Health apps on mobile devices provide an unprecedented opportunity for ordinary people to develop social connections revolving around health issues. With increasing penetration of mobile devices and well-recorded behavioral data on such devices, it is desirable to employ digital traces on mobile devices rather than self-reported measures to capture the behavioral patterns underlying the use of mobile health  apps in a more direct and valid way.The objectives of this study were to (1) assess the demographic predictors of the adoption of mHealth apps; (2) investigate the temporal pattern underlying the use of mHealth apps; and (3) explore the impacts of demographic variables, temporal features, and app genres on the use of mHealth apps.Logfile data of mobile devices were collected from a representative panel of about 2500 users in Hong Kong. Users’ mHealth app activities were analyzed. We first conducted a binary logistic regression analysis to uncover demographic predictors of users’ adoption status. Then we utilized a multilevel negative binomial regression to examine the impacts of demographic characteristics, temporal features, and app genres on mHealth app use.female vs Bmale=–0.18; P=.006). The use of mHealth apps demonstrates a significant temporal pattern, which is found to be moderately active during daytime and intensifying at weekends and at night. Such temporal patterns in mHealth apps use are moderated by individuals’ demographic characteristics. Finally, demographic characteristics were also found to condition the use of different genres of mHealth apps.It was found that 27.5% of mobile device users in Hong Kong adopt at least one genre of mHealth app. Adopters of mHealth apps tend to be female and better educated. However, demographic characteristics did not showcase the predictive powers on the use of mHealth apps, except for the gender effect (BOur findings suggest the importance of dynamic perspective in understanding users’ mHealth app activities. mHealth app developers should consider more the demographic differences in temporal patterns of mHealth apps in the development of mHealth apps. Furthermore, our research also contributes to the promotion of mHealth apps by emphasizing the differences of usage needs for various groups of users. According to a population-based survey in Germany in 2015, 21% of smartphone users adopt mHealth apps . DemograWith well-recorded behavioral data on mobile devices, it is desirable to employ digital traces on mobile devices rather than self-reported measures to capture behavioral patterns underlying the use of mHealth apps in a more direct and valid way. More importantly, the time-stamped digital traces can empower researchers to understand the temporal patterns, such as circadian rhythms and weekday-weekend difference, in the use of mHealth apps. The circadian rhythm in human behavior plays a crucial role in guiding people’s daily lives . EmpiricHong Kong provides a very good testbed to understand the adoption and use of mHealth apps. Hong Kong is one of the most populous cities in the world but also among the top 10 regions with the greatest life expectancy at birth . Mobile By analyzing the behavioral log data of mobile devices collected from a representative panel of ordinary users in Hong Kong, we aim to (1) assess the demographic predictors of the adoption of mHealth apps, (2) investigate the temporal pattern underlying the use of mHealth apps, and (3) disentangle the intertwined effects of demographic factors, temporal features, and app genres on the use of mHealth apps. The findings of this study advance our knowledge of demographic profiles of the adopters of mHealth apps and enhance our understanding of behavioral patterns underlying the use of mHealth apps, which possesses significant implications for promoting the adoption and use of mHealth apps in different dimensions of public health.The data of the study were collected from a mobile audience study in Hong Kong. Users in the panel were recruited by a marketing research firm for local media organizations. To assure the representativeness of the panel sample, the panel was weighted against Hong Kong population census estimates in terms of the cross-distribution of age and gender. An on-device meter was installed on mobile devices (using Android and iPhone) of the users in the sample, to passively track all the activities on the devices without interrupting the users, who were informed about and agreed to the tracking and subsequent analyses of mobile app uses under the anonymous condition. The starting and ending time of each app use was recorded by the installed meter. The observation period for this study was from July to November 2017. All personally identifiable information about the users was removed before we were given access to the data. To further protect user privacy, the specific name of all mobile apps was removed, although the generic category  is available, which provides the basis for this study to measure mHealth app use.The apps adopted by all users were categorized into dozens of genres based on Google mobile app categories. Only the adoption and use of health apps are examined in this study. Of all the apps adopted by the users, 155 are health apps, which are categorized into 5 genres based on their functional features: generic activity tracking apps , health records log apps , sleep management and relaxation apps , training and coaching apps , and weight and diet management apps .To understand who is more likely to adopt mHealth apps, a binary logistic regression is run to predict the adoption status of mHealth apps among mobile device users, with adopters of mHealth apps coded as 1 and nonadopters coded as 0. This analysis includes the whole panel of all users . Demographic variables, including gender, age, education degree, occupation status, parenting status, and marital status, are included as explanatory variables in the model.Furthermore, following Dutton et al’s conceptualization of patterns of use for technologies , the useThen, a multilevel negative binomial regression is run to account for within-individual and between-individual level differences on the use of mHealth apps. This analysis only includes participants who adopted the mHealth apps (N=713). Negative binomial regression is employed here to handle the dependent variable with discrete probability distributions, such as count data and time data . As the It was found that 27.52% (713/2591) of the users in the study adopt at least one genre of mHealth apps. The majority of the users  adopt only 1 genre of mHealth apps, 15.0% (107/713) adopt 2 genres, and 3.8% (27/713) adopt at least 3 genres.The most popular genre of mHealth apps is the generic activity tracking, followed by health records log apps, weight and diet management apps, training and coaching apps, and sleep management and relaxation apps. On average, users spend 85.8 seconds in 1-time health app usage (SD=238.2 seconds). Users spend the longest time on sleep management and relaxation apps , followed by health records log apps , training and coaching apps , generic activity tracking , and training and coaching apps .P<.001). Better-educated users are more likely to adopt mHealth apps than less-educated users. Clerks are more likely to adopt mHealth apps, in comparison with workers . However, age, marital status, and parenting status of mobile device users do not significantly influence the adoption of mHealth apps.The binary logistic regression analysis results are summarized in A null model with the intercept only is first estimated to get the intraclass correlation coefficient (ICC). The ICC is 0.36, indicating that 36% of the variance in the use of mHealth apps could be attributed to between-individual differences . The high ICC detected here also implies that a multilevel design can provide adequate statistical power to account for the use of mHealth apps. A series of 3 multilevel negative binomial regressions are run to uncover the between-individual and within-individual antecedents underlying the use of mHealth apps. The analytical results of main effects are summarized in the R2 is estimated for the 3 multilevel models reported in R2 describes the proportion of variance explained by both the between-level and within-individual factors included in the 3 models. Model 1, which includes the between-individual variables as independent variables, explains 35.6% of the variance in the use of mHealth apps. The addition of within-individual factors in model 2 increases the explanatory power by 0.8% . Model 3, which incorporates the interactions between within-level factors  and between-individual factors, adds 1.1% of the variance .The conditional Gender is the only significant demographic predictor of use of mHealth apps. Female users  tend to spend less time on mHealth apps than male users . It is surprising to find that all other between-individual variables, including age, education degree, occupation status, parenting status, and marital status, do not exert statistically significant main effects on the use of mHealth apps.Temporal patterns have significant effects on the use of mHealth apps. Users are found to spend more time on mHealth apps during weekends (estimated duration=88.3 seconds) than during weekdays (estimated duration=85.2 seconds). Meanwhile, the use of mHealth apps tends to be more enduring at night (estimated duration=93.2 seconds), whereas less enduring in the morning (estimated duration=82.9 seconds).There are significant differences among the use of different genres of mHealth apps. Training and coaching apps is the most enduring (estimated duration=126 seconds), followed by sleep management and relaxation apps (estimated duration=110 seconds), health records log apps (estimated duration=95.2 seconds), weight and diet management apps (estimated duration=90.2 seconds), and generic activity tracking apps (estimated duration=79.3 seconds).The temporal patterns in the use of mHealth apps are found to be moderated by between-individual variables, as suggested by the significant cross-level interaction effects between temporal features, app genres, and demographic characteristics.First, the gender difference on the use of mHealth apps is significantly greater in the morning than that in other time windows of the day, as shown in Third, users’ education level is found to condition the temporal patterns in the use of mHealth apps. Users with different education levels tend to spend similar amount of time on mHealth apps in the morning and at night, whereas better-educated users spend significantly less time on mHealth apps in the daytime and during the weekends.Besides, occupation is found to moderate the temporal patterns in the use of mHealth apps. Users of different occupations spend similar amount of time on mHealth apps at noon and night, whereas in the afternoon and evening time, housewives and retired users spend notably more time, and students spend significantly less time. Besides, student and unemployed users are found to have more stable use time schedules on mHealth apps no matter it is weekday or weekend, whereas workers, managers, administrators, and professionals spend significantly less time on mHealth apps during the weekdays than weekends.Finally, our work also observed that demographics could differ the use of different genres of mHealth apps. First, the gender difference on the use of sleep management and relaxation apps is significantly greater than that of generic activity tracking apps. Second, education level is found to moderate the use of different genres of mHealth apps. Users with different education levels tend to spend similar amount of time on the use of generic activity tracking apps, whereas users with middle-level education spend significantly less time on training and coaching apps.As shown in Parenting and marital status are also found to be moderate the use of different genres of mHealth apps. The differences between users with different parenting status are larger in the use of training and coaching apps compared with the use of generic activity tracking apps, whereas the differences between users with different marital status are larger in the use of health records log apps and sleep management apps.The first objective of this study was to assess the demographic predictors of health app adoption and use with a valid logfile dataset. Our results are consistent with previous studies that better educated and female mobile device users are more likely to adopt mHealth apps. However, we did not find the significant main effect of other demographic variables on the use of mHealth app, except for the gender difference. Second, our study aims to investigate the temporal pattern of health app use. The results indicate that the use of mHealth apps not only demonstrates a circadian rhythm but also differentiates between the weekdays and weekends. Noon and night are the peaks for the use of mHealth apps around a day. Besides, users spend longer time on mHealth apps on weekends than on weekdays. Finally, the findings show significant interaction effects between temporal features, app genres, and demographic characteristics on the use of mHealth apps. The gender difference on the use of mHealth apps is significantly greater in the morning. Users of different age groups spend significantly similar amount of time on mHealth apps at noon and night, whereas older users spend less time on mHealth apps in the morning and evening compared with the youngers. Besides, better-educated users spend significantly less time on mHealth apps in the