorine .Cryptosporidium; however, the evidence of acquired immunity suggests that one could be effective [Nitazoxanide can treat cryptosporidiosis in immunocompetent children 1–11 years old  and is pffective .Cryptosporidium in developed countries have been studied in detail, less is known about risk factors for cryptosporidiosis in countries where it is endemic [Cryptosporidium infection identified malnutrition, contact with domestic animals, non-exclusive breastfeeding in infants, lack of sanitation facilities, and crowded living conditions as possible risk factors for infection in low- and middle-income countries [Cryptosporidium infection in Kenyan children [Cryptosporidium in children include being HIV-positive [Although outbreaks of  endemic . Reviewsountries ,14. Few children –17. In Kpositive .Cryptosporidium infections in Kenyan children under five years old with MSD, assess clinical, environmental, and behavioral characteristics associated with Cryptosporidium infection, and describe the outcomes and consequences of cryptosporidiosis.We describe the prevalence of We evaluated data collected in Kenya from cases enrolled in GEMS, a four-year, prospective, age-stratified, health facility-based matched case-control study of MSD among children aged 0–59 months residing within a defined and enumerated population. The rationale, study design, clinical and microbiologic methods, and assumptions of GEMS have been described elsewhere ,19. BrieCryptosporidium oocyst antigens were detected in whole stool specimens by enzyme immunoassay . Detailed laboratory methods are described elsewhere [Cryptosporidium. Restriction fragment length polymorphism analyses and DNA sequencing of polymerase chain reaction (PCR) products were used to identify Cryptosporidium genotypes for these specimens at the U.S. Centers for Disease Control and Prevention (CDC) [At enrollment, demographic, clinical, epidemiological information, and stool samples were collected. lsewhere . DNA wason (CDC) .To assess each child’s health status, a home visit including focused physical exams and anthropometric measurements was conducted ~60 days (acceptable range 50–90 days) following enrollment. Mortality that occurred at any time between enrollment and this follow-up was recorded.In Kenya, children were enrolled between January 31, 2008 and January 29, 2011, and again from October 31, 2011 to September 30, 2012. The study was conducted in Siaya County, in the areas of Gem and Asembo, and during the second enrollment period, in the areas of Asembo and Karemo due to the Kenya Medical Research Institute (KEMRI)/CDC health and demographic surveillance system moving activities. This health and demographic surveillance system has been operating in these communities since 2001. The study setting has high rates of child mortality, malaria, HIV, and tuberculosis, and has been described elsewhere ,22.Acute diarrhea was defined as having 1–6 days of diarrhea in the 21-day period; having 7–13 and ≥14 days refer to prolonged and persistent diarrhea, respectively.At enrollment caretakers were (1) asked how many days the case child had been experiencing diarrhea in the week before presenting at the health facility and (2) instructed on how to record the presence/absence of diarrhea for 14 days following enrollment on a Memory Aid form . The totHeight and weight for each child were measured at enrollment and at 60-day follow-up; details on measurement methods are described elsewhere . Height/A subset of cases and their biological mothers had HIV status captured. Children ≥18 months old had a rapid HIV antibody test and children <18 months old had a confirmatory PCR test. Persons identified as HIV positive were referred to care and treatment.Surface water was defined as drinking water coming from a pond, lake, river, stream, or dam, as is standard practice , or watePartial breastfeeding refers to providing children with breast milk and supplementing with other food or liquid, whereas exclusive breastfeeding refers to providing children only breast milk without supplementation.Cryptosporidium positivity, univariable logistic regression models were used to compute odds ratios (ORs) and 95% confidence intervals (CIs). Since Cryptosporidium risk factors may be modified by age and the sample size might limit detection of interactions, we assessed for effect modification by age category for all variables in separate models with a p<0.05 cutoff for significance. To assess whether each risk factor was confounded by socioeconomic status (SES) we ran models with and without SES and considered confounding if effect sizes changed >10%.Analyses were performed in SAS 9.4  and R 3.4.0 . To assess variables associated with Cryptosporidium-positive. The first model examined the clinical presentation at enrollment of case children, including age strata and sex  and the interaction was significant at alpha<0.05, results were stratified accordingly.For anthropometry analyses, effect modification by age and sex was assessed by including interaction terms one-by-one into the models. If interaction could be assessed  who were only enrolled as a case once. We also compared athogens  Tables.Written informed consent was collected from all parents of children who participated in GEMS. The GEMS protocol was approved by the Scientific and Ethical Review Committees of KEMRI (Protocol #1155) and the Institutional Review Board (IRB) of the University of Maryland School of Medicine, Baltimore, MD, USA (UMD Protocol #H-28327). CDC  formally deferred its review to the UMD IRB (CDC Protocol #5038).Cryptosporidium was identified in 195 cases (11.0%). Cryptosporidium infections were more frequently identified in infants (<12 months old), with a peak in Cryptosporidium infection at 6–11 months old . Other demographic and household characteristics were similar between Cryptosporidium-positive and Cryptosporidium-negative cases . Only age category and mucus in stool remained in the final multivariable clinical model (not presented). The findings were the same when children who were enrolled multiple times as a case were excluded. Having mucus in the stool remained significantly associated with Cryptosporidium infection controlling for age .The clinical presentation of  similar . Mucus iCryptosporidium-positive cases with daily information on diarrhea experienced prolonged or persistent diarrhea, compared to approximately half (51%) of Cryptosporidium-negative cases ; cases experiencing persistent diarrhea were also significantly more likely to be Cryptosporidium-positive compared to cases experiencing acute diarrhea .Approximately two-thirds (66%) of ve cases . CompareCryptosporidium and stunting/severe stunting. Among girls, Cryptosporidium-positive cases had significantly greater odds of being stunted at baseline than Cryptosporidium-negative cases . There were no other statistically significant differences in malnutrition indicators between Cryptosporidium-positive and Cryptosporidium-negative cases at enrollment , underweight , or wasted  compared to Cryptosporidium-negative cases, controlling for baseline status for each measure  were HIV-positive, compared to 3.0% (28/932) of Cryptosporidium-negative cases (p = 0.39). There was no significant association between being Cryptosporidium-positive and having an HIV-positive biological mother .HIV status was available for 58.8% of GEMS-Kenya cases. Of the 114 Cryptosporidium-positive and Cryptosporidium-negative cases (Most children under two years old (81.4%) were partially breastfed. Breastfeeding was similar between ve cases .Cryptosporidium-positive cases and Cryptosporidium-negative cases who were hospitalized at enrollment . Among those with 60-day follow-up information, 9 (4.8%) of 187 Cryptosporidium-positive cases and 53 (3.5%) of 1,531 Cryptosporidium-negative cases died by the time of follow-up (p = 0.35). The cause of death, as per verbal autopsy, for the 9 children who died and had Cryptosporidium identified in their stool was as follows: HIV/AIDS related (n = 5), diarrhea/gastroenteritis (n = 1), pneumonia (n = 1), and anemia (n = 1); one child did not have a verbal autopsy completed.There was no significant difference in the proportion of Cryptosporidium infection .The most common caretaker-reported primary drinking water sources were rainwater (35%), surface water (31%), other improved water sources (23%), and other unimproved water sources (11%); . CompareCryptosporidium infection compared to those who didn’t , predominantly driven by those who boiled water. Only two households reported filtering.Few caretakers of GEMS-Kenya case children reported boiling or using a ceramic filter to treat drinking water; however, those reporting one of these methods had significantly lower odds of Cryptosporidium-positive and Cryptosporidium-negative cases  of these specimens. Of the 43 specimens, 35 (81%) were of the species C. hominis and 6 (14%) were C. parvum. C. meleagridis and C. canis were found in one specimen each.DNA was extracted from a random subset of 64 (40%) of the 160 Cryptosporidium-positive cases, 142 (72.8%) also had one or more additional enteric pathogens identified in their stool; enteric co-infections were common