daytime and during the weekends. We also found that demographics  could differ the use of different genres of mHealth apps.Compared with prior studies, the adoption rate of mHealth apps in Hong Kong revealed in this study is quite higher than that found in Germany  and the The study also finds a weekly and daily circadian rhythm of mHealth apps use. People spend longer time on health apps on the weekends than in a weekday. Besides, health app use reaches the peak at noon and night, throughout the 24-hour cycle a day. The pattern is largely matched with the temporal pattern in the use of mobile devices that mobile phone use being moderately active during the daytime but intensifying during break time and after work time ,23. ThesFinally, our findings provide evidence that users of different demographic  demonstrate different temporal patterns in the use of mHealth apps across circadian rhythm and the day of the week. First, the use difference between male and female in the morning indicates the gender role in the household: wives generally take more housework and child care responsibilities at home in the morning . The uneThis study is subject to some limitations that can be addressed in future studies. For example, we lack the information about user’s health conditions, initial motives, and behavioral outcomes in the use of mHealth apps. Research has found strong predictive powers of motivations on health-related behavior change  . People Second, although the meter in this study could passively track the activities on the devices without any interruptions to the panelists, there is concern that surveillance may have effects on user’s behaviors on mobile phone. One possible assumption is that panelists may avoid doing extreme activities  and try to conduct more health-conducive activities to meet social desirability. However, this limitation should have minimal impacts on the validity of the results, as the efforts for panelists to take to meet the social desirability in this study are relatively high . This impact could be rather minimal compared with that of self-reported measures because participants in survey method could easily conceal their real status and report more frequent health activities without any actual efforts.By analyzing the behavioral log data of mobile devices collected from a representative panel in Hong Kong, this study explores the temporal patterns in the use of mHealth apps and examines the intertwined effects of demographic factors, temporal features, and app genres on the use of mHealth apps. Users of different demographic characteristics are found to have their own preference of the app genres and distinct schedules on app use across the circadian rhythm and the week.Our study could contribute to the public health research and industries both theoretically and practically. First, our research adds to existing research by reporting the temporal patterns of mHealth app use. Maintaining the biological circadian rhythm is a necessity for human health. The intervention of the circadian rhythm in an individual’s health-related habit could influence their health situation. Thus, understanding the temporal patterns of individual’s health app use is of great importance for health maintaining and health intervention research.Second, our study could contribute to the promotion of health-related apps and activities. Our work shows that users with different demographic characteristics prefer different genres of mHealth apps. For example, managers, administrators, and professionals spend more time on training and coaching apps, whereas less time on sleep management and relaxation apps. Thus, our findings can assist the health promotion practitioner accurately select the appropriate target group and meet the health needs of the target audience.Finally, our research could also contribute to the development of mHealth apps. We explored the temporal patterns in the use of mHealth apps and found that users of different demographic  have different use schedules on mHealth apps across the circadian rhythm and the week. Thus, mHealth app developers could consider more about the demographic differences in temporal patterns when they design and develop health apps to meet the customers’ needs.


Despite the universalization of immunization against the six vaccine-preventable diseases (VPDs), the coverage of full immunization among the children under age five has remained a challenge globally. The 2015–16 National Family Health Survey (NFHS) indicated large disparity in the coverage of different vaccination doses  including full immunization across the districts of India. The spatial distribution of poor performing districts in terms of vaccination and the district level spatial, contextual determinants contributing to the low coverage have been poorly studied. Using the recent household survey , this study examined the spatial heterogeneity and the factors associated with low vaccination coverage among the children aged 12–23 months across India.I, Univariate and Bivariate LISA, Ordinary least square (OLS) and spatial models were employed to achieve the overall aim of the study.This study used the data from fourth round of National Family Health Survey conducted in 2015–16. District-level prevalence of each of the vaccination doses including full immunization, were analysed. Moran’s I statistics confirmed the spatial dependence between specific vaccination and the set of independent variables. District-level prevalence of the specific vaccine and full immunization showed significant spatial clustering across India. The adjusted coefficients from the spatial error model confirmed that district-level proportion of utilization of post-natal care, institutional births, neonatal tetanus protection of the last birth, women’s education and coverage of health insurance showed statistically significant association with every doses of vaccination coverage.At the national level, the prevalence of full immunization was 62 percent. Specific vaccination coverage for BCG, three doses of polio, three doses of DPT and measles were 92, 73, 78 and 81 percent, respectively. The value of the bivariate Moran’s The full and specific immunization coverage was considerably low in the geographical hotspots as compared to the national coverage. Maternal and child health care services utilization, financial assistance to the mothers through JSY scheme and mother’s education were found to determine full immunization as well as the specific vaccination coverage. Appropriate intervention should be designed to reduce the geographical disparity in the coverage of specific and full immunization across India and thus safeguard child health protecting the children from the vaccine preventable diseases across the geography. Despite the fact that the universalization of immunization against six vaccine-preventable diseases (VPDs)  has been the most cost-effective intervention among the different public health interventions in developing countries over the last decade, the coverage of full immunization among children under the age of five years has remained a challenge globally ,2. WhileEvidences suggest that the South Asian countries have made significant progress in bringing down child mortality rates from 129 per 1000 live births to 53 during the period from 1990 to 2015. Yet about two million children died before reaching the age of five in 2016 in this region and half of these deaths were due to VPDs . India cNumerous studies have been conducted to examine the socio-demographic and economic determinants of child immunization in India and in other countries. The studies have explored a range of factors influencing full immunization coverage, however, they did not take into account the geographic variance in the prevalence of vaccination uptake –11. ConsAssessing all the required vaccinations for full immunization and identifying factors that influence each vaccination component of full immunization at the district level will help researchers and policy makers understand the current situation, gaps and challenges. This would also help the National Health Policy for Childhood Immunization program in India to guide the design of interventions to reduce the gap in childhood vaccination. The geographic snapshots of child immunization can potentially help ensure that every child in India accesses full immunization leading to VPDs free and a healthy life. Additionally, insights from the report can be used by Government officials, researchers and policymakers to improve upon the current National Program on Immunization in India, strengthen existing policies and help design, pilot and implement cost-effective measures in smaller and remote areas to improve the coverage of routine immunization.https://dhsprogram.com/data/dataset/India_Standard-DHS_2015.cfm?flag=1 and therefore, does not require any separate ethical approval. All four NFHS surveys have been conducted under the stewardship of the Ministry of Health and Family Welfare (MoHFW), Government of India (GOI). MoHFW designated the International Institute for Population Sciences (IIPS), Mumbai, as the nodal agency for all rounds of the survey. Like the earlier three rounds, this round also provides crucial insights on the different aspects of maternal, child, adolescent and adult health indicators. Additionally, it also provides clear estimates of malnutrition, anaemia, hypertension, HIV, and blood glucose levels through a series of biomarker tests and measurements.The analysis of the study is based on the recently published data from the fourth round of National Family Health Survey (NFHS-4) conducted during 2015–16 which is available on the Demographic and Health Survey (DHS) website A stratified two stage sampling design was adopted by considering the urban and rural areas as the natural strata. 2011 Census lists were used as the sampling frame for the selection of the sampling units. The Primary Sampling Units (PSUs) in the survey were villages in rural areas and Census Enumeration Blocks (CEBs) in urban areas. Within each rural stratum, PSUs were selected based on probability proportional to size (PPS) sampling from the sampling frame used. In urban areas, CEBs were also selected through PPS sampling. In every selected rural and urban PSUs, an estimated number of households were segmented. Then two of the segments were randomly chosen for the survey using systematic sampling with probability proportional to segment size. Therefore, theNFHS-4 cluster is either a PSU or a segment of a PSU. In the second stage, from the selected rural and urban clusters, households were randomly selected using systematic sampling. Four survey questionnaires  were canvassed in 17 local languages using Computer Assisted Personal Interviewing (CAPI).Total 601,509 households (HHs) were selected and from those households, a total of 699,686 eligible women  in the age group of 15–49 years and 112,122 eligible men  in the age group of 15–54 years were interviewed. All the digital maps were generated using the country representative district level shape file.The outcome variables used for this study are the district-wise proportions of: (1) children aged 12–23 months fully immunized , (2) children aged 12–23 months who received BCG, (3) children aged 12–23 months who received 3 doses of polio vaccine, (4) children aged 12–23 months who received 3 doses of DPT vaccine and (5) children aged 12–23 months who received measles vaccine.After an exhaustive review of literature and following the frameworks of previous studies, we identified the set of independent variables for this specific study –16. As thttps://github.com/datameet/maps/tree/master/Districts. The digital map has been used under the Creative Commons Attributions 2.5 India license. The shape file was created using the administrative atlas of Census 2011, India. And the map was projected in WGS 1984 UTM zone 43N.The district level shape file  of India was obtained from GitHub at I, Univariate Local indicator of Spatial Association (LISA) cluster map and significance maps were produced. The Spatial weight matrix (w) of order 1 has been generated using the Queen’s contiguity method to quantify the spatial proximity between each possible pair of observational entities in the dataset [I measure of spatial autocorrelation indicates the degree to which data points are similar or dissimilar to their spatial neighbours [I statistic values were computed. The formula to compute the Moran’s I statistic is as follows [wij is the standardized weight matrix between observation i and j with zeroes on the diagonal; and S0 is the aggregate of all spatial weights, i.e. A series of district-level quantile maps have been generated to understand the spatial pattern of child immunization coverage in India. To examine the spatial dependence and clustering of different doses of vaccination and full immunization coverage, Moran’s  dataset ,18. Intuighbours . So, to  follows :UnivariI statistic is expressed as follows:wij is the standardized weight matrix between observation i and j with zeroes on the diagonal; and S0 is the aggregate of all spatial weights, i.e. Similarly, the bivariate Moran’s I usually takes values in between −1 to +1, where positive values suggest the spatial clustering of the similar values and negative values indicate the clustering of dissimilar values. A zero value indicates a random spatial pattern with no spatial autocorrelation. Univariate LISA measures the correlation of neighbourhood values around a specific spatial location [Ii) is given by the following:A positive spatial