throughout the study population  of genotyped samples were C. hominis. Among MSD cases, being an infant, having mucus in stool, and having prolonged or persistent duration diarrhea were associated with being Cryptosporidium-positive. Boiling drinking water and using rainwater as the main drinking water source appeared to protect against Cryptosporidium infection in MSD cases. Among girls, Cryptosporidium-positive cases were more likely to be stunted at baseline compared to Cryptosporidium-negative cases. Cryptosporidium-positive cases had longer-term consequences in terms of malnutrition, as these children were more likely to stunted, underweight, or wasted at follow-up (controlling for baseline status), and have significantly larger negative changes in height- and weight-for-age z-scores.This study evaluated the clinical, environmental, and behavioral characteristics associated with Cryptosporidium adhering to the small intestine mucosa, possibly causing inflammation [Cryptosporidium-positive and Cryptosporidium-negative cases, as was observed in another study of Kenyan children with diarrhea [Cryptosporidium among children with MSD in this setting and underscores the need for point of care rapid diagnostics for Cryptosporidium.Except for having mucus in stool, which could be associated with ammation , the clidiarrhea . This fiCryptosporidium identified in their stool compared with children aged 24–59 months. The peak of infection at 6–11 months in this study is similar to the age pattern of Cryptosporidium infections previously reported in sub-Saharan Africa, though an earlier peak than other studies in Kenya [Cryptosporidium infections in young children is concerning as Cryptosporidium infections in early childhood have been associated with numerous poor outcomes, sometimes lasting beyond the initial infection [Infants were over three times more likely to have in Kenya . This tinfection , as evidCryptosporidium-positive cases compared to other children with MSD. Prolonged and persistent diarrheal episodes occurring in infants have been previously associated with growth shortfalls [Cryptosporidium-positive cases who were underweight and wasted increased from baseline to follow-up. This could result from many days of diarrhea experienced by these children. There was also an increase in the proportion of Cryptosporidium-positive cases who were stunted from baseline (29%) to follow-up (39%). Undernutrition and stunting among children in low- and middle-income countries have predicted decreased performance in school and on cognitive tests in previous research [Cryptosporidium infections in children [Cryptosporidium-positive and 3.5% of Cryptosporidium-negative cases had died. Although the difference was not statistically significant, this warrants close future attention since other research has shown an association between Cryptosporidium and excess mortality for children who became infected in infancy [Prolonged and persistent duration diarrhea, and growth shortfalls subsequent to enrollment were significantly more pronounced among ortfalls . The proresearch , thus evchildren . By the Cryptosporidium infection in rural western Kenya, since the main host for C. hominis is humans [Cryptosporidium infection . Notably, in another study, C. hominis was associated with more severe clinical symptoms in Kenyan children compared to C. parvum [Like other studies in Kenya ,16,32, os humans . Infectinfection , though Cryptosporidium infections. Rainwater may be less contaminated with Cryptosporidium, or this finding could be related to the seasonality of Cryptosporidium infections. The proportion of households using rainwater as the main drinking water source varied by month, ranging from 3%-74%. We did not explore Cryptosporidium infections by month/season, as the biweekly enrollment targets for GEMS make interpretation of pathogen-specific seasonal analyses challenging. However, the fact that using rainwater as the primary drinking water source and boiling drinking water were both protective against Cryptosporidium infections indicates that drinking water source choices and certain treatment options may be effective in reducing Cryptosporidium infections and signals that water may play a role in transmission.Using rainwater as the main drinking water source was common and was significantly protective against Cryptosporidium-positive GEMS cases and GEMS controls, as reliable population weights were not available at the time of analysis. The factors associated with Cryptosporidium compared to other individuals with MSD may be different from those risk factors