autocorrelation indicates that points with similar attribute values are closely distributed in space whereas negative spatial autocorrelation indicates that closely associated points are more dissimilar. Moran’s location . It detelocation ,22. The Hot Spots: Locations with high values, with similar neighbours (High-High).Cold Spots: Locations with low values, with similar neighbours (Low-Low).Spatial Outliers: Locations with high values, but with low-value neighbours (High-Low) and locations with low values, but with higher values of neighbours (Low-High).Four types of spatial autocorrelation were generated based on the four quadrants of Moran’s scatter plots which are termed as follows:In addition to univariate LISA, bivariate LISA measures were estimated to analyse the association of certain characteristics of regions with different outcomes of child immunization. The bivariate LISA presented as below:I statistic classified by the type of spatial autocorrelation where red color represents the Hotspots, deep blue represents the Cold Spots, and light blue and light red color represents the Spatial Outliers. To examine the potential correlates of different vaccination doses along with full immunization, we performed a set of standard statistical regressions. First, we employed the ordinary least square (OLS) model to check the primary association between the independent variables and the outcomes of interest and further estimated the spatial autocorrelation in the residuals from the OLS model to examine the endogeneity due to spatial dependence. As we found the corresponding Moran’s I value statistically significant for each of the outcomes, we then further estimated the spatial autoregressive models- spatial lag and spatial error model to get the unbiased estimates of the associations between the outcomes and the predictors correcting the spatial endogeneity present in the data. In the case of a typical spatial lag model, it is assumed that the observations are spatially dependent and lagged to each other in the neighbourhood areas whereas spatial error model assumes that the residuals are correlated in the neighbourhood of the spatial units. Spatial error model unlike the spatial lag model takes into account the effect of the omitted variables  which are not present in the model but may affect the estimation. Diagnostics tests for both the models were carried out and the value of Lagrange Multiplier of each of the models was found statistically significant. Next we compared the AIC values to identify the final model and we found error model to be the best fit for this specific study. The following are the functional forms of the statistical regressions employed in this specific study. The basic equation of linear regression (OLS) can be defined as:Using the LISA functions in Geo-Da environment, cluster and significant maps were generated. The cluster map is a special choropleth map. The map identifies those locations having a significant local Moran’s Spatial Lag Model (SLM), if the dependent variable (Y), is correlated with the weighted average of its value in its neighbourhood and other locations where ρ is the spatial lag parameter, this relationship can be expressed as follows:Spatial Error Model (SEM), if spatial dependence enters through residuals, then the following model appropriately controls the spatial effect:™, Texas); Arc-GIS version 10.1, Esri, California and Geo-Da version 1.12.1.129, Teknowledgist, New York were used for the analysis.Here, λ is the spatial auto-regressive parameter and the error ζ is independently and identically distributed. Both spatial error and spatial lag models are estimated by maximizing the corresponding likelihood functions . Stata vI statistic values indicate a highly significant spatial dependence in the coverage of different vaccination doses including full immunization across the districts of India. LISA cluster and significance map in Estimated Moran’s Bivariate LISA estimates of spatial autocorrelation presented in Results from OLS and SAR models describing the effect of the predictors on the outcomes, after adjusting for the spatial effect are presented in λ) was 0.58 .The estimated coefficients from OLS, SLM and SEM model gives the level of associations between the variables with Polio vaccination coverage across the districts . Postnatρ) for DPT vaccine has been found to be 44percent  among the children aged 12–23 months across the districts of India. We found that only 62 percent of the total children were fully immunized. Not only that, among the different doses of routine immunization, BCG showed the highest level of coverage (92 percent) followed by Measles (81 percent), DPT (78 percent). Despite the fact that the Indian immunization programme had a lot of focus on Polio eradication, just 73% children aged 12–23 months were vaccinated for polio as per the recent estimate. It was also observed that the coverage rate of polio vaccine has seen a decline from 78 percent to 73 percent from 2005–06 to 2015–16. To speed up the coverage of essential health services in India, several efforts have been initiated including the Universal Immunization Program , the Childhood Survival and Safe Motherhood Program , the National Health Policy , and the National Rural Health Mission . The UIP in India is one of the largest public health intervention in the World in terms of beneficiaries, number of immunization sessions, quantities of vaccines used, and the geography it covers. Though UIP has an annual budget of $500 million, it has not been able to reach all children in India and now the second comprehensive multi-year plan (CMYP) for the duration of 2013–17 to achieve the program objectives of India’s universal immunization program seems to be lagging behind the targets ,25. EvenThe statistical analysis has made an important contribution in evaluating the recent estimates of the different components of child (12–23 months) immunization using advanced geo-statistical techniques. Such analysis gives a quick snapshot of disparities in immunization coverage at the sub-national levels which can help in developing priorities for those geographical units (districts) that need more attention. The analysis demonstrated spatial dependence, disparities and district level distal determinants of immunization coverage across India with special focus on the spatial dimension. This study identified the hotspots and cold spots of every component of child vaccination  across the districts. Sharp regional disparities are evident in the coverage of different vaccination doses including full immunization with the presence of many cold spots in north-east and central part of India and hotspots in the southern parts. These results also highlighted the north-south inequality in the coverage of childhood vaccination. And the finding is consistent with the previous studies which attribute to the regional or state-level inequalities in the coverage of immunization due to the differential in socio-economic and health-care facility related factors like place of residence, wealth status, gender preference and health infrastructure ,27,28.The finding of this study suggested that women’s education had a positive impact on every vaccination  dose coverage, was found to be consistent with previous studies which assessed the link between maternal education and child health ,15. ThisAnother key finding was that full ANC, PNC, institutional births, and mothers who received cash incentives under Janani Suraksha Yojana (JSY) scheme had a positive impact on full immunization and its components. This can be attributed to the fact that mothers participating in health care services usually become aware about the importance of immunization for her child’s health while discussing with the health professionals. Again, such schemes provide cash incentives to overcome various financial challenges in accessing health services. The schemes like JSY could also subsequently motivate mothers to join the immunization program by using health facility services. Previous studies have also established the linkage of maternal health care services and its influence on child health and immunization coverage in different country settings ,30.This study potentially contributes to the understanding of meso scale determinants of different doses vaccination coverage in districts of India. We used a recently published nationally representative factsheet data involving representative samples from all the 640 districts of India and thus, the results obtained from this analysis could be generalized across India. The study produced the snapshot of the most recent vaccination situation prevailing in India. At the same time, this study identified the meso scale risk factors of every vaccination doses of the ongoing full immunization programme for India which may help policy makers and planners to design new interventions to improve the coverage in the geographical coldspots where the coverage is eventually low compared to the other parts of India. Additionally, this study assessed the spatial heterogeneity of the different doses of vaccination using exploratory spatial data analysis (ESDA) methodology to estimate the risk factors considering the spatial distribution and dependence of immunization coverage of different doses. Furthermore, while giving away the estimates we used the National Family Health Survey (NFHS) which provides a nationally representative sample of women of childbearing age to collect the particular demographic information on fertility and mortality, anthropometry, family planning, maternity care, child feeding, vaccination, child morbidity and AIDS through a core questionnaire. And utilizing this data, estimates could be generated at national and at the sub-national levels. Thus taking the advantage of the sampling design of the data, district level estimation has been done to assess the determinants of low immunization coverage.The study also has some limitations. Firstly, within a district level framework, this study examined the pattern of district level coverage of different vaccination doses and its meso scale determinants of low coverage across the districts. This could be further extended to lower disaggregated levels like the PSU or community levels to identify the intra-district disparity of vaccination among the children which may in turn help to find out the community level contextual factors determining the coverage of vaccination within districts. Secondly, though the study identified the geographical cold spots across India where the coverage of immunization is substantially low, but it did not investigate the phenomenon of the lower coverage of vaccination beyond the meso-scale framework. Third, the study is based upon cross-sectional data considering the children aged 12–23 months only across the districts and not all the children less than five years of age which would have helped to understand the extended scenario of vaccination among the children across India. Fourth, we used the health insurance variable and did not use the wealth variable which is the household level asset based information DHS provides to proxy the economic well-being of the household. To mention, the factsheet data lacked the district level aggregated information on proportion of poor or rich households which could be compiled from the unit level NFHS data. So, it could be exercised to look at the effect of economic condition (rich-poor distribution) prevailing across the districts and the related achievement in terms of vaccination coverage in those districts. As wealth based information are available from the unit level data of NFHS, controlling other covariates, the wealth effect could also be examined. Another basic limitation of NFHS data includes reporting and recall bias, particularly age and other retrospective data.Despite the fact that child vaccination coverage in India has seen a substantial increase over the last couple of decades, one-third of the children in India are not yet immunized. Results of our study clearly indicate regional disparities in childhood immunization levels. Though, the government and donor-funded programs have been consistently making efforts to improve the childhood immunization especially in the states of northern and central India, the focus on the north-eastern region has been limited. Even the existing program in the northern and central India does not seem to be very effective due to high number of cold spots in this region. This calls for more innovative models like incentivization and adoption of alternative ways of bringing mothers and children to the health facilities. The results indicating a positive association between childhood immunization and birth registration, institutional deliveries, having MCP card, and receipt of incentive under JSY schemes suggest that mothers’ exposure to health facilities can be one of the factors to positively influence the childhood vaccination upstream. This association is getting even stronger when the mother is educated reiterating the fact that increasing exposure of mothers to different MCH services via different health-care promotional activities help her in recognizing the need for availing health services not only for herself but for her children too. The Government may strengthen the MCH services via different health-care promotion activities. Although, JSY scheme shows a promising link between the components of child immunization, efforts are still needed to increase the coverage of this scheme as the coverage of this scheme is just 36 percent as per the recent data.