that would be seen when compared to healthy controls. Using MSD as a condition for inclusion for our study may lead to spurious associations, as it is potentially a common effect of both the exposures and the outcome of interest [Cryptosporidium infections was limited due to the small number of single-pathogen Cryptosporidium infections; however, those who presented with Cryptosporidium alone had similar characteristics to those who presented with multiple-pathogen Cryptosporidium infections. We were not able to assess the association between breastfeeding and Cryptosporidium because of (1) the collinearity between breastfeeding and age, and (2) the small number of children who were either exclusively or not breastfed in certain age groups. We also could not examine anthropometric outcomes by age or by the number of enteric pathogens isolated in stool, due to the small number of Cryptosporidium-positive children in some age groups and the small number of cases who presented with single-pathogen Cryptosporidium infections. We examined HIV status and malnutrition in our analyses, and performed a sensitivity analysis related to enteric co-infections; however, we did not have information on other co-morbidities that may be associated with Cryptosporidium infection.A limitation of this work is that a comparison could not be made between interest . Our abiCryptosporidium differed between GEMS and MAL-ED, especially for children 1–2 years old; however, GEMS generally considered more severe cases of diarrhea than MAL-ED. Other differences between the studies have been described elsewhere [Cryptosporidium to be significantly associated with diarrhea among infants, there were differences between study sites; in other studies Cryptosporidium has been isolated in non-diarrheal stools as often as in diarrheal stools [e.g., the time from diarrhea onset to stool collection) or laboratory methods may partially explain the differences observed, and host susceptibility and other risk factors are likely to vary across settings [Cryptosporidium infections have been associated with growth shortfalls in asymptomatic children without diarrhea, thus identification and treatment of Cryptosporidium should remain a priority for young children in settings where it is endemic [The burden of diarrhea attributable to lsewhere . While Gl stools ,36. Disssettings . However endemic ,36.Cryptosporidium infections and diarrhea early in life, underscores the need for preventive measures aimed at households with young children, as well as improved diarrhea case management. Early diagnosis and management of cryptosporidiosis may mitigate subsequent growth deficits and other long-term consequences. Increased availability of nitazoxanide or new treatments, point of care rapid diagnostics for Cryptosporidium, additional insights into the role of appropriate WASH practices and technologies in childhood cryptosporidiosis, and vaccine development could reduce the burden of disease in such settings. Since Cryptosporidium-positive cases experienced more days of diarrhea and subsequent malnutrition than other MSD cases, increased promotion of the use of zinc in the management of diarrhea, and continued feeding of children with diarrhea should be undertaken, per WHO/UNICEF guidelines [Cryptosporidium infection among infants should remain a priority.The high prevalence of cryptosporidiosis among young children in our study, coupled with other research that shows extended long-term effects of idelines . As rotaS1 Checklist(DOC)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.


To synthetize the scientific evidence on the association between serum lipids and premature mortality in Latin America (LA).Five data bases were searched from inception without language restrictions: Embase, Medline, Global Health, Scopus and LILACS. Population-based studies following random sampling methods were identified. The exposure variable was lipid biomarkers . The outcome was all-cause and cause-specific mortality. The risk of bias was assessed following the Newcastle-Ottawa criteria. Results were summarized qualitatively.N = 27,903) were included for the synthesis. Three papers reported on the same study from Puerto Rico (baseline in 1965), one was from Brazil (1996) and one from Peru (2007). All reports analysed different exposure variables and used different risk estimates . None of the reviewed reports showed strong association between individual lipid biomarkers and all-cause or cardiovascular mortality.The initial search resulted in 264 abstracts, five (The available evidence is outdated, inconsistently