Long perceived as a primitive and poorly differentiated brain structure, the primate insular cortex recently emerged as a highly evolved, organized and richly connected cortical hub interfacing bodily states with sensorimotor, environmental, and limbic activities. This insular interface likely substantiates emotional embodiment and has the potential to have a key role in the interoceptive shaping of cognitive processes, including perceptual awareness. In this review, we present a novel working model of the insular cortex, based on an accumulation of neuroanatomical and functional evidence obtained essentially in the macaque monkey. This model proposes that interoceptive afferents that represent the ongoing physiological status of all the organs of the body are first being received in the granular dorsal fundus of the insula or “primary interoceptive cortex,” then processed through a series of dysgranular poly-modal “insular stripes,” and finally integrated in anterior agranular areas that serve as an additional sensory platform for visceral functions and as an output stage for efferent autonomic regulation. One of the agranular areas hosts the specialized von Economo and Fork neurons, which could provide a decisive evolutionary advantage for the role of the anterior insula in the autonomic and emotional binding inherent to subjective awareness. The forebrain representation and integration of the physiological condition of the organs and tissues of the body (interoception) shapes perceptual awareness and underlies the neurobiology of subjective feelings . The neuIn anthropoid primates, the insular cortex constitutes a separate cortical lobe, located on the lateral aspect of the forebrain, in the depth of the Sylvian or lateral fissure (LF) . See al. The exclongus) gyri in the posterior lobule (l1 and l2), three short (brevis) anterior gyri in the anterior lobule , and one accessory gyrus (ac), which is continuous with the ventral transverse gyrus (t). The orientation and size of the gyri as well as the exact number of short gyri varies across individuals and hemispheres , like the rest of the human neocortex . It is dispheres . The accispheres . When laispheres . Notablyispheres  which waispheres .per se with the human accessory APS. Unlike in humans, beyond this shallow dimple, there is no distinct APS separating the insula from the orbital prefrontal cortex; they are rather continuous.The macaque insula is almost entirely lissencephalic , which complicates establishing homologies solely based on macroscopic criteria . The macOne major step in examining the organization of a brain region beyond its gross anatomy is to establish its architectonic parcellation. This is typically based on the microscopic examination of local variations in cellular (cytoarchitecture) and/or fibrous (myeloarchitecture) organization patterns in thin (tens of microns) brain sections colored with classical histological staining methods or standard immunohistochemical methods . Using p1. As shown in detail in the next section, although complex, our novel architectonic map offers a clear and explanatory structural Bauplan for the examination of the connectivity, and functional organization of the insula.The granular sector of the insula contains four areas including one anterior area (Idfa) and one posterior area (Idfp) straddling the fundus of the SPS, and two areas in the posterior end of the insula, one dorsal (Igd) and one ventral (Igv). The dysgranular sector contains four areas. They are the dorsal (Idd), mound (Idm), ventral (Idv), and posterior ventral fundal (Ivfp) dysgranular areas. The mound area Idm is contained within and makes up most of the ventral mound observed in the macroscopic examination of the gross morphology of the macaque insula. Three of the dysgranular areas  contain three to five smaller architectonic subareas. These subareas form together a series of “insular stripes” that are orientated horizontally, in parallel with the dorsal fundus areas Idfa and Idfp. Finally, the anterior agranular sector contains seven areas. Two areas are located posterior to the limen (L): the posterior agranular area (Iap), which contains two subareas, and the anterior ventral fundal area (Ivfa), which prolongs the dysgranular Ivfp anteriorly. The five other agranular areas  are located anterior to the limen, mostly in the putative homolog of the human FI, except for Iapm and Iapl, which cross the shallow vertical ridge thought to define the posterior limit of the putative homolog of the FI. Notably, in the macaque monkey, the VEN and FN occur in a small cluster  that corVarious parcellation schemes have been proposed for the human insula since the original work of Brodmann . Our mapThe architecture of the anterior lobule of the human insula remains to be mapped. A volumetric comparison made across 30 primate species indicates that the human anterior insula, including the FI, grew disproportionally more than the rest of the insula and the cerebral cortex, in humans compared to all other primate species . This diBauplan described above and functionally inherent with the homeostatic optimization of energy utilization introduced by Based on a review of classical tract-tracing data from our and other laboratories as well as of functional studies in the macaque monkey, we recently generated a novel working model of the macaque insula . In the This model begins with a dorsal “primary interoceptive cortex,” formed by Idfp and Idfa, which receives topographically organized spinal and cranial interoceptive afferents via the spinal lamina I (SpL1) and the nucleus of the solitary tract (nTS), and then via the posterior and basal parts of the small, primate-specific ventral median nucleus of the thalamus (VMpo and VMb), respectively , 2014. IThe region straddling the SPS or dorsal fundus of the insular cortex constitutes the primary cortical terminus of a primate specific interoceptive afferent pathway representing the ongoing physiological status of the organs and tissues of the body . This inPublished and preliminary electrophysiological and imaging works in the macaque monkey showed that the posterior dorsal fundus of the insula, Idfp, responds to innocuous and noxious thermal stimuli as well as to noxious mechanic pinch stimuli, with a somatotopic representation of the foot, hand, and face from posterior to anterior . Taste sStudies in humans showed that areas likely homologous to Idfp in the dorsal posterior fundus of the insula respond to graded cooling  and to gDespite accumulating evidence, the anatomical and functional identification of the dorsal fundus of the primate insula as a primary sensory cortex for interoception remains a matter of debate. In many prior anatomical studies, an architectonic border was drawn medial to the center of the fundus of the lateral sulcus , as we dA prior physiological study obtained responses to whole body stimulation and to auditory stimuli in the posterior insula of the macaque monkey . AnotherThese findings are consistent with the original physiological evidence that the macaque’s PIVC occupies the retroinsular region of the LF and extends into the adjacent posterior granular insula ,b. The pIn our architectonic study, we divided the classical dysgranular sector into four areas and we subdivided three of these areas  into thin horizontal stripes . Recent As mentioned earlier, Tracing studies with injections in other cortical and subcortical structures generally also support the view that the dorsal dysgranular areas and the mound dysgranular areas have distinct connections. For example, “patches” or “slabs” of anterograde or retrograde labeling were produced in the dorsal dysgranular areas but only sparsely  in the mound areas with tracer injections in the dorsolateral “sensorimotor” region of the striatum , the “moThe entire insula has widely distributed interconnections with several amygdalar nuclei, including the lateral nucleus, different divisions of the basal nucleus, and the central nucleus . HoweverThe functional associations of these particular higher-order regions suggest that the mound and ventral dysgranular areas might have a crucial role in behaviors involving the face and hands in relation to social communication. For instance, the pre-SMA area is associated with “signaling when a movement can be executed, according to the environmental context” . The porAn extensive series of tracing studies of the orbital and medial prefrontal cortex (OMPFC) indicates that each of its 22 areas has distinct connections, grouping the areas into 2 networks, an orbital “viscerosensory” network that may be involved in the assessment of food stimuli  and has In the model of Although the anatomical isolation of Iai from the other anterior insular areas appeared obvious in the prior contributions by Price and colleagues, a recent re-examination of the relevant tracing cases indicated some of the anterograde and, more particularly, retrograde labeling originally attributed to Iai may also belong to the adjacent area Ial. This redefinition of the areal localization of labeling became evident after the discovery of the VEN and FN in the anterior insula in the macaque monkey . Indeed,The von Economo neuron and fork neuron are morphologically specialized, or “atypical,” cortical projection neurons [as opposed to the “typical” pyramidal neuron (PN) ]. In priWhile the VEN and FN were assumed to occur only in humans and great apes, among primates , both ceAs in humans, the VEN and FN in macaques are present in layer 5b of the anterior agranular insula. They account for about 3 and 1% of the total number of local layer 5 neurons, respectively . They arJust like in humans, the macaque VEN (and FN) expresses various genes that occur only in a small fraction of local PN. These genes include those coding for the neurofilament protein SMI-32, disrupted-in-schizophrenia-1 protein (DISC-1), dopamine D3 receptor, serotonin 2b receptor, vesicular monoamine transporter 2 VMAT-2; , and gamFEZF2 and CTIP2, two transcription factors essential for the developmental specification of subcerebral  cortical projection neurons  or regulation of autonomic control (PAG), hence reducing interoceptive prediction error or “free-energy” . The larThe present model and the overall architectonic sectorization of the insula from granular to agranular share several characteristics with the classical somatic sensory-motor cortices. The primary interoceptive cortex in the dorsal fundus of the insula is granular and receives high-resolution sensory inputs, like the primary somatosensory cortex in the post-central gyrus of the parietal lobe . The agrOne dimension that needs to be added to the sensory-motor axis relates to the anatomical sympathetic and parasympathetic autonomic branches of the autonomic nervous system. The dorsal fundus of the insula is topographically organized with a posterior-to-anterior representation of spinal (foot-to-hand), trigeminal (head/face), and vagal (taste/viscera) inputs. The available tract-tracing and functional evidence indicates that this spino-cranial plan is reproduced across the different dysgranular stripes. A recent model suggested that the spinal and cranial afferents to Idfp and Idfa represent the ascending counterpart of the anatomically defined sympathetic  and parasympathetic  branches of the autonomic nervous system, respectively . An earlCognition and emotion have been traditionally separated, although such conceptual separation likely misses the evolutionary, developmental and neuroanatomical intimacy of the neurobiological mechanisms underlying “cognition,” and “emotion” . FunctioMuch remains left to do to understand how the insula is anatomically organized, processes interoceptive, metabolic and poly-modal activities, and possibly contributes to the emergence of subjective feelings in humans. The present working model of the insula in the macaque monkey resembles prior meta-analytic models of the human insula  and offeThe author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The kidneys are key contributors to body homeostasis, by virtue of controlled excretion of excessive fluid, electrolytes, and toxic waste products. The syndrome of uremia equals the altered physiology due to irreversible loss of kidney function that is left uncorrected for, despite therapeutic intervention(s). The intestines and its microbial content are prime contributors to this syndrome. The intestinal barrier separates the self  from the environment. In the large intestine, the intestinal barrier keeps apart human physiology and the microbiota. The enterocytes and the extracellular mucin layer functions form a complex multilayered structure, facilitating complex bidirectional metabolic and immunological crosstalk. The current review focuses on the intestinal barrier in chronic kidney disease (CKD). Loss of kidney function results in structural and functional alterations of the intestinal barrier, contribution to the syndrome of uremia. The kidneys are key contributors to body homeostasis, by virtue of controlled excretion of excessive fluid, electrolytes, and toxic waste products. The effects of alterations in kidney function on body homeostasis are complex. Our basic understanding is that a reduced kidney function will lead to less excretion of inorganic and organic solutes, thus leading to altered body homeostasis . HoweverChronic kidney disease is defined as structural and/or functional abnormalities of the kidneys that are present for at least three months . For mosOne important characteristics of chronic kidney disease is retention of organic solutes. Often, these are referred to as uremic retention solutes (URS). Metabolomics studies point to retention of numerous as yet unidentified solutes . The relA second key feature of chronic kidney disease is the high incidence of inflammation and malnutrition ,10,11. IAs more and more data point to a key role of the gut in the syndrome of uremia, it is worthwhile to have a closer look at the gut, and especially the intestinal barrier, which is the frontier between the organism and the outside world.The human gut, and especially the large intestine, is colonized by trillions of microorganisms. These microbiota encode at least 150-fold more genes than the human genome, together referred to as the microbiome . Humans For millions of years, the gut microbiome has co-evolved with the host. The cohabitation provides microorganisms with a stable environment, while microorganisms provide the host with a broad range of functions such as digestion of complex dietary macronutrients, defense against pathogens, production of nutrients and vitamins, maintenance of the immune system. This biological symbiosis is now jeopardized by unprecedented changes in human lifestyle and environment. Antibiotic use and other drug therapy, diets poor in dietary fiber and rich in red meat, excessive sanitation and birth by Caesarean section are all known to have profound effects on the gut microbiota .Recent data also indicate that chronic kidney disease associates with a distinct gut microbiota composition ,20,21 anSimilar to the skin, the intestinal barrier is the physiological barrier that separates the self  from the environment. It is important to acknowledge that the colonic intestinal wall not only acts as a gatekeeper protecting against the invasion of pathogens and toxins but also as a choirmaster of the immune system-microbiota alliance. When operating optimally, this alliance interweaves the innate and adaptive arms of immunity in a dialog that selects, calibrates, and terminates responses in the most appropriate way .A better insight in complex crosstalk between the host and the gut microbiota in health and disease may open new avenues for  therapy. The present review focuses on the structure and functionalities of the colonic intestinal barrier both in health and in CKD.The anatomy and physiology of the intestinal barrier varies across the length of the intestinal tract. A broad division can be made between the small intestine, which has a lower exposure to bacteria and usually is not colonized, and the large intestine, which is home to the largest and most diverse microbial community residing within the human body. In this review, we will focus mostly on the intestinal barrier of the large intestine, although some data also suggest CKD-related alterations in the intestinal barrier of the upper gastro-intestinal tract .The gastro-intestinal tract is lined by a single epithelial cell layer. It consists predominantly of enterocytes, interspersed with specialized cell-types such as goblet cells and neuro-endocrine cells. Direct contact between the epithelial cell layer and the gut microbiota is limited by a specialized mucus layer, produced by goblet cells and enterocytes . The mucThe inner mucous layer is produced by the goblet cells and consists predominantly of the gel-forming MUC2 mucin that is cross-linked by six different covalent and noncovalent bonds . Under cThe outer mucous layer equally contains MUC2 mucin. The ultrastructural characteristics however are altered by host protease activity, increasing average pore size facilitating penetrance into the mucous layer. The mucin-bound carbohydrate layer provides energy for the adherent bacteria, together with the complex carbohydrates from dietary sources that escaped digestion in the small intestine.The mucous bilayer, predominantly secreted by the goblet cells, is the first line of defense against microbiota. The enterocytes itself also produce a number of membrane-bound mucins. These mucins consist of a large highly glycosylated extracellular mucin domain as well as a cytoplasmic domain in interaction with the cytoskeleton. Some of these cytoplasmic tails may regulate the externalization of several ion channels such as the sodium/hydrogen exchanger 3 (NHE3) and the cystic fibrosis transmembrane conductance regulator (CFTR) .Behind the barrier formed by the complex multilayered mucins, the enterocytes form a second line of defense between the gut lumen and mammalian milieu interne. The enterocyte plasma membrane prevents transcellular flux of most hydrophilic solutes. Transcellular transport almost exclusively consists of actively regulated transport. To prevent paracellular flux of luminal solutes, the intestinal epithelial cells are sealed together by the zonula occludens complex (tight junction).Despite the fact that the intestinal barrier is composed of a multilayered structure, thus shielding the human internal environment from the colonic microbial content, there is intense cross-talk between both compartments. Broadly speaking, this bidirectional communication consists of both metabolic as well as immunological signals, aiming to maximize the win-win between commensal microbiome and the host.Tight junctions are selectively permeable and capable of discriminating between solutes on the basis of either size and/or charge. At least two distinct routes are involved in paracellular permeability : a chargThe pore pathway is mainly determined by the claudin (CLDN) family, of which the best studied proteins are CLDN1 and CLDN2 ,33,34. TNutrients as glucose, amino acids, peptides, vitamins but also bile acids present in the intestinal lumen cannot cross the intestinal epithelium by the transcellular or paracellular pathways and they enter the enterocyte and then reach the portal circulation via different membrane transporters. Moreover, uptake and efflux transporters allow the movement of molecules in the opposite direction to keep blood levels of potentially toxic compounds low. Interestingly, transporters are one of the determinants of the pharmacokinetics of high number of orally administered drugs. While much research has been focused on the role of transporters in the liver and kidney, less is known about the importance and the types of transporters in the intestine .Membrane drug transporters are classified into the solute carrier (SLC) and the ATP-binding cassette (ABC) transporter super-families, both include more than 400 transporters ,40. ApicGut homeostasis is maintained by the strategical location of the gut associated lymphoid tissue (GALT) at the mucosal interface, allowing surveillance and innate and adaptive effector functions of immunocytes. Intestinal epithelial cells cooperate in this immune defense, as they express receptors, process and present antigens, and release mediators that facilitate bidirectional communication with the immune system. Innate Immunity is the first line of immunological defense against potentially luminal harmful substances. The main cellular elements of the innate response are enterocytes, goblet and Paneth cells, as well as subepithelial neutrophils, dendritic cells, macrophages, eosinophils, and mast cells. Innate responses are triggered by pathogen-recognition receptors (PRRs), which serve as sensors of pathogen-associated molecular patterns (PAMPs) present in pathogenic and commensal bacteria. PRRs activate inflammatory responses characterized by nuclear factor-κB (NF-κB) activation; subsequent chemokine and cytokine production, recruitment and immune cells activation; and release of antimicrobial molecules (defensins and cathelicidins) .Adaptive immunity, essential for the development of tolerance, is triggered by antigen exposure and is characterized by immunological memory which confers long-term protection to the host.Often, the metabolic and immunological signaling are discussed as two separate dedicated pathways. Several lines of evidence point to closely intertwined systems, where metabolites interfere with immunological signaling and vice versa.Vaziri et al. were the first to explore the intestinal permeability and its structural components in animals, using experimentally 5/6th nephrectomy induced CKD. They observed intense infiltrates of lymphocytes into the lamina propria . Using tThese experiments predicted augmentation of intestinal permeability in CKD, as a result of the loss of tight junction proteins. Animal experiments confirmed the loss of intestinal integrity and increased translocation of living bacteria across the intestinal barrier into the liver, in combination with increased serum levels of bacterial endotoxin .It has been hypothesized that increased gut permeability contributes to inflammation in patients with advanced CKD ,44,45. IThe number of metabolites that cross the intestinal barrier via active transport is near-endless, ranging from nutrients, bacterial metabolites as well as pharmaceutical agents. Surprisingly little is known about the role of these transporters in patients with advanced CKD. For some metabolites, more data are available. These will be discussed, as an illustration of the complex alterations in the regulation of active transport across the intestinal barrier in CKD.ABCG2 transporter is the key intestinal transporter. The basolateral transporter responsible for the uptake