reported on several lipid biomarker definitions and used different methods to study the long-term mortality risk. These findings strongly support the need to better ascertain the mortality risk associated with lipid biomarkers in LA. An unfavourable serum lipid profile such as increased total cholesterol or LDL-cholesterol is an important determinant of cardiovascular diseases causing large negative health consequences in low- and middle-income countries (LMICs) . UnderstEpidemiological studies have reported inconsistent findings about the association between lipids and premature cardiovascular mortality . The ProWe conducted a systematic review of the literature following the PRISMA guidelines . The proWe searched for observational prospective cohort studies without any language restrictions regardless of publication time. The study population comprised of individuals from all LA countries. Studies addressing LA people in foreign countries or foreigners in LA countries were excluded. We aimed for population-based studies which had followed a random sampling technique to select the study population. Hospital-based studies, convenient samples or participants selected based on a diagnosis  or risk factor  were excluded. The exposure of interest was any lipid biomarker, including but not limited to total cholesterol, HDL-cholesterol, LDL-cholesterol or triglycerides.The search was conducted in five data bases: Embase, Global Health and Medline through Ovid, Scopus and LILACS. The search was conducted on December 21st, 2018. No additional sources of scientific information were considered. The search strategy used in these search engines is available in the The search results were downloaded and compiled in EndNote, where duplicates were identified and excluded. A second search for duplicates was conducted online with Rayyan . ScreeniWhen multiple reports were found for one study, the following algorithm was followed to select one report for inclusion in qualitative synthesis: (i) if they reported on different outcomes , then all the reports were included; and (ii) the report which analysed the longer follow-up time was included.With the final list of selected reports, information was extracted onto an Excel sheet developed by the authors before data collection started and was not modified afterwards; this form collected similar information as in The Newcastle-Ottawa Scale was used to assess the risk of bias in the selected reports . The risWe conducted a qualitative synthesis, and where relevant the risk estimates as described in the original report were summarized. No quantitative synthesis such as a meta-analysis was possible to conduct because of the few retrieved reports, which also exhibited large heterogeneity in the lipid biomarkers assessed, outcomes, and statistical methods.This project was classified as non-human subject research. This is a systematic review of published and open information where no human subjects participated. Approval from an IRB/ethics committee was not necessary.N = 27,903)  . Of the  27,903)  and two  27,903)  and Braz 27,903) . Figure Three reports collected baseline data in 1965 , one in Other studies reported mean values. For example, Werle and colleagues studied cardiovascular mortality associated with one-unit change (mg/dL) in LDL-cholesterol , HDL-cholesterol , and Apo-A  . Garcia-p < 0.05) for each mg/dL increase in total cholesterol , we did not systematically search grey literature such as conference abstracts. We argue that, even if these sources had provided additional references, these would contain probably limited information.Although some of the selected studies reported on relevant lipid biomarkers such as LDL-cholesterol, they failed to analyse clinically relevant definitions. For example, Lazo-Porras and colleagues reported on several combinations of lipid metrics , but did not report on high LDL-cholesterol, which happens to be the lipid mainly targeted by pharmacological treatment for cardiovascular prevention .Previous large individual-level meta-analysis have assessed mortality risk associated with one unit change in lipids . In thisThe INTERHEART, a case-control global endeavour studying myocardial infarction, reported that the association between this cardiovascular outcome and total cholesterol as well as non-HDL cholesterol was small in LA, in comparison to other world regions . AlthougStrong scientific evidence is needed to develop successful policies, inform resources allocation, and advance clinical practice. Regarding lipid biomarkers and its associated mortality risk, much research is needed. A proposed call to action for LA is presented in Despite limited scientific research in the field of lipid biomarkers in LA in general, there is a growing interest about this health profile in the clinical and public health communities of LA . This inTo the best of our knowledge, no relevant international organization has set goals, targets or health and research policies for the management and control of lipid biomarkers or dyslipidaemias in LA. Although a group of practitioners and researchers of LA has published a regional consensus highlighting key features of lipid profiles in LA , furtherMost of the risk estimates used in the studies was total cholesterol. This lipid biomarker, although relevant and inexpensive, does not allow to identify whether a reduction of LDL-cholesterol or an increase of HDL-cholesterol is needed. A key determinant of lipid fraction is diet. Certain foods will increase LDL-cholesterol whilst others will improve HDL-cholesterol and viceversa . BecauseOther determinants of lipid profiles are weight status and physical activity, whereby obesity increases LDL-cholesterol and decreases HDL-cholesterol whilst physical activity reduces LDL-cholesterol. Overweight and obesity have dramatically increased across LA in the last decades . Also, aTo date, it is not possible to ascertain the association between lipid biomarkers and mortality risk in LA. The available evidence is outdated, and the definitions of lipid biomarkers are inconsistent. In addition, different methods were used to measure the long-term mortality risk in LA populations. These findings strongly suggest conducting larger studies within the LA population to get valuable risk estimates of the associations between serum lipids and premature mortality.10.7717/peerj.7856/supp-1Supplemental Information 1Click here for additional data file.10.7717/peerj.7856/supp-2Supplemental Information 2Click here for additional data file.10.7717/peerj.7856/supp-3Supplemental Information 3Click here for additional data file.


This paper proposes an emergency Traffic Adaptive MAC (eTA-MAC) protocol for WBANs based on Prioritization. The main advantage of the protocol is to provide traffic ranking through a Traffic Class Prioritization-based slotted-Carrier Sense Multiple Access/Collision Avoidance (TCP-CSMA/CA) scheme. The emergency traffic is handled through Emergency Traffic Class Provisioning-based slotted-CSMA/CA (ETCP-CSMA/CA) scheme. The emergency-based traffic adaptivity is provided through Emergency-based Traffic Adaptive slotted-CSMA/CA (ETA-CSMA/CA) scheme. The TCP-CSMA/CA scheme assigns a distinct, minimized and prioritized backoff period range to each traffic class in every backoff during channel access in Contention Access Period (CAP). The ETCP-CSMA/CA scheme delivers the sporadic emergency traffic that occurs at a single or multiple BMSN(s) instantaneously, with minimum delay and packet loss. It does this while being aware of normal traffic in the CAP. Then, the ETA-CSMA/CA scheme creates a balance between throughput and energy in the sporadic emergency situation with energy preservation of normal traffic BMSNs. The proposed protocol is evaluated using NS-2 simulator. The results indicate that the proposed protocol is better than the existing Medium Access Control (MAC) protocols by 86% decrease in packet delivery delay, 61% increase in throughput, and a 76% decrease in energy consumption. Wireless Body Area Networks (WBANs) offer a paradigm shift towards proactive management and early diagnosis of various diseases. The vital-signs data, such as body temperature, Heartbeat Rate (HR), Respiratory Rate (RR), Blood Pressure (BP), Electrocardiogram (ECG), Electroencephalogram (EEG), Electromyography (EMG), and pH-level are collected and analyzed by the use of different types of Bio-Medical Sensor Nodes (BMSNs) placed on/in the human body, or on wearable clothing. The heterogeneous-natured BMSNs  generate various kinds of data packets containing the vital-signs information. Therefore, traffic prioritization is necessary during channel access due to the heterogeneous nature of vital-signs information –4. Some In WBAN, the patient’s body is observed by heterogeneous-natured BMSNs and thus, the applications consist of heterogeneous traffic rates which become variable in an emergency situation. For example, the BMSNs that are used to observe heartbeat, temperature, and blood pressure have low-rate traffic in a normal situation, but generate high rate of traffic in an emergency. The applications with low-rate traffic require less energy consumption  whereas In this