of UA from the blood into the enterocyte is unknown. SLC22A6 and SLC22A7 are potential candidates since they are expressed in the basolateral side of the enterocytes and are able to transport UA [ABCG2 [ABCG2 knockout mice have higher concentrations and lower intestinal excretion of uric acid [ABCG2 variant Q141K (rs2231142) was found to be associated with elevated serum concentrations of uric acid [ABCG2 in the intestine triggered by an elevation of serum UA may play a compensatory role in its increasing intestinal excretion [Intestinal excretion accounts for approximately one-third of total body clearance of uric acid (UA), whereas kidney clearance accounts for the other two-thirds. In physiological conditions, kidney clearance is mainly regulated by the apical SLC2A9 together with the basolateral SLC22A6 (OAT1) and SLC22A8 (OAT3) transporters, whereas the apical sport UA . The avaA [ABCG2 , as ABCGric acid  and the ric acid . Interesxcretion ,52.Several other URS are associated with cardiovascular complications and poor survival in chronic kidney disease ,54,55. CSLC22A4 gene, encoding OCTN1, in cultured cells inhibited uptake, and SLC22A4 knockout mice exhibited complete deficiency of ergothioneine. These findings suggest that OCTN1 is essential for intestinal absorption of ergothioneine, and that no escape mechanism is available [Recently, Shinozaki et al. provided evidence for another altered intestinal transporter system, mediated by the organic cation transporter 1 (OCTN1)-ergothinoneine axis . The carvailable . In a movailable . This covailable .In CKD patients, the dysregulation of drug transporters  has to bThe intestinal barrier separates the self  from the environment, shielding mammalian physiology from the outside world. In the large intestine, the intestinal barrier shields the eukaryotic milieu interne from direct contact with the microbiota. Its complex multi-layered structure, consisting of the enterocytes and the extracellular mucin layer functions as a tight seal. At the same time, the composition of the mucin, the characteristics of the tight junctions and a host of active transporter systems allow for a complex bidirectional metabolic and immunological crosstalk. The loss of kidney function interferes with the functions of the intestinal barrier. As a result, the effectiveness of the intestinal barrier is reduced and exposure to bacterial products is increased. CKD also interacts in complex ways with the active transport mechanisms, thus altering body homeostasis of numerous solutes. Our understanding of the effects of CKD on these processes is far from complete .


The radial nerve has a long and tortuous course in the upper limb. Injury to the nerve can occur due to a multitude of causes at many potential sites along its course. The most common site of involvement is in the proximal forearm affecting the posterior interosseous branch while the main branch of the radial nerve is injured in fractures of the humeral shaft. Signs and symptoms of radial neuropathy depend upon the site of injury. Injury to the nerve distal to innervation of triceps brachii results in loss of extensor function with sparing of function of the triceps resulting in the characteristic ‘wrist drop’. Injury in the mid-arm is associated with loss of sensation in the dorsolateral aspect of the hand, the dorsal aspect of the radial three-and-a-half digits and in the first web space. Involvement of only the posterior interosseous nerve (PIN) results in weakness of the wrist and digit extensors. Diagnosis relies on clinical examination, electrodiagnostic studies and imaging findings. Plain radiographs are used to identify fracture sites, callus or tumours as cause of compression. Technological advances in ultrasonography have allowed direct visualisation of the involved nerve with assessment of the exact site, extent and type of injury. It yields unmatched information about anatomical details of the nerve. MR imaging adds to soft-tissue details and helps in characterising the lesion. This pictorial review aims to illustrate a wide spectrum of causes of radial neuropathy and emphasises the importance of imaging modalities in diagnosis of neuropathies.Radial nerve injuries are assessed by clinical examination and diagnosed using electrodiagnostic and imaging studies.• Knowledge of anatomical relations and course of the nerve is necessary to identify the nerve at pre-determined anatomical locations.• Altered echogenicity and signal intensity, discontinuity of the nerve, focal thickening and cause of compression can be assessed by imaging modalities.• MR imaging helps in confirmation of the ultrasound findings, differentiating similar appearing lesions and provides additional soft-tissue details.•  Radial nerve pathologies include compressive syndromes, entrapment neuropathy, focal intrinsic lesions and peripheral nerve sheath tumours. The radial nerve has a long and tortuous course in the upper limb and lies in close proximity to the bone in the spiral groove, making it susceptible to injuries. The prevalence of radial nerve palsy following fracture of the humerus shaft is 11.8% . ClinicaIntroduction of high-frequency ultrasound probe has made direct visualisation of peripheral nerves possible, thus providing anatomical details about the nerve. Ultrasonographic findings of peripheral nerves were first reviewed by Fornage in 1988 . Since tVarious previous publications have mentioned methods to identify the nerve in specific anatomical locations and various peripheral nerve pathologies –7. ExtenThe radial nerve originates from the ventral rami of C5 – T1 and lies in the posterior cord of the brachial plexus with the axillary artery as its anterior relation. Within the axilla, it has three branches: sensory posterior cutaneous nerve of the arm and motor branch to the long and medial head of the triceps. It passes anterior to the subscapularis, latissimus dorsi and teres major. This is the first possible site of compression. An anomalous muscle, the accessory subscapularis-teres-latissimus is reported in literature to be another cause of compression of the radial nerve at this level . AnotherIt enters the posterior compartment of the arm by travelling through the triangular interval bounded by the teres major superiorly, the long head of the triceps medially and the lateral head of the triceps laterally. The radial nerve then exits the axilla, courses through the lateral head of triceps brachii and winds around the spiral groove accompanied by the profunda brachii artery. Lorem et al.  describeThereafter, it descends in the arm and comes to lie between the brachialis and brachioradialis giving motor supply to both the muscles in addition to the extensor carpi radialis longus (ECRL) and extensor carpi radialis brevis (ECRB). This too is a constant relation which can be identified on ultrasound when scanning the lateral aspect of the lower arm Figs. c and d. The superficial branch courses medially, deep to the brachioradialis, lateral to the radial artery into the wrist. It pierces the lateral fascia to enter the anatomical snuffbox and gives sensory innervation to the dorsal surface of three and a half digits on the radial aspect. It also innervates the extensor digitorum, the extensor digiti minimi and the extensor carpi ulnaris muscles.The normal peripheral nerve has a honeycomb appearance which is identified on imaging. The central spots are the nerve fascicles which are formed by bundles of nerve fibres surrounded by the perineurium. Each nerve fibre is also surrounded by an endoneurium which is not visible on imaging with the currently available resolution. The fascicles are in turn embedded and surrounded by the epineurium which forms the sheath of the peripheral nerve . The dimHigh-resolution ultrasound: A high-frequency linear probe is required for scanning peripheral nerves. We used a probe with frequency set at 14 Hz. The nerve should be identified in a cross section as it has a characteristic honeycomb appearance which helps in demarcating it from the surrounding soft tissue. After identifying the nerve in its short axis at pre-determined anatomical locations, it can be traced proximally and distally throughout its length. The nerve is more echogenic to the surrounding muscle and less echogenic to the surrounding tendon. The pathological segment of the nerve will show loss of the normal honeycomb structure, decreased echogenicity, discontinuity, focal enlargement or neuroma formation. Adjacent compressive lesions, muscle and soft-tissue oedema, and joint effusions can also be identified.MR imaging: We used a 3-T MRI scanner with a dedicated protocol for visualisation of the radial nerve. T1, T2 fat-saturated and proton density (PD) fat-saturated sequences were acquired with a slice thickness of 3 mm and interslice gap of 0.3 mm. Gadolinium-based contrast was used for post-contrast images if required. Knowledge of the anatomical relations of the radial nerve is necessary to identify the nerve in its short axis. T1-weighted images allow clear visualisation of the nerve in its short axis as the peripheral rim of fat in the nerve sheath appears hyperintense while the fascicles appear as dots, hypointense to the surrounding muscles. Epineurial or perineurial fat remains bright on T2-weighted imaging (T2WI) which can mask pathological changes in the nerves. Fat suppression is thus needed for identification of pathological segment of nerve on T2 and PD sequences , 20. FocPatients with radial neuropathy can present either with motor dysfunction or sensory symptoms only. Pain over the lateral aspect of the arm extending up to the wrist is the most common complaint in cases of radial tunnel syndrome . Injury Compression of the superficial branch causes paralysis of the extensor carpi ulnaris, extensor digiti quinti and extensor digitorum communis, while compression of the PIN causes paralysis of the abductor pollicis longus, extensor pollicis brevis, extensor pollicis longus and extensor indicis proprius. Function of the extensor carpi radialis longus is spared as the fibres arise more proximally from the main branch of the radial nerve. This results in finger drop with deviation of the wrist to the radial aspect which is the classical presentation in cases of PIN palsy. Wartenburg syndrome is entrapment of the superficial branch at the distal radius and presents with pain and numbness in the posterior part of the thumb .Patients with peripheral nerve sheath tumours may present with visible swelling with no motor or sensory deficit.Clinical examination and electrodiagnostic studies (nerve conduction velocity [NCV] and electromyography [EMG]) have been the mainstays of diagnosis in neuropathies as they provide essential information about the type of dysfunction and help in clinical monitoring. EMG may not be positive for 3–6 weeks following injury. Tinel’s sign helps in assessing the possible site of injury and helps in assessment of improvement over time. Nerve injuries were classified by Seddon in 1943 and expanded by Sunderland in 1951. Mackinnon and Dellon in 1992 added grade VI injury to Sunderland’s grading scheme and defined it as a mixed type of injury which denotes various types of injuries across the cross section of the nerve –27. TablA plain radiograph shows the fracture site in cases of post-traumatic radial nerve palsy. Callus formation and soft-tissue swellings can also be noted on plain radiographs. It may also demonstrate a fat stripe of lipoma or a bony lesion in proximity to the course of the nerve.High-resolution ultrasound and MRI help in direct visualisation of the nerve with anatomical delineation of the pathological segment. These also provide essential information about the surrounding soft tissue and the muscles innervated by the injured nerve. Imaging studies help in better clinical decision making, need for operative interference, time of intervention and possible complications.Causes of radial nerve palsy are manifold with fracture of the humerus shaft being the commonest association. It can occur due to entrapment of the nerve at anatomical sites, entrapment within scar tissue, pressure by tourniquet, under-arm crutches, healing callus, etc. Iatrogenic radial nerve palsy is another common cause of injury which can occur after fracture reduction or after operative management of fracture of the humerus or radius. Elbow surgeries like arthroplasty, radial head fracture repair, synovectomy can cause PIN palsy. Penetrating injuries like gun shot injuries, animal bites, sharp objects, and intramuscular injections can cause direct insult to the nerve. Thermal and burn injuries are another cause of radial nerve palsy which may also include other nerves in the region of the burn. Systemic demyelinating diseases, lead poisoning or neurotoxic drugs may affect the radial nerve along with other peripheral nerves.Tumour and tumour-like lesions involving the radial nerve include eripheral nerve sheath tumours (PNSTs), fibrolipomatous hypertrophy, intraneural lipomas, intraneural ganglion, true neuromas and pseudo neuromas .Post-traumatic radial nerve palsyFracture of humerus shaft is the most common cause of radial nerve injury in the upper arm . The oveFigure Penetrating trauma to the armThe radial nerve has a superficial course and can be injured by penetrating objects. The insult may cause complete transection of the nerve resulting in discontinuity of the nerve or result in formation of a neuroma in continuity. Such traumatic neuromas occur due to a disorganised attempt at nerve regeneration. They may be palpable as a small, firm mass or visible only on imaging as a focal fusiform mass in continuity with the nerve. As they occur due to local fibrosis, they are hypoechoic relative to surrounding muscle on ultrasound imaging , 29.Pseudo-neuroma and true neuroma can be reliably differentiated by imaging studies. Pseudo-neuromas occur due to focal enlargement of the nerve due to compression or entrapment and correspond to grade III Sunderland injury. True neuromas occur due to scarring of the nerve with fibrotic regeneration with resultant loss of fascicular architecture. This corresponds to a grade IV Sunderland type of nerve injury. Presence of fascicular architecture in an enlarged nerve on MRI signifies a pseudo-neuroma, while discontinuity of fascicular architecture is seen in a true neuroma. Figure Figure Entrapment or compression neuropathyThis may occur due to entrapment at normal anatomical sites which most commonly include PIN entrapment at the arcade of Frohse. Other sites include the triangular space, within the triceps brachii or the spiral groove. Compression by anomalous muscle, the accessory subscapularis-teres-latissimus, may also occur. Entrapment within scar tissue may occur following injury or chronic inflammatory states. Figure Iatrogenic causesIatrogenic causes of radial nerve palsy may be manifold. Immediate post-operative wrist drop may be due to direct injury to the nerve, local hematoma causing compression, implant abutting the nerve or due to ‘tourniquet palsy’ or residual block.Figure Figure Tourniquet palsy is usually transient and recovers with physiotherapy and medical management . High-rePeripheral nerve sheath tumour (PNST) PNSTs include neurofibroma and schwannoma and may be benign or malignant. Deep-seated neurofibromas may have neurological symptoms, while superficial neurofibromas are usually small painless masses. Schwannomas typically present as a slow-growing, painless, soft-tissue mass located eccentrically with the parent nerve usually separable from the lesion.Plain radiography is usually normal in PNST. High-resolution ultrasound shows a hypoechoic fusiform mass in continuity with the parent nerve. MRI is the imaging modality of choice to differentiate between PNST and traumatic neuromas. Classical signs of PNST seen on MRI include a T1 iso-hypointense, T2 hyperintense fusiform mass in continuity with the nerve. The lesion may show low signal intensity in the centre on T2-weighted images corresponding to the higher collagen content in the centre. This is the characteristic target sign of PNST on MRI. Another sign is the split fat sign best seen on T1-weighted images wherein the hyperintense fat around the fusiform mass suggests intermuscular location of the lesion. A fascicular pattern may be detected within the mass which also supports its neurogenic origin. Figure The appropriate management of radial nerve palsy depends primarily on accurate determination of its cause, severity, duration and level of involvement. Treatment of radial nerve palsy may be either operative or non-operative. Introduction of use of imaging in cases of neuropathy has ushered in an era of a multimodality approach in patient care and appropriate clinical decision making. Imaging helps to identify cases requiring operative interference like discontinuity in the nerve, neuroma formation, cases of entrapment, etc. Other cases like tourniquet palsy, compression by local hematoma, or post-operative neuritis may be managed conservatively and monitored clinically. Open radial nerve injuries that result in a loss of nerve continuity are managed surgically by primary repair, nerve grafts, or tendon transfers.Diffusion tensor imaging and tractography are now being used for peripheral nerve pathologies. Jengojen et al.  used difUse of contrast in peripheral nerve pathologies helps in better characterisation of the lesions. True neuromas can be differentiated from PNST by lack of post-contrast enhancement in the former . Hybrid Use of high-resolution ultrasound in imaging of peripheral neuropathy is a relatively new use of this age-old modality. Literature review shows many studies and reports from around the world discovering this aspect of ultrasound , 37–41. There are various underlying aetiologies for pathology of the radial nerve as described above. Patients presenting with symptoms of radial nerve palsy have been conventionally diagnosed using clinical and electrodiagnostic findings. Use of high-resolution ultrasound and MRI will usher in a new era of a multimodality approach in diagnosis and treatment of nerve pathologies. It allows direct visualisation of the nerve with every anatomical detail which will help in better clinical decision making. This pictorial review describes the hallmark of imaging findings in a wide spectrum of radial nerve pathologies.


The emergence of clinical isolates associated to multidrug resistance is a serious threat worldwide in terms of public health since complicates the success of the antibiotic treatment and the resolution of the infectious process. This is of great concern in pathogens affecting the lower respiratory tract as these infections are one of the major causes of mortality in children and adults. In most cases where the respiratory pathogen is associated to multidrug-resistance, antimicrobial concentrations both in serum and at the site of infection may be insufficient and the resolution of the infection depends on the interaction of the invading pathogen with the host immune response. The outcome of these infections largely depends on the susceptibility of the pathogen to the antibiotic treatment, although the humoral and cellular immune responses also play an important role in this process. Hence, prophylactic measures or even immunotherapy are alternatives against these multi-resistant pathogens. In this sense, specific antibodies and antibiotics may act concomitantly against the respiratory pathogen. Alteration of cell surface structures by antimicrobial drugs even at sub-inhibitory concentrations might result in greater exposure of microbial ligands that are normally hidden or hardly exposed. This alteration of the bacterial envelope may stimulate opsonization by natural and/or specific antibodies or even by host defense components, increasing the recognition of the microbial pathogen by circulating phagocytes. In this review we will explain the most relevant studies, where vaccination or the use of monoclonal antibodies in combination with antimicrobial treatment has demonstrated to be an alternative strategy to overcome the impact of multidrug resistance in respiratory pathogens. Streptococcus pneumoniae (pneumococcus) that has greater incidence in children under 5 years old and adults over 60 years old, although the mortality is much higher in elderly population worldwide   .S. pneumoniae (S. aureus (MRSA) dissemination of resistance has become a serious threat worldwide  protecting against the most common serotypes that are resistant to antibiotics. These vaccines were commercialized at the beginning of this century to promote immunization against pediatric population, although PCV13 is also indicated for adults. The general use of these vaccines induced a drastic decrease of the incidence of IPD caused by serotypes included in the vaccines and also reduced the prevalence of non-susceptible serotypes to antibiotics  and serum amyloid P component (SAP) are the main acute phase proteins in human and mice, respectively . CRP levocytosis , 33. A dagocytes . Moreoveruginosa , 48, wheumophila , 50. In ruginosa .S. aureus   . To figher spp.) , 73, 74.floxacin .P. aeruginosa, bispecific antibodies targeting the serotype-independent type III secretion system (injectisome) virulence factor PcrV and persistence factor Psl exopolysaccharide have shown to be very effective increasing the antimicrobial activity of different antibiotics against MDR strains  and B (CDB1) demonstrated that the addition of these antibodies to antibiotics metronidazole or vancomycin, significantly reduced the recurrence of C. difficile infection (Finally, a randomized, double-blind, placebo-controlled study of two neutralizing, fully human monoclonal antibodies against nfection .The use of prophylactic measures including vaccination or even the use of monoclonal antibodies to treat or prevent severe infections caused by MDR pathogens is a realistic approach to fight these infections and reduce the impact of antimicrobial resistance in respiratory pathogens. The ability of certain antibiotics of showing an immunomodulatory effect which is strongly enhanced by the action of the host immune response is an alternative and promising strategy to eradicate or at least ameliorate the impact of MDR bacterial isolates in clinical practice. Further research in this field will contribute to identify and characterize novel prophylactic and therapeutic measures that in combination with current antimicrobial drugs may be effective solutions against the emergence of MDR pathogens, limiting their impact in public health.MD, JS, SdM, and JY prepared the text. JS and JY produced the included figure. All authors assisted in the conception of this review, interpretation of the relevant literature and editing the manuscript. All authors gave approval of the final version submitted.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.


Brain is a vital organ of the human body which performs very important functions such as analysis, processing, coordination, and execution of electrical signals. For this purpose, it depends on a complex network of nerves which are ensheathed in lipids tailored myelin; an abundant source of lipids in the body. The nervous system is enriched with important classes of lipids; sphingolipids and cholesterol which compose the major portion of the brain particularly in the form of myelin. Both cholesterol and sphingolipids are embedded in the microdomains of membrane rafts and are functional units of the neuronal cell membrane. These molecules serve as the signaling molecules; hold important roles in the neuronal differentiation, synaptogenesis, and many others. Thus, their adequate provision and active metabolism are of crucial importance in the maintenance of physiological functions of brain and body of an individual. In the present review, we have highlighted the physiological roles of cholesterol and sphingolipids in the development of the nervous system as well as the association of their altered metabolism to neurological and neurodegenerative diseases. Brain is an eminent organ of the human body; it comprises of more than 100 billion nerve cells which communicate by well-known structures called synapses. It serves as the primary center for initiation, coordination, interpretation, and integration of most of the nerve messages . InteresCholesterol, a vital constituent for normal functioning of the nervous system, plays an important role both during the developmental stage and in adult life . Brain cCholesterol metabolism in CNS is different from that in PNS. The blood brain barrier (BBB) hinders the passage of plasma lipoproteins to CNS, therefore, cholesterol requirement of CNS is met with locally synthesized cholesterol . In CNS,The regeneration is the healing or complete replacement of damaged neural cell. It appears a basic requirement for maintaining a normal physiology at post injury stage, but unfortunately, this ability is limited in higher organisms including human . The neuSynaptogenesis is the process of synapse formation required for the functional development of brain. Cholesterol dependent synaptogenesis and cholesterol availability are limiting factors in the development of synapses in brain. Glial cells provide plenty of cholesterol in the form of cholesterol-Apo-E complex for massive synaptogenesis , 35. ThePeripheral nerve injury (PNI) can have a potentially devastating impact on a patient’s quality of life, resulting in severe disability with substantial social and personal cost . The reqThe cholesterol-rich transporter lipoprotein Apo-E has been reported to accumulate at the site of injury after nerve crush . Simply In the event of a crush injury and abnormal cholesterol transport; the peripheral nerve shows delayed axonal regeneration, but remyelination is not affected by cholesterol unavailability . This shAlthough cholesterol has been shown to be positively associated with the physiological functions of the brain, however, any alteration in its metabolism leads to the onset of various brain ailments as discussed below:One of the major NDDs is Alzheimer’s disease (AD), which is characterized by the β-amyloid (Aβ) peptides aggregation and senile plaques , 49. TheParkinson’s disease (PD) is the second most prevalent NDDs after AD. Its pathology involves the loss of dopaminergic neurons in SN (substantia nigra) and the accumulation of α-synuclein and formation of Lewy bodies as well . It was Huntington’s disease (HD) belongs to the family of NDDs, is caused by a mutation of autosomal dominant allele and by the abnormal extension of CAG repeat in Htt (huntingtin) gene. It is characterized by the degeneration of neurons of cortex and striatum regions . The choA subtype of glutamate receptors named N-methyl-D-aspartate receptors (NMDARs), which mediates excitatory neuronal transmission, plays a critical role in brain functions . NeuroloSphingolipids (SP) are the composite molecules essentially found in all eukaryotes and a few of the viruses and prokaryotes. This class of lipids is derived from cell membrane lipids named as sphingomyelin (SM) . HydrophThe process of synaptogenesis usually occurs throughout the lifespan of a healthy individual but it is critical during early development of the brain. In this regard, a well-known class of lipids named as SP plays an important role. Synaptogenesis and synaptic plasticity involve various phenomenon such as recurrent presynaptic stimulation and long-term potentiation . ImportaMammalian brain includes resident neural stem cells (NSCs) which facilitates the development and functional maturity of neurons in embryonic expansion and this process continues throughout adult life . Axonal It is important to safeguard the proper metabolism, composition, and integrity of sphingolipids for the maintenance of physiological functions the brain. Not surprisingly, defects in the metabolism of SP have been associated with numerous neurological diseases like PD, AD, and HD.Generally, it is speculated that exact cause of PD is still unknown, but the neurodegeneration followed by the fibrillation and accumulation of α-synuclein in neurons is suggested to be the main contributing factor , 90. It Alzheimer’s disease (AD) is mainly characterized by the formation of plaques followed by the accumulation of Aβ peptides. Numerous key enzymes are also involved in the progression of AD including neprilysin, BACE-1 and a complex of γ-secretase play a critical role in the development and treatment of AD. Ceramide and SM are the two major classes of sphingolipids that can be transformed by sphingomyelinase (SMase) and SM synthase (SMSs) respectively. These are the important factors involved in the pathology of AD. Ceramides promote the generation and accumulation of Aβ by stabilizing the BACE-1 . The SM The implications of altered sphingolipids metabolism in neurological and psychiatric disorders have been reviewed extensively. This impaired metabolism either involves the degradation pathways or biosynthesis of sphingolipids and their metabolites. Moreover, there is very limited data available on this subject.Epilepsy is a disorder with abnormal brain activity, causes unusual behavior and continuous episodes of seizures. Dysregulated metabolism of lipids is an important factor of modified activity of brain. Similarly, the altered metabolism of sphingolipids also points towards its crucial role in the pathogenesis of epilepsy. In this context, the possible mechanistic approach relies on the heterozygous deletion of CERS2 (Ceramide synthase 2) gene and the homozygous mutation in CERS1 and CERS1 gene is primarily involved in the synthesis of C18-ceramide. In neuroblastoma, CERS1 down-regulation initiates pro-apoptotic pathways and induces ER stress. The CERS-2 is known for maintaining membrane integrity and mutation in this gene leads to the detachment and degeneration of myelin sheath and ultimately inadequate neuronal myelination results in their deterioration . UnfortuDietary sources are accounted as major contributors of cholesterol and sphingolipids levels within the living system. Similarly, nutraceuticals, the dietary supplements are also taken for their potential advantageous health effects. Nutraceuticals provide health benefits and are related to functional food. Thus, they affect the lipid metabolism to a great extent by different biochemical pathways . AdequatSphingolipids and their metabolites are regulated by increased or decreased dietary intake. Although, all foods contain a good amount of sphingolipids but milk, eggs, fish, chicken liver and cottage cheese are especially rich in SP. In regard to the dietary habits, the western diets contain SM in concentrations of approximately 200–400 mg/day . Milk anCholesterols plays a key role in the maintenance of brain health. It serves as a fundamental constituent of myelination and is also essential for development and functional outcomes. Sufficient availability of cholesterol for synapse formation is a critical step in the structural and functional development of our nervous system. Following a nerve injury, cholesterol is required for axonal regeneration. Previous studies have proved that the injured nerves positively respond to the exogenously supplied cholesterol. Thus, targeting cholesterol metabolism may provide a way to combat problems with regeneration of injured nerves. Literature suggests that controlling the cholesterol transportation or improving the cholesterol availability in NDDs may provide protection or may delay the onset of disease. Being an important part of membrane lipid rafts, sphingolipids play a vital role in the life cycle of cells. There are different types of sphingolipids that exist in the brain and contribute structurally in membrane microdomains formation. Although, this review has illustrated various underlying mechanisms of cholesterol and sphingolipids metabolism in relation to the brain health and physiology, but further rigorous research is required for the evaluation of other antecedent facts. Moreover, in this review, the association between impaired cholesterol and sphingolipids metabolism and NDDs, neurological and neuropsychiatry diseases has also been discussed in detail. Further research is critical for the advancement of the therapeutical applications of cholesterol and sphingolipids metabolism targeting agents depending on their effects on impaired metabolism in different diseases.