paper, an Emergency Traffic Adaptive MAC (eTA-MAC) protocol is proposed for WBANs based on Prioritization in order to address the above mentioned gaps. The protocol is divided into three parts: Traffic Class Prioritization-based slotted-CSMA/CA (TCP-CSMA/CA) scheme, Emergency Traffic Class Provisioning-based slotted-CSMA/CA (ETCP-CSMA/CA) scheme, and Emergency-based Traffic Adaptive slotted-CSMA/CA (ETA-CSMA/CA) scheme.The rest of this paper is organized as follows. Section 1 discusses related work. Section 2 presents design of the eTA-MAC protocol in detail. Section 3 presents performance evaluation of the proposed schemes. Finally, Section 4 concludes the paper.Different MAC schemes have been proposed for emergency-based traffic adaptivity. These include the following:In , Yoon eti instead of BE in the backoff period range equation. Therefore, the specific backoff period range assigned to the BMSNs of each traffic class remains unchanged in every backoff. Consequently, it consumes more energy in high traffic load. Furthermore, the backoff period ranges for high priority traffic classes are repetitively used in the backoff period ranges for low priority traffic classes. This situation results in a high collision among high and low priority packets. As a consequence, the performance of the whole scheme is reduced in terms of delay, throughput, and energy consumption. Similarly, it has fixed Emergency Time Slots (ETS) for emergency traffic. Such allocation results in wastage of resources in normal situations. In PLA-MAC, the emergency traffic is identified by using traffic-class value and traffic-generation rate which is not the practical approach. This is because the patient’s survival is based on HR, RR, temperature and BP vital-signs and thus, are considered by the doctors in an emergency situation  as a backoff period range to the BMSNs with emergency packets and this backoff period range is repetitively used in all the backoff period ranges. Again, all the backoff period ranges start from zero and remain unchanged in all backoffs. Therefore, the collision rate increases and consequently, the retransmission rate also increases resulting in longer delay. In normal situation, the TCP-CSMA/CA scheme of eTA-MAC protocol observes the lowest average packet delivery delay in normal situations because each traffic class gets a distinct, minimized, and prioritized backoff period range in every backoff. Even in the last backoff, the upper limit of the backoff period range for lowest traffic class is 31 which reduces packet delivery delay of BMSNs belonging to the lowest level TC. Thus, TCP-CSMA/CA scheme of eTA-MAC reduces the average packet delivery delay and attains improvement of 58%, 23%, 59% as compared to the PLA-MAC, eMC-MAC, and PG-MAC schemes, respectively.In an emergency situation, eMC-MAC also assigns very low backoff period range to the BMSNs with emergency packets. Instead, the BMSNs with low priority data packets get higher backoff period range during contention. Therefore, the traffic of the BMSNs with low priority data packets is delayed. The backoff period range is assigned to BMSNs with emergency data packets repetitively used in the backoff period ranges of all backoffs, and every backoff period range starts from zero. The results show that the BMSNs with low priority data packets can access the channel before the BMSNs with emergency data packets. Thus, emergency data packets delay. Moreover, the assigned backoff period ranges remain unchanged in all backoffs which also increases collision and packet delivery delay. In eMC-MAC, the average packet delivery delay increases gradually and becomes worse after 11In case of an emergency situation ETC is created dynamically. Moreover, a distinct and lowest backoff period range is assigned to BMSNs with emergency data packets, which belongs to ETC in every backoff. Hence, BMSNs with EDPs transmit data packets with lower delay. Also, BMSNs that belong to CTC, RTC, DTC, and NTC get distinct, minimized, and prioritized backoff period range in every backoff. Even the BMSNs that belong to the lowest priority traffic class, i.e., NTC get very low backoff period range, i.e., –35 even In addition,  shows thATLAS shows very high average packet delivery delay as shown in Figs Similarly, PLA-MAC does not provide any lifetime management system for emergency and normal data packets in case of an emergency. This causes high collision rate increase the retransmission rate as well as the average packet delivery delay. As shown in , the oveFigs In PG-MAC, very low backoff period ranges are assigned to BMSNs with ED, PD or ND in every backoff during contention. The traffic load increases due to the usage of very low backoff period ranges. The increased traffic load causes a high collision and decreases the throughput. Furthermore, the backoff period range assigned to BMSNs with EDs repetitively used in all the backoff period ranges that are assigned to BMSNs with PDs or NDs. Thus, the collision rate increases and thus, decreases the throughput of emergency data packets. The proposed eTA-MAC protocol performs better as compared to the PG-MAC because it creates ETC dynamically in an emergency situation. It also assigns a distinct, lowest and prioritized backoff period range to BMSNs with emergency or normal data packets in every backoff. In normal situations, the achieved throughputs of TCP-CSMA/CA scheme of eTA-MAC are 55% compared to PLA-MAC, 56% compared to eMC-MAC, and 61% as compared to PG-MAC. In emergency situations, the achieved performances of ETCP-CSMA/CA scheme of eTA-MAC are 43% as compared to PLA-MAC, 23% as compared to eMC-MAC, and 52% as compared to PG-MAC.Additionally,  shows hiATLAS does not provide traffic prioritization, and all the BMSNs, without distinction, use the same backoff period range in every backoff during contention. It creates unnecessary traffic load over the network which results in a high collision. The lifetime of the data packets expires before transmission due to this high collision. But ATLAS does not provide any mechanism to stop the transmission of dead data packets over the network which also creates unnecessary traffic load on the network, causing more increases in collision rate. Hence, the high collision rate also increases the retransmission rate and thereby, reduces the overall throughput of ATLAS, as shown in Figs Similarly, PLA-MAC does not manage the transmission of emergency and normal dead data packets in an emergency situation. Therefore, the overall throughput of the network is reduced in PLA-MAC and becomes worse after the eleventh BMSN as shown in . The thrThe highest energy consumption of BMSNs is observed in PLA-MAC during normal and emergency situations as shown in Figs The ATLAS shows lower energy consumption of BMSNs as compared to PLA-MAC as shown in Figs Additionally, PLA-MAC does provide a mechanism to stop the transmission of dead emergency and normal data packets in an emergency situation. Thus, as the number of packets per second increases, the collision rate also increases. In PLA-MAC, the data packet loss rate is increased due to the collisions. The lost data packets require retransmission which increases the energy consumption of each BMSN. Hence, PLA-MAC shows very high energy consumption. However, ETA-CSMA/CA scheme comparatively consumes less energy at each transmission rate because it stops the transmission of dead emergency and normal data packets in an emergency situation. Hence, upon varying the number of BMSNs, ETA-CSMA/CA consumes 37% less energy as compared to ATLAS and 76% less energy compared to the PLA-MAC. On varying the number of packets per second, ETA-CSMA/CA consumes 28% less energy as compared to ATLAS and 85% less energy compared to the PLA-MAC.The purpose of the current study was to provide contention-based prioritized channel access to heterogenous-natured BMSNs in normal or sporadic emergency situations with emergency-based traffic adaptive approach. All types of BMSNs either with emergency or normal traffic must perform contention to access the channel in CAP. There is a problem in the design of IEEE 802.15.4 based slotted-CSMA/CA which raises three issues during contention that need to be resolved. First, the heterogeneous-natured patient’s vital-signs traffic need prioritized channel access. Second, is sporadic emergency traffic which requires instantaneous transmission with minimum delay and packet loss without ignoring the normal traffic. Third, there is the need for a dynamic adjustment of traffic in order to accommodate the variations in heterogeneous traffic rates due to an emergency situation with a balance between throughput and energy. Moreover, the BMSNs with normal traffic require energy preservation. The developed eTA-MAC protocol offers a more realistic solution in line with the patient’s body and proves to be better than the benchmark protocols in terms of packet delivery delay, throughput, and energy consumption.S1 File(XLSX)Click here for additional data file.S2 File(XLSX)Click here for additional data file.S3 File(XLSX)Click here for additional data file.S4 File(XLSX)Click here for additional data file.S5 File(XLSX)Click